Cholesterol and Statins

Holly ChongCardiology Pharmacist

Bromley Hospitals NHS Trust

The Background

Statins represent the largest drug cost to the NHS (£738 million in 2004)

Statin use is increasing by 30% a year in England

Most statin prescriptions in England are for simvastatin and atorvastatin, usually at moderate or low doses

Simvastatin 40mg is now available at very low cost£3.40 per month compared to atorvastatin 10-20mg (18.03-£24.64 per month)

High Cost Statin Prescribing

Lipid management guidance– NHS policy:

NSF – cholesterol targets 5 / 3NICE TA 94 – defining risk

– DOH strategy cost-effective RxImplement NICE Tag 94

– JBS-2 (2005)?New targets 4 / 2Audit standard 5 / 3 ‘aspirational’

National Context

Increasing statin use 20-30% per yearHuge variation in use 19.2%-85% simvastatin!Atorvastatin accounts for 2/3 of expenditure

Implementation of NICE TA 945.2 million population require txCost = £230 million pa using simvastatinCost = £1,068 million pa using 50% atorva / 50% simvaDifference = £839 million per year

Key Issues for the CPFStatins

Increasing ‘cost-effective’ statin prescribing:Consensus on first-line agent

Statin-switching polices

Addressing implementation issues

What about JBS-2?

Can we ‘future-proof’ our guidance?

The following guidance represents the consensus view of the SELCN Prescribing Forum

But does not override the individual responsibility of healthcare professionals to make decisions appropriate

to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer

Key Messages

1. Statins should be considered for patients– With cardiovascular disease (CVD)– At high risk of developing CVD

• Non diabetics, CVD risk > 20% over next 10 yrs• All diabetics >40 yrs old

2. A statin with lowest acquisition cost to be used first line ie., simvastatin

3. Simvastatin starting dose should be 40mg with evening meal.

4. National cholesterol treatment targets– Total cholesterol <5.0mmol/L or 20%– LDL cholesterol <3.0mmol/L or 30%

5. Cholesterol levels rechecked within 3 months of initiation. Liver function tests (ALT and AST) checked within first year of therapy.

Frequently Asked Questions

26 questions and answers

Calculation of CVD riskwww.bhsoc.org/resources/prediction_chart.htm

http://cvrisk.mvm.ed.ac.uk/calculator/bnf.htm

Type I diabetics excluded due to under-estimation (NICE guidance 15)

CVD risk prevention charts

Cardiovascular Disease Risk Prediction Chart reproduced with permission from The University of Manchester Department of Medical Illustration, Manchester Infirmary. © University of Manchester. Wood D, Wray R, Poulter N et al. Heart 2005;91(Suppl V):1-52

Simvastatin 40mg daily

First-lineAverage reduction in LDL-cholesterol 41%Equivalent to atorvastatin 10mg dailyMajority of patients will achieve treatment target (TC<5mmol/L, LDL<3mmol/L)Heart Protection study showed it can reduce mortality and CVS eventsUsing simvastatin 40mg instead of atorvastatin 10mg will save PCT £ 176 per patient per yr

Can cholesterol be too low for initiating lipid lowering therapy?

Wood D, Wray R, Poulter N et al. Heart 2005;91(Suppl V):1-52.

High dose statins in acute coronary syndrome (ACS)

PROVE-IT trial (atorvastatin 80mg vs pravastatin 40mg)

Statistically significant reduction in composite CV mortality and morbidity

A to Z trial (simvastatin 40mg then 80mg vs placebo then 20mg)

Beneficial in early stages of ACS

NICE guidance expected in January 2008

Raised triglyceridesMost elevations of TG are secondary to other causes such as excess alcohol intake, diabetes, renal or liver disease

Statins have a triglyceride lowering effect

There are few outcomes studies with other lipid lowering drug classes

Statins should still be first-line

If TG>10 risk of pancreatitis – seek specialist advice

Age is not the deciding factor for initiating statins

Cessation of statins in certain patient groupsCoexisting life-threatening condition (<2 years lifespan)

Active liver disease (2 consecutive measurements of serum transaminases with 3x ULN)

Inflammatory muscle disease (polymyositis) or CK>5x ULN

Pregnant or breast-feeding

Diet is important in cholesterol loweringBMI>29 have 4x increased risk of CHD

Every reduction in 10kg reduces TC by 0.5mmol/l

Are Statins Safe?

Serious adverse effects are rare

Meta-analysis compared statin and placeboStatins increased S/E by 39% (NNH = 197)

Statins reduced CV events by 26% (NNT = 27)

For 1000 patients, prevent 37 CV events and observe 5 adverse effects

Atovastatin associated greatest risk of adverse events

Liver enzymes

Measure LFTs before statin therapy, 12 weeks after initiation or change of dose and at 12 monthly intervals thereafter

Hepatotoxicity - dose related

Counsel patients

Most LFT elevations seen within the first 12 weeks of initiation and transient

IF transaminases increase to more than 3x ULN, discontinue statin

Pravastatin (water-soluble) may be suitable alternative

Drug interactions with simvastatinMetabolised by cytochrome P450 enzyme system

Interacting drug Prescribing advice

Potent CYP3A4 inhibitors:

Protease inhibitors

Azole antifungals

Macrolides

Avoid simvastatin

Ciclosporin

Niacin >1g daily

Do not exceed 10mg simvastatin

Verapamil

Amiodarone

Do not exceed 20mg simvastatin

Diltiazem Do not exceed 40mg simvastatin

Anticoagulants Effect of anticoagulant (warfarin) increased, monitor INR and adjust accordingly

Rifampicin Reduces plasma levels of simvastatin so may need to increase dose

Current problems in pharmacovigilance. MHRA. Vol. 30. Oct 2004.

Grapefruits and Pomegranates

Avoid eating grapefruit/pomegranate or drinking grapefruit/pomegranate juice

Both are potent inhibitor of CYP450 3A4

Interaction leads to 9-fold increase in peak serum drug level – increase risk of rhabdomyolysis

If patient wants to continue eating grapefruits/pomegranate, pravastatin or rosuvastatin are alternatives

Muscle aches on a statin

Rule out common causes (exercise)Check thyroid function testsMeasure CK

If elevated >5 x ULN – stopIf elevated <5 x ULN – monitor and repeat in 1 monthIf still elevated, reduce dose and recheck in 1 month If continue to be elevated – seek advice.

Patients to be counselled to seek urgent medical advice if experience unexplained muscular ache

Will simvastatin work if taken in the morning?

Simvastatin marginally less effective at lowering cholesterol when taken in morning

One study showed a difference:TC 0.38mmol/LLDL cholesterol 0.25mmol/L

Still substantial reduction in cholesterol from baseline so should be used first-line

Simvastatin side effects

Gastrointestinal side effects and insomnia common

Avoid taking on an empty stomach at night

Best taken with of after evening meals at 6pm

If continued GI effects and insomnia, consider taking simvastatin in the morning or lunchtime

Recheck cholesterol levels if dose permanently move to morning

Improving concordance

Estimated 50% stop within 1 year and 75% stop within 5 years

Important as healthcare professionals to explain:regular treatment is required to reduce CV risk and treatment is for life, otherwise benefit lostLikelihood of serious side effects is low but to seek medical attention if muscular pain with malaise, fever or dark urine

Check concordance and reinforce importance of continued treatment at follow-up

Cholesterol lowering effect not sufficient with simvastatin 40mg

Compliance?

Increase simvastatin dose to 80mg

Additional reduction of 6%

Switch to atorvastatin 40mg daily and increasing to 80mg daily

Additional reduction of 8-12%

Ezetimibe 10mg daily may be considered in addition to simvastatin (NICE technology appraisal expected Nov 2007)

Good News!Statin Progress

% Low Cost Statin Prescribing for PCTs in the SE London Sector

0

10

20

30

40

50

60

70

80

90

100

Jun-06 Sep-06 Dec-06 Mar-07 Jun-07Month

% Bexley

Bromley

Greenwich

Lambeth

Lewisham

Southwark

PCT Increase %

Bexley 11.2

Bromley 5.9

Greenwich 16.8

Lambeth 11.4

Lewisham 9.1

Southwark 10.2

SEL Hospital Trust % Low Cost Statin Prescribing

Hospital

Bromley

Queen Mary’s Sidcup

King’s College

Queen Elizabeth

GSTFT

Lewisham

% Aug-07

94

90

87

86

79

76

Cost SavingLow Cost Statins

PCT

Bexley

Bromley

Greenwich

Lambeth

Lewisham

Southwark

Apr-Aug 2007(£)

120,220

65,531

92,497

75,524

81,475

99,187

Total: 534,434

What Next?

New guidance awaited:NICE Ezetimibe TA – due Nov 28th

NICE Hyperlipidaemia guideline – due Jan 08 (delayed)

NICE diabetes guideline – due Feb 08

Expect to see:New treatment targets for secondary prevention

Clarification of the role of ezetimibe

Thank you and Questions?