Statins

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In vivo human potency of statins on U.K market 2005

(dates first ever marketed anywhere[1])

Web Resources for Statins
Relevant Clinical Literature
UK Guidance

Statins are a class of drug that by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase have revolutionised the treatment of hypercholesteraemia and secondary pathologies such as ischaemic heart disease [2],[3]. They are used in primary prevention in those with various hyperlipidaemias and secondary prevention of ischaemic heart disease and ischaemic stroke. Their role in other primary prevention has lead to controversy and ability to evaluate the marked size of the nocebo effect in the general population as about 25% for a well publicised side effect[4].

Contents

History

Two Japanese scientists (Akira Endo and Masao Kuroda) commenced research into inhibitors of HMG-CoA reductase in 1971 reasoning that organisms might produce such products as the enzyme is important in some essential cell wall components[5]. This work lead to the identification of the first clinically useful compound lovastatin(mevinolin) [6] from a mould in the mid 1970's. This agent was first used in the more severe forms of hypercholesteraemia in the 1977[5] followed by landmark trials [7] with simvastatin that showed the potential for cardio-prevention. Cerivastatin was withdrawn in 2001 because of a ten times higher incidence of rhabdomyolysis than the other statins. The clinical evidence for benefit of higher doses of statins in secondary prevention of cardiovascular disease started to accumulate in the first decade of the 21st century.

Indications

See current NICE guidelines.
LogoKeyPointsBox.pngOn metaanalysis statins in proportion to their action in reduction in LDL cholesterol significantly reduce[8]:
  • All cause mortality
  • Major vascular events
  • Primary prevention: dyslipidaemia but no evidence that affects mortality in unselected populations. In populations with a risk factor for cardiovascular disease but no prior cardiovascular disease they reduce relative risk by quite impressive margins and have net safety[8].
    • High risk patients (10 year CHD risk of more than 13%) is beneficial
    • Medium risk men (annual risk of coronary heart disease events of 0.6–1.5% a year) is beneficial and in woman is likely to be beneficial There is some evidence that overall benefit might be limited to high-risk men aged 30–69 years in the clinical trial populations which leads to continued controversy as overall mortality is not affected by statins and they do have adverse effects[9].
    • Low risk has unknown effectiveness. This is possibly because low risk is ill defined and in some trials adverse event rates are hard to establish accurately. Perhaps raised CRP as a risk factor is only significant in low risk patients[10].
  • Dyslipidaemia in diabetes
  • Secondary prevention of ischaemic cardiac events is beneficial
    • Secondary prevention of nonfatal ischaemic events with high dose statins is a challenging trade off between benefits and harms as it is certainly likely to be beneficial in selected populations but comes at a resource premium and is difficult to generalise on these grounds for say all age and sex presentations of acute coronary syndrome without PCI. For example elderly women cost about 5 times more to treat to benefit than younger men and would not have been a resource effective population health intervention group to target in the UK in 2007[11]. The most evidence is for high dose atorvastatin and indeed it can be expected to be an increasingly resource effective use of the drug as the cost of the drug is expected to reduce in most major economies. Such use is tempered by secondary analysis that suggests in typical European populations or with respect to total morbidity or mortality high dose statins may have less marginal benefit, and this is more so in ischaemic stroke[12]. The tendency for clinicians to advocate this therapy acutely because of reductions in clinical events of immediate relevance to them and the patient has to be considered in terms of an evidence base that does not show overall reduced mortality and morbidity until 2 years after the index event[13].
  • Peripheral vascular disease is likely to be beneficial
  • Secondary prevention of strokes is likely to be beneficial.
  • In primary prevention of stroke the absolute risk reduction in 4 years works out at about 0.85, much less than the absolute benefit in preventing coronary artery disease which is more of the order of 2.5%/annum[14].
  • Preoperative use before cardiac surgery seems to only reduce postoperative atrial fibrillation likely to be beneficial[15]

Undefined Indications

  • There is increasing evidence of benefit if given before any major surgery.[16]
  • The relevance of the specific effects of statins on both LDL cholesterol and CRP in primary and secondary prevention is an area of controversy. Patients with high CRP appear to benefit from statins with rosuvastatin being beneficial in primary prevention for patients without previous lipid lowering therapy, diabetes mellitus, renal impairment, or hypertension and LDL cholesterol levels of less than 3.4 mmol/l but with C-reactive protein level of 2.0 mg/l or more[10]. However this might be artifact or a specific drug effect, as it is not found with simvastatin 40mg[17]. Early analysis had suggested that in secondary prevention a wide range of statins were effective if they achieve CRP values on treatment below 2mg/l [18][19]. These observations are seen by some to be problematical in the application of the cholesterol hypothesis to explain statin efficacy, at least in primary prevention.
  • GISSI-HF showed that rosuvastatin was likely to be ineffective or harmful in chronic heart failure[20]. While this effect appears to be consistent for rosuvastatin over 3 trials, atorvastatin has 6 trials showing beneficial decrease in hospitalisation for worsening heart failure (OR 0.30)[21]. The status of simvastatin is unknown due to too small studies at lower dose than usually used now although it does improve left ventricular ejection fraction.
  • Venous thromboembolic disease is reduced by moderate dose rosuvastatin in a low risk population [22].
  • In chronic renal disease there is mixed evidence. On meta-analysis this transpires to reflect progressively less relative effectiveness, the worse the renal failure, but perhaps similar absolute benefit. As of 2013 it appears that there may even be small benefit in patients on dialysis[23]. This is in contrast to earlier work[24][25]. Statins are beneficial in terms of coronary events, but subgroup analysis suggests the gain maybe confined to those with the highest cholesterol (>5.5mmol/L), who tend to be obese, diabetic, middle aged males[25]. In post transplant patients statin treatment is unlikely to be benefical with a reduction of events that does not impact survival or need for coronary intervention[26].
  • Gall stones are reduced in long term treatment with presumptive health gain from the reduced rate of cholecystectomy[27].
  • As a topical ointment it is a specific treatment for CHILD syndrome

Statins in older people

Bandolier give the following statement in their document [28] - "Statins are effective in older people, and just as effective as in people aged under 65 or 70 years.". Also, the NLH Q&A Service has answered a number of similar questions [29]. This is suggestive evidence as the definitive clinical trials in primary intervention in the elderly have most certainly not been done[30] and there is little evidence for benefit in women.

Statins are unlikely to be benefical in:

  • Preventing fractures[31]
  • Alzheimers disease[32] (But see below - clinical differences)
  • Macular degeneration[33]
  • Oesophageal maligancy may be reduced[34]

Clinical Differences

Much clinical use of statins reflects marketing rather than the practice of evidenced based medicine. In Quebec by 2003 Atorvastatin had 44% of the market share while simvastatin had 29.9%. In contrast up to the previous year simvastatin had 133,341 of RCT patient-years of follow-up compared to 1457 for atorvastatin [37].

Rosuvastatin is the most potent inhibitor of HMG-CoA reductase on the market. It may also have some real clinical advantages despite less evidence base as although myopathy risk seems fairly statin independent, over 20,000 patient years of experience in Saskatchewan and the UK found lower risk of death compared to other statins (RR of death 0.42 - 95% CI: 0.32-0.57[38] and 0.55 - 95%CI: 0.44-0.68[39] respectively). However a randomised control trial comparing rosuvastatin 40mg to atorvastatin 80mg found no significance difference in clinical outcomes, even if proxy measures favoured rosuvastatin. The regimes had similar adverse event withdrawal rates at 7%[40]. The best evidence base in primary and secondary prevention relates to simvastatin and atorvastatin and as can be seen by the potency chart simvastatin 40mg has similar potency to atorvastatin 10-20mg in lowering LDL cholestrol from a meta-analysis of randomised controlled trials done by Law et al.[41]. Fluvastatin and pravastatin have lower potency. Pravastatin (a natural product) has less potential for interactions with other drugs.Interestingly the relative difference in potency is less in long term studies (greater than 12 weeks) and perhaps this explains the epidemiological observation that mortality and morbidity benefit is not as clearly drug dependent as is the reduction in cholesterol predicted from short term studies.

It is difficult to assume that all the benefits of statins are due to their actions on cholesterol metabolism alone and on atheroma. Indeed there is some evidence, such as in dementia and heart failure that there may be individual properties divorced from a class effect. The pooled studies have shown on meta-analysis [42] ,[43] that the reduction in major vascular events is proportional to the reduction in LDL cholesterol levels at 1 year. In contrast population studies of secondary prevention in those over 65 years and long term follow up of RCTs have shown no evidence suggesting better outcome with one statin over another[44] so the issue of which statin is best in the major populations at risk remains unclear. There is evidence in both primary prevention[45]and secondary prevention[46] that lowering the C-reactive protein may be as an important a surrogate laboratory measure as LDL cholesterol.

LogoKeyPointsBox.pngHigh dose statin trials in acute coronary syndrome show clinical benefit but this does not seem to translate into convincing mortality benefit in stroke and marginal resource benefit depends upon subgroup and cost of the statin[47].

Recent clinical trials have shown that high dose atorvastatin (80mg) has benefit with selected outcomes after certain acute ischaemic event presentations but the overall marginal benefits against the higher expected toxicity of this dose are unclear in populations that differ significantly from the populations studied. Analysis of the raw data (the primary data presented in most studies is biased towards composite outcomes that include only one aspect of morbidity) from high dose statin trials in acute coronary syndrome has suggested benefit relative to standard statins is restricted to American, and absent in European participants offered aggressive early intervention strategies[48]. High dose atorvastatin after stroke or TIA reduces the incidence of strokes and of cardiovascular events but at 5 year follow up has no mortality benefit and a higher incidence of non fatal haemorrhagic stroke.[49] In patients over 65 years enrolled in the TNT trial while primary events in those on 80mg compared to 10mg atorvastatin were reduced absolutely by 2.3%[50]:

  • There was a non significant 0.6% increase in death at the higher dose due to non-cardiovascular mortality
  • Treatment-related adverse events were 8.3% on 80mg atrovastatin and 5.2% on 10mg atrovastatin.

.

There is weak evidence that simvastatin but not atorvastatin or lovastatin is associated with a reduced incidence of dementia and Parkinson's disease[51]. However the intervention trials have shown no benefit (or harm) with simvastatin and pravastatin in Alzheimer's disease[52]. Rosuvastatin does not improve left ventricular ejection fraction while simvastatin and atorvastatin do[21].

Switching Statins

The only fair clinical trial evidence exists for simvastatin and low dose atorvastatin. There was no peer reviewed evidence for harm for this swap [53] although a study from the UK GP database as reported in a press release from the manufacturer of atorvastatin raises concerns[54]. For maximum objective effectiveness you might want to give simvastatin at night[55] and this may also minimise subjective side-effects. Although fluvastatin has a good safety profile and clinical evidence base, the transfer from another statin to fluvastatin might best be done only when strong clinical indications exist. This recommendation is based on a higher incidence of significant cardiovascular presentations when use of fluvastatin was encouraged by pricing mechanisms in New Zealand, possibly because non equivalent doses were substituted [56].

Toxicity

LogoKeyPointsBox.pngAdvise patients to report muscle pain. But realise that the same proportion of patients get muscle pain with statins as with placebo. Raised CPK is more of a reason to stop the statin!

The safety profile for currently marketed statins is well characterised[57] and very similar in terms of events reported to adverse reaction databases. There is some randomised controlled trial data on meta-analysis suggesting differential toxicity. On this evidence atorvastatin may more commonly produce any adverse effects[58] perhaps because of the number of recent trials using very high dose (80mg) which is associated with diarrhoea, abdominal pain, or nausea compared to lower doses of the drug or say 80mg simvastatin[59]. Fluvastatin is lowest in producing any adverse effect. Statin therapy increased the risk of adverse effects by 39% (OR = 1.4; 95% CI, 1.09-1.80) with number needed to harm of 197) compared with placebo. Thus treating 1000 patients with a statin would prevent 37 cardiovascular events, and 5 adverse events would be observed[60]. There is one large observational study that confirms that while the NNT at 37 (27 to 64) in women and 33 (24 to 57) in men is consistent with this, the NNH due to cataracts is actually close to this in women at 33 (28 to 38) and it is possible the significance of this sideeffect has been underestimated in the randomised controlled trials[34]

All statins are contraindicated in pregnancy and breastfeeding. There are isolated reports of congenital abnormalities in the babies of women who took statins during early pregnancy.

Flag of the United Kingdom.png

Clinical calculators exist that display the risks as well as benefits of statins see QIntervention

Myopathy

Statins are very safe drugs. However there is a risk of myopathy (which does not always show the expected characteristic rise in creatine kinase.[61] Myopathy sometimes, rarely, includes severe rhabdomyolysis (incidence less than 5/100,000 patient years with current statins and lower at typical secondary prevention doses in clinical use).[62] Simvastatin 80mg does appear to have a higher risk of myopathy than other licensed doses of the statins on the market.

Risk reassurance

There is very little real evidence for a number of popular concerns in terms of absolute risk including:

  • Diabetes (the 1 case of new diabetes in 255 patients treated for 4 years has to be seen in context of 5.4 vascular events prevented in those 255 patients)
  • Sleep disturbance
  • Mood disorders
  • Dementia
  • Cancer (the association may be with excess LDL cholesterol reduction[63])
  • Peripheral neuropathy eg relative risk of 3·7 (95% CI 1·8–7·6), absolute risk 0·1%.
  • Acute renal failure with a number needed to harm of several hundred over 5 years

However the risk of lens opacities increasingly seems to be real.

Monitoring

PRODIGY suggestions are:[64]:

  • 8-12 weeks after the start of treatment OR an increase in dose check lipid levels (non-fasting TC and HDL-C) and liver function tests (AST or ALT). These same tests are required at an annual test. NOTE. If LDL-C or TG levels are needed a fasting sample must be used.

However LFT abnormalities can have unpredictable onset, and hepatitis is only reasonably common with higher doses.

If muscle symptoms suspected, check CK levels (but as noted above, a normal CK does not exclude myopathy).

LogoKeyPointsBox.pngReasonable arguments can be made for not measuring lipids initially, giving a standard dose of a statin to all members of a defined population and not measuring lipids either immediately, or at intervals thereafter. These are not current practice but the arguments and the costs and benefits involved should be understood by those not following them

Compliance

It is only useful to use differential LDL cholesterol as an aid to monitor statin compliance in the subset of patients who are totally non-compliant where at 1 year deterioration (increase) in LDL cholesterol by 1mmol/l or more is highly suggestive of non adherence. Partial compliance can not be detected in this way[65].

Factors aggravating toxicitiy

There is a correlation with dose. All the present statins have an acceptible profile but it is important, particularly at the higher ends of the dosage range of each statin to give full consideration of this issue. All agents are more likely to be toxic in those with renal impairment and possibly hypothyroidism. Active liver disease is a contra-indication as are porphyria and pregnancy.

Combination of a statin with a fibrate is regarded as significantly more likely to produce muscle damage, although both classes of drug are known to produce this side effect on their own. Gemfibrozil in particular should not be used in combination with a statin. Nicotinic acid at therapeutic doses used to treat hypercholesteraemia has also been associated with this problem when given with a statin. Both simvastatin and atrovastatin have the potential for increased plasma levels when given with certain cytochrome modifying drugs such as clarithromycin.

Such interactions are most likely to be significant at the higher end of each drug's dosage range and in those with particular genotypes.[66] The role of statins in modulating the response to infection is unclear and advice has been given that simvastatin should be withheld during course of certain anti-microbial agents.

LogoKeyPointsBox.png

"Some statins (particularly simvastatin and atorvastatin) are metabolised by cytochrome p450 (CYP3A4) and co-administration of potent inhibitors of this enzyme (such as ‘azole’ anti-fungal agents or HIV protease inhibitors) may particularly increase plasma levels of these drugs and so increase the risk of dose-related side effects, including rhabdomyolysis. The risk of serious myopathy is also increased when high doses of simvastatin are combined with less potent inhibitors of CYP3A4, including amiodarone, verapamil and diltiazem." UK Committee on Safety of Medicines [67]

Other Side Effects

Headache, altered liver function tests, paraesthesia (a burning neuropathy seems characteristic), abdominal pain, flatulence, non-specific changes in bowel habit, nausea and vomiting are known. Rash and allergic reactions are rare. There is presently no evidence that prophylactic use of coenzyme Q10 is useful. Indeed the coenzyme Q10 issue (it is most certainly depleted with chronic statin therapy) is a reason why the outcomes of statin trials must be evaluated in terms of total mortality and morbidity over long periods of time, as they have been, rather than using short term cardiovascular and lipid surrogates.

Analysis shows that with atorvastatin, fatal stroke is increased in diabetics with advanced renal failure needing haemodialysis and there is no net gain from using the drug [68]. Such associations are not completely implausible and clinicians would be wise to be aware of them.

Pharmacology

There is a strong suspicion that statins may do more than inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Indeed they may

  • act as anti-inflammatory agents
  • prevent in vivo oxidation
  • modulate cellular immunity
  • modulate endothelial action
  • increase nitric oxide bioavailability

These effects might be modulated by interference with isoprenoid synthesis or specific actions of some statins to block cell adhesion receptors. Indeed some effects, say on special AT-rich sequence binding protein 1 are specific for hydrophobic statins and not by hydrophilic pravastatin[69]. Currently much interest is in the epidemiological correlation of about a 15% reduction in severe sepsis and mortality from infection [70].

Timing of Dose

Ideally before sleep - in the evening for most people, presumably the morning for night workers.

The argument for this is that physiological studies show that most cholesterol is synthesised when dietary intake is low. The effect is marginal. What is most important is that the treatment is taken[71], dose and timing are secondary. Since the argument is physiological, the evidence being specific to simvastatin should not matter, but the effect is said to be less observed with rosuvastatin. Bandolier provides more detail[72].


Statin Withdrawal

An increased frequency of cardiac events in those undergoing coronary bypass surgery has been associated with peri-operative statin withdrawal [73]. There is increased cardiovascular ischaemic event rate up to 1 year after withdrawal in acute stroke [74] and this event rate seem to be tripled in the first 90 days after stopping a statin[75].

References

  1. Armitage J. The safety of statins in clinical practice. Lancet 2007.(Epub ahead of print) (Direct link – subscription may be required.)
  2. The Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389
  3. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267-78.
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External links

MeReC. Update on Statins. 2004 >>>statins/indications