NICE QIPP about Lipitor Robert Trotter Clinical Effectiveness Consultant LIP2894c Date of preparation: April 2009 Prescribing information for atorvastatin is available on the last slide
Roadmap Background Financial Clinical NICE Lipitor in ACS and stable CVD Clinical data Health economics
Opportunity Reference www.productivity.nhs.uk -3-
Pressures -4-
Standardised Mortality Rates for CHD Blackpool 139 Central Lancashire 100 North Lancashire 105 Reference www.nchod.nhs.uk -5-
A 0.5mmol/L difference in LDL-C could lead to an 11% difference in major vascular events and a 6% difference in all cause mortality 50% Major vascular events are MI, stroke and revascularisation Proportional Change in Event Rate (SE) 40% 30% 20% 10% 0% 0.5 1.0 1.5 2.0 90,056 patients from 14 trials over 5 years -10% Change in LDL Cholesterol (mmol/l) CTT Collaborators (2005) Lancet; 366:1267-78 Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78
Cholesterol Treatment Trialists (CTT) meta analysis 90,056 patients, 14 trials, 5 years For every 1mmol/L reduction in LDL-C 12% reduction in all cause mortality 19% reduction in coronary mortality 21% reduction in major vascular events 23% reduction in major coronary events 17% reduction in stroke 24% reduction in revascularisation while lowering LDL-C from 4mmol/L to 3mmol/L reduces the risk of vascular events by about 23%, lowering LDL-C from 3mmol/L to 2mmol/L also reduces (residual) risk by about 23% Cholesterol Treatment Trialists Collaborators, Lancet 2005
NICE Lipid Modification Clinical Guidelines (May 2008) Primary Prevention Secondary Prevention ACS Start S40* or a drug of similar efficacy and cost for adults >40 yrs with >20% 10 year CVD risk (Framingham) -No target level for TC or LDL-C -No repeat lipid profile but review management according to clinical judgement and patient preference If statins not tolerated for primary prevention, consider: fibrates, anion exchange resins, ezetimibe Start S40* or a drug of similar efficacy and cost If TC not <4mmol/L or LDL-C not <2mmol/L consider up-titrating to S80 or a drug of similar efficacy and cost Patients with clinical evidence of: -CHD -Stroke or transient ischaemic episode -Peripheral artery disease Use an audit level of TC = 5mmol/L to assess progress in groups with CVD. Recognise that less than half will achieve TC < 4mmo/L or LDL-C < 2mmol/L Identified by NICE as: -New-onset angina -Unstable angina -Myocardial Infarction Offer higher intensity statin** without delay irrespective of baseline cholesterol Measure lipid levels at 3 months If statins are not tolerated for secondary prevention, consider: fibrates, anion exchange resins, nicotinic acid, ezetimibe Be mindful of: 1) Patient preference 2) Co-morbidities 3) Other therapies 4) Benefit and risks NICE recommend lipid lowering drugs for which there is evidence in clinical trials of a beneficial effect on CVD morbidity and mortality. * If there are potential drug interactions or 40mg simvastatin is contraindicated, offer a lower dose of simvastatin or pravastatin ** Higher intensity statins are statins used in doses that produce greater cholesterol lowering than simvastatin 40mg, for example simvastatin 80mg S40 = simvastatin 40; S80 = simvastatin 80mg; ACS = Acute Coronary Syndrome Flow chart adapted from NICE CG67 Quick Reference Guide http://www.nice.org.uk/nicemedia/pdf/cg67quickrefguide.pdf Accessed September 2008 NICE CG67 Lipid Modification Clinical Guidelines http://www.nice.org.uk/nicemedia/pdf/cg67niceguideline.pdf Accessed September 2008
Most patients will not achieve NICE recommendations of lowering TC to <4mmol/L for secondary prevention with generic statins alone NICE analysis suggests that in patients with established CVD: 31% will attain TC<4mmol/L on simvastatin 40mg 1 37% will reach TC<4mmol/L on simvastatin 80mg 1 1 NICE CG67 Costing Report section 3.3.10 http://www.nice.org.uk/nicemedia/pdf/cg67costingreport.pdf Accessed September 2008
The Law meta-analysis of 164 randomised statin trials Law et al (2003) BMJ 326: 1423-1430 Jones et al (1998) Am J Cardiol 81:582 587
NICE Type II Diabetes Clinical Guidelines (May 2008) Age >40 diabetic and low CV risk (consider low CV risk if none of the risk factors listed below apply) Age >40 diabetic and high CV risk (consider high CV risk if one of the risk factors listed below apply) List of risk factors overweight hypertensive (>140/80mmHg despite anti-hypertensive therapy) microalbuminuria smoker high-risk lipid profile history of CV disease family history of CV disease Assess CV risk with UKPDS. If CV risk >20% over 10 yrs No CV risk assessment required Offer S40 or a statin of similar efficacy and cost If not at target uptitrate to S80 If there is CVD or albuminuria, intensify therapy with a more effective statin or ezetimibe to achieve cholesterol targets Assess lipid profile at 1-3 months after starting treatment Treat to achieve target TC< 4mmol/L or LDL-C<2mmol/L S40 = simvastatin 40; S80 = simvastatin 80mg Flow diagram adapted from NICE CG66 Quick Reference Guide http://www.nice.org.uk/nicemedia/pdf/cg66t2dqrg.pdf Accessed September, 2008 NICE CG66 http://www.nice.org.uk/nicemedia/pdf/cg66t2dqrg.pdf Accessed September, 2008
PROVE IT: Death, MI or ACS rehospitalisation % of patients with death, MI or rehospitalisation for ACS 25 20 15 10 5 0 Early Benefit Acute Phase Late Benefit Chronic Phase ARR 4.3% NNT =24 over 2 years Pravastatin 40 mg (LDL-C 2.5mmol/L) Atorvastatin 80 mg (LDL-C 1.6mmol/L) 20.0% 15.7% 24% RRR HR 0.76 (0.66-0.88) P=0.0002 0 6 12 18 24 30 Ray et al (2005) JACC 46: 1405-10 Months following randomisation
An early benefit becomes apparent at day 15 and significant at day 30 % of patients with death, MI or rehospitalisation for ACS 5 4 3 2 1 0 Pravastatin 40 mg 4.2 % Atorvastatin 80 mg 3.0 % 28% RRR HR 0.72 (0.52-0.99) P = 0.046 0 5 10 15 20 25 30 Days following randomisation Ray et al (2005) JACC 46: 1405-10
A second late benefit was also demonstrated for patients remaining on atorvastatin % of patients with death, MI or rehospitalisation for ACS 12 10 8 6 4 2 0 6 12 18 Months following randomisation Pravastatin 40 mg 13.1% Atorvastatin 80 mg 9.6% 28% RRR HR 0.72 (0.58-0.89) P=0.003 24 Ray et al (2005) JACC 46: 1405-10 *Analysis excluding patients with events in the first 6 months
Post MI patients had significantly fewer events on high dose atorvastatin vs moderate dose simvastatin over 5 yrs Post hoc analysis of 999 post MI patients in the IDEAL trial (within 2 months of MI) Cumulative Hazard of MI (%) 20 Simvastatin 20-40mg 16 12 8 4 Atorvastatin 80mg NNT 18 over 5 years 46% relative risk reduction 0 HR = 0.54 (95% CI = 0.35, 0.82), P=0.004 0 1 2 3 4 5 Years Since Randomisation Pedersen et al. Presented at World Congress of Cardiology 2006
PROVE IT- total costs (drug + hospitalisation) per patient - 56 3,500 3,184 3,236 3,000 Mean cost ( ) 2,500 2,000 1,500 1,000 = hospitalisation costs = drug costs 500 0 Atorvastatin n=2,099 Pravastatin n=2,063 Presented at ISPOR 2006, Abstract A193, Value in Health, 9(6)
Conclusions from ACS studies The evidence for intensive lipid lowering with atorvastatin in patients with acute coronary syndrome is significant and clinically compelling 1,2 The benefit appears rapidly and is maintained long term 1,2 Less intensive lipid lowering appears to increase risk in this patient group in comparison to intensive therapy 1-2 NICE recommend that patients with ACS should be treated with a higher intensity statin* without delaying until lipid levels are available 3 1 Ray et al (2005) JACC 46: 1405-10 2 Pedersen et al. Presented at World Congress of Cardiology 2006 3 NICE CG67 Lipid Modification Clinical Guidelines http://www.nice.org.uk/nicemedia/pdf/cg67niceguideline.pdf Accessed March 2009
Abbreviated prescribing information for atorvastatin Abbreviated prescribing information: Lipitor Presentation: Lipitor is supplied as film coated tablets containing 10mg, 20mg, 40mg or 80mg of atorvastatin. Indications: In patients unresponsive to diet and other non-pharmacological measures, Lipitor is indicated for the reduction of elevated total cholesterol, LDL-cholesterol, apolipoprotein B, and triglycerides in adults and children aged 10 years and older with primary hypercholesterolaemia, heterozygous familial hypercholesterolaemia or combined (mixed) hyperlipidaemia. Lipitor also raises HDL-cholesterol and lowers the LDL/HDL and total cholesterol/hdl ratios. Lipitor is also indicated for the reduction of elevated total cholesterol, LDL-cholesterol, and apolipoprotein B in patients with homozygous familial hypercholesterolaemia. Lipitor is indicated for reducing the risk of cardiovascular events in patients with Type II diabetes and one additional risk factor, without clinically evident coronary heart disease, irrespective of whether cholesterol is raised. Dosage: The usual starting dose is one Lipitor 10mg tablet daily. Doses should be individualised according to baseline LDL-C levels, the goal of therapy, and patient response. Doses may be given at any time of the day with or without food. The maximum daily dose is 80mg. For patients taking drugs that increase plasma exposure to atorvastatin the starting dose should not exceed 10mg and maximum dose of less than 80mg may have to be considered. Doses above 20mg/day have not been investigated in patients aged <18 years. In primary prevention trials, the dose was 10mg/day. Contraindications: Hypersensitivity to any of the ingredients, active liver disease, unexplained elevations in serum transaminases, pregnancy and breast-feeding and in women of child-bearing potential not using contraception. Warning and precautions: Liver function tests should be performed before initiation and periodically thereafter and in patients who show signs and symptoms of liver injury (monitor raised transaminases until they return to normal). Drug dosage should be reduced or therapy discontinued if persistent elevations occur above 3-times the upper limit of normal. Lipitor should be used with caution in patients with a history of liver disease and/or alcoholism. For patients with prior haemorrhagic stroke or lacunar infarct, the balance of risks and benefits of atorvastatin 80 mg is uncertain and the potential risk of haemorrhagic stroke should be carefully considered before initiating treatment. Patients with signs and symptoms of myopathy should have their creatine phosphokinase (CPK) levels monitored. Lipitor should be discontinued if CPK levels are markedly or persistently raised or myopathy is diagnosed or suspected. Lipitor should be prescribed with caution in patients with pre-disposing factors for rhabdomyolysis. Risk of myopathy may increase when administered with certain medications that increase the plasma concentration of atorvastatin. If co-administration is required a dose reduction or if not practical a temporary suspension should be considered; the starting dose of atorvastatin should be 10 mg. In the case of ciclosporin, clarithromycin and itraconazole a lower maximum dose should be used. Although interaction studies with atorvastatin and fusidic acid have not been conducted, severe muscle problems such as rhabdomyolysis have been reported in post-marketing experience with this combination - therefore patients should be closely monitored and temporary suspension of atorvastatin treatment may be appropriate. As with other statins, rhabdomyolysis with acute renal failure has been reported. Patients with galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption should not take this product. Pregnancy and lactation: Lipitor is contraindicated in pregnancy and lactation. Side effects: Side effects most frequently reported in controlled clinical studies: constipation, flatulence, dyspepsia, abdominal pain, headache, nausea, myalgia, asthenia, diarrhoea, insomnia, elevations in ALT and CPK levels. Other side effects have been reported in clinical trials and post-marketing (See Summary of Product Characteristics). Legal category: POM. Date of Revision: February 2009 Package quantities, marketing authorisation numbers and basic NHS price: Lipitor 10mg (28 tablets), PL16051/0001 18.03, Lipitor 20mg (28 tablets), PL16051/0002 24.64, Lipitor 40mg (28 tablets) PL16051/0003 24.64, Lipitor 80mg (28 tablets) PL 16051/0005 28.21. Marketing Authorisation Holder: Pfizer Ireland Pharmaceuticals, Pottery Road, Dun Laoghaire, Co. Dublin, Ireland. Lipitor is a registered trade mark. Further information is available on request from: Medical Information, Pfizer Limited, Walton Oaks, Dorking Road, Tadworth, Surrey KT20 7NS. Ref: LR 10_0. Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Pfizer Medical Information on 01304 616161 Date of preparation: April 2009 LIP2894c