Clinical:Statins

Statins are a class of drug that by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase have revolutionized the treatment of hypercholesterolemia and associated secondary pathologies such as coronary artery disease ^[1],[2]. They are used in primary prevention in those with various hyperlipidaemias and secondary prevention of ischemic heart disease and ischemic stroke.

History

Two Japanese scientists 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. This work lead to the identification of the first clinically useful compound lovastatin(mevinolin) ^[3] from a mould in the mid 1970's. This agent was first used in the more severe forms of hypercholesteraemia in the 1980s followed by landmark trials 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 Cerivastatin was withdrawn in 2001 because of a ten times higher incidence of rhabdomyolysis than the other statins.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

• Primary prevention: dyslipidaemia
  • High Risk(10 year CHD risk of more than 13%)
  • Medium risk(annual risk of coronary heart disease events of 0.6–1.5% a year) 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^[4].
• Dyslipidaemia in diabetes
  • with higher risk for macrovascular complications
• Secondary prevention of ischemic cardiac events
• Peripheral vascular disease
• Secondary prevention of ischemic strokes
• 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^[5].
• Preoperative use before cardiac surgery^[6]

Undefined Indications

• 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 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^[7]. In secondary prevention a wide range of statins appear to be effective if they achieve CRP values on treatment below 2mg/l ^[8][9]. These observations are seen by some to be problematical in the application of the cholesterol hypothesis to explain statin efficacy.
• Perioperative use to reduce cardiovacular risk ^[10]
• GISSI-HF showed that rosuvastatin was harmful in chronic heart failure^[11]. While this effect appears to be consistent for rosuvastatin over 3 trials, atorvastatin has 6 trials showing decrease in hospitalization for worsening heart failure (OR 0.30)^[12]. The status of simvastatin is unknown due to 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 ^[13].
• Gall stones are reduced in long term treatment with presumptive health gain from the reduced rate of cholecystectomy^[14].

Statins in older people

"Statins are effective in older people, and just as effective as in people aged under 65 or 70 years"^[15].^[16].

Statins have no good evidence of benefit in:

• Preventing fractures^[17]
• Alzheimers disease^[18]
• Macular degeneration^[19]
• Oesophageal maligancy may be reduced^[20]

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 ^[21].

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^[22] and 0.55 - 95%CI: 0.44-0.68^[23] respectively). The best evidence base in primary and secondary prevention relates to simvastatin and atorvastatin. 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 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^[24] so the issue of which statin is best in the major populations at risk remains unclear. There is evidence in both primary prevention^[7]and secondary prevention^[25] that lowering the C-reactive protein may be as an important a surrogate laboratory measure as LDL cholesterol.

High dose statins

Recent clinical trials have shown that high dose atorvastatin (80mg) has benefit with selected outcomes after certain acute ischemic event presentations, such as those open to PCI. The overall marginal benefits against the higher expected toxicity of this dose are unclear in populations that differ significantly from those studied. ^[26]. 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 hemorrhagic stroke.^[27] 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%^[28]:

• 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.

. Elderly women cost about 5 times more to treat to benefit than younger men. The most evidence is for high dose atorvastatin and this can be expected to be an increasingly resource effective use of the drug as its cost is expected to reduce in most major economies. With respect to total morbidity or mortality high dose statins may have less marginal benefit with overall reduced mortality and morbidity not occurring until 2 years after the index event^[29].

There is weak evidence that simvastatin but not atorvastatin or lovastatin is associated with a reduced incidence of dementia and Parkinson's disease^[30]. However the intervention trials have shown no benefit (or harm) with simvastatin and pravastatin in Alzheimer's disease^[31]. Rosuvastatin does not improve left ventricular ejection fraction while simvastatin and atorvastatin do^[12].

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 ^[32] although a study from the UK GP database as reported in a press release from the manufacturer of atorvastatin raises concerns^[33]. For maximum objective effectiveness you might want to give simvastatin at night^[34] 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 ^[35].

Toxicity

Advise patients to report muscle pain but do 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^[36] 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 effect^[37] 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^[36]. Fluvastatin may produce least 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^[37]. 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^[20]

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.

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.^[38] 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).^[39] 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:

• Sleep disturbance
• Mood disorders
• Dementia
• Cancer (the association may be with excess LDL cholesterol reduction^[40])
• 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

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

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.^[41] 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.

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.^[42]

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 ^[43]. Such associations are plausible 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. Currently much interest is in the epidemiological correlation of about a 15% reduction in severe sepsis and mortality from infection ^[44].

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^[45], 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. ^[46].

Statin Withdrawal

An increased frequency of cardiac events in those undergoing coronary bypass surgery has been associated with peri-operative statin withdrawal ^[47]. There is increased cardiovascular ischaemic event rate up to 1 year after withdrawal in acute stroke ^[48] and this event rate seem to be tripled in the first 90 days after stopping a statin^[49].

References

1. ↑ 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
2. ↑ 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.
3. ↑ Thompson GR, Ford JM, Jenkinson M, Trayner I. Efficacy of Mevinolin as adjuvant therapy for refractory familial hypercholesteraemia. Quarterly J Med 1986, New Series, 60: 803-811.
4. ↑ Abramson J, Wright JM. Are lipid-lowering guidelines evidence-based? Lancet 2007;369(9557):168-9.
5. ↑ Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet neurology. 2009 May; 8(5):453-63.
6. ↑ Liakopoulos OJ, Choi YH, Haldenwang PL, Strauch J, Wittwer T, Dörge H, Stamm C, Wassmer G, Wahlers T. Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30 000 patients. European heart journal. 2008 May 27.
7. ↑ ^{7.0 7.1} Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207
8. ↑ Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E. C-reactive protein levels and outcomes after statin therapy. The New England journal of medicine. 2005 Jan 6; 352(1):20-8.
9. ↑ Milionis HJ, Rizos E, Kostapanos M, Filippatos TD, Gazi IF, Ganotakis ES, Goudevenos J, Mikhailidis DP, Elisaf MS. Treating to target patients with primary hyperlipidaemia: comparison of the effects of ATOrvastatin and ROSuvastatin (the ATOROS study). Current medical research and opinion. 2006 Jun; 22(6):1123-31.
10. ↑ Kapoor AS, Kanji H, Buckingham J, Devereaux PJ, McAlister FA. Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies. BMJ. 2006;333(7579):1149.]
11. ↑ Gissi-Hf Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Aug 29.
12. ↑ ^{12.0 12.1} Lipinski MJ, Cauthen CA, Biondi-Zoccai GG, Abbate A, Vrtovec B, Khan BV, Vetrovec GW. Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. The American journal of cardiology. 2009 Dec 15; 104(12):1708-16.
13. ↑ Glynn RJ, Danielson E, Fonseca FAH, Genest J, Gotto AM Jr., Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Ridker PM. A Randomized Trial of Rosuvastatin in the Prevention of Venous Thromboembolism NEJM www.nejm.org March 29, 2009 (10.1056/NEJMoa0900241)
14. ↑ Bodmer M, Brauchli YB, Krähenbühl S, Jick SS, Meier CR. Statin use and risk of gallstone disease followed by cholecystectomy. JAMA : the journal of the American Medical Association. 2009 Nov 11; 302(18):2001-7.
15. ↑ Statins in older people
16. ↑ Ali R, Alexander KP. Statins for the primary prevention of cardiovascular events in older adults: a review of the evidence. The American journal of geriatric pharmacotherapy 2007;5(1):52-63.
17. ↑ Toh S, Hernández-Díaz S. Statins and fracture risk. A systematic review. Pharmacoepidemiology and drug safety 2007;16(6):627-40.
18. ↑ Zhou B, Teramukai S, Fukushima M. Prevention and treatment of dementia or Alzheimer's disease by statins: a meta-analysis. Dementia and geriatric cognitive disorders 2007;23(3):194-201.
19. ↑ Klein R, Knudtson MD, Klein BE. Statin use and the five-year incidence and progression of age-related macular degeneration. American journal of ophthalmology 2007;144(1):1-6.]
20. ↑ ^{20.0 20.1} Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ (Clinical research ed.). 2010; 340:c2197.
21. ↑ Brophy J, Costa V. Statin wars following coronary revascularization -- Evidence-based clinical practice? Can J Cardiol. 2006; 22(1): 54-8]
22. ↑ García-Rodríguez LA, González-Pérez A, Stang MR, Wallander MA, Johansson S. The safety of rosuvastatin in comparison with other statins in over 25 000 statin users in the Saskatchewan Health Databases. Pharmacoepidemiology and drug safety. 2008 Apr 21.
23. ↑ García-Rodríguez LA, Gonzalez EM, Wallander MA, Johansson S. The safety of rosuvastatin in comparison with other statins in over 100 000 statin users in UK primary care. Pharmacoepidemiology and drug safety. 2008 Apr 21.
24. ↑ Zhou Z, Rahme E, Pilote L. Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention. Am Heart J. 2006 Feb ; 151(2): 273-81
25. ↑ Milionis HJ, Rizos E, Kostapanos M, Filippatos TD, Gazi IF, Ganotakis ES, Goudevenos J, Mikhailidis DP, Elisaf MS. Treating to target patients with primary hyperlipidaemia: comparison of the effects of ATOrvastatin and ROSuvastatin (the ATOROS study). Current medical research and opinion. 2006 Jun; 22(6):1123-31.
26. ↑ Wiviott SD, de Lemos JA, Cannon CP, Blazing M, Murphy SA, McCabe CH, Califf R, Braunwald E. A tale of two trials: a comparison of the post-acute coronary syndrome lipid-lowering trials A to Z and PROVE IT-TIMI 22. Circulation. 2006;113(11):1406-14.
27. ↑ Amarenco P, Bogousslavsky J, Callahan A, Goldstein LB, Hennerici M, Rudolph AE, et al. High-dose atorvastatin after stroke or transient ischemic attack. The New England journal of medicine. 2006;355:549-59.
28. ↑ Wenger NK, Lewis SJ, Herrington DM et al. Outcomes of Using High- or Low-Dose Atorvastatin in Patients 65 Years of Age or Older with Stable Coronary Heart Disease. Ann Intern Med 2007; 147: 1-9
29. ↑ Morrissey RP, Diamond GA, Kaul S. Statins in acute coronary syndromes: do the guideline recommendations match the evidence? Journal of the American College of Cardiology. 2009 Oct 6; 54(15):1425-33.
30. ↑ Wolozin B, Wang SW, Li N, Lee A, Lee TA,Kazis LE. Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease BMC Medicine 2007;5:20
31. ↑ McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD003160. DOI: 10.1002/14651858.CD003160.pub2
32. ↑ Bandolier on Statin Switching
33. ↑ Patients Who Switched from Established Lipitor Therapy to Simvastatin Experienced a Significant 30 Percent Increase in Relative Risk of Cardiovascular Events or Death, New Observational Study Shows accessed 5 Sept 2007
34. ↑ Bandolier on dose timing of statins
35. ↑ Thomas MC, Mann J. Increased thrombotic vascular events after change of statin. Lancet 1998;352:1830-1
36. ↑ ^{36.0 36.1} Armitage J. The safety of statins in clinical practice. Lancet 2007.
37. ↑ ^{37.0 37.1} Silva MA, Swanson AC, Gandhi PJ, Tataronis GR. Statin-related adverse events: a meta-analysis. Clinical therapeutics 2006;28(1):26-35.
38. ↑ Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, Vladutiu GD, England JD. Statin-associated myopathy with normal creatine kinase levels. Annals of internal medicine. 2002 Oct 1; 137(7):581-5.
39. ↑ Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004;292:2585-90.
40. ↑ Alsheikh-Ali AA, Maddukuri PV, Han H,Karas RH. Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer J Am Col Card 2007;5409-18
41. ↑ Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R. SLCO1B1 variants and statin-induced myopathy--a genomewide study. The New England journal of medicine. 2008 Aug 21; 359(8):789-99.
42. ↑ http://www.mhra.gov.uk/home/groups/pl-p/documents/publication/con007448.pdf
43. ↑ Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, Ritz E. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353(3):238-48.]
44. ↑ Hackam DG, Mamdani M, Li P, Redelmeier DA. Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis. The Lancet 2006; 367:413-418
45. ↑ Shroufi A, Powles JW. Adherence and chemoprevention in major cardiovascular disease: a simulation study of the benefits of additional use of statins. J Epidemiol Community Health 2010;64:109-113 doi:10.1136/jech.2009.091033
46. ↑ Statins: when should you take the tablet? http://www.medicine.ox.ac.uk/bandolier/booth/cardiac/stattime.html
47. ↑ Schouten O, Hoeks SE, Welten GM, Davignon J, Kastelein JJ, Vidakovic R, Feringa HH, Dunkelgrun M, van Domburg RT, Bax JJ, Poldermans D. Effect of statin withdrawal on frequency of cardiac events after vascular surgery. Am J Cardiol. 2007 Jul 15;100(2):316-20.
48. ↑ Colivicchi F, Bassi A, Santini M, Caltagirone C. Discontinuation of statin therapy and clinical outcome after ischemic stroke. Stroke; a journal of cerebral circulation. 2007 Oct; 38(10):2652-7.
49. ↑ Cubeddu LX, Seamon MJ. Statin withdrawal: clinical implications and molecular mechanisms. Pharmacotherapy. 2006 Sep; 26(9):1288-96.