13 June 2007 NICE HTA: Ezetimibe for the treatment of primary (heterozygous familial and nonfamilial) hypercholesterolemia Appraisal Consultation Document (ACD) Many thanks for providing the ACD for the above appraisal. AstraZeneca welcomes this opportunity to comment and acknowledges that positive changes have been made regarding the clarity of the wording (recommendation 1.2) and the place of Inegy in the preliminary guidance. However, we believe important comments submitted in response to the first ACD have not been adequately considered; we appreciate this opportunity to further address them. Please find our specific comments below. Overall comment As stated previously, there are a wealth of clinical and cost-effectiveness data and experience on statins as a class. In comparison, the data for cholesterol absorption inhibitors are limited and without any long-term follow-up. We believe it is therefore appropriate to ensure optimisation of statins before considering the addition of ezetimibe. Place of ezetimibe in lipid lowering treatment pathway Whilst we acknowledge that uncertainty around the use of ezetimibe has been reflected in the additional research recommendation (6.1), we would have expected NICE to go further and restrict ezetimibe use to patients not reaching their treatment goals on second line statins. We strongly believe that due to the lack of experience with this new drug class, ezetimibe is more appropriately positioned after use of a more effective statin rather than alongside (i.e. following optimisation of the statin treatment pathway). There is conclusive evidence that the use of statins to lower LDL-cholesterol (LDL-C) levels results in a reduction in observed cardiovascular events including, cardiovascular and coronary heart disease mortality. Whilst AstraZeneca fully supports the ACD acknowledgement of this link, we would like to caution that this benefit should not automatically be extended to non-statin lipid lowering therapies. For instance, despite evidence of lipid lowering, fibrates have failed to demonstrate a similar significant improvement in major cardiovascular outcomes such as coronary heart disease mortality. In the FIELD study, whilst use of fenofibrate reduced the total number of cardiovascular events due to nonfatal myocardial infarction and revascularisation, it did not significantly improve the primary end point, i.e. the incidence of major coronary events compared to placebo 1. Therefore, it would be prudent to first ascertain the effect of cholesterol absorption inhibitors on cardiovascular events through appropriately designed studies before generalising the benefits of statins on cardiovascular events to this new class of lipid lowering therapy. Further, as stated in our response to the previous ACD, optimising the statin treatment pathway also results in minimisation of the cost burden of treating increasing numbers of patients to appropriate targets. When simvastatin 40mg does not achieve desired cholesterol targets, clinicians may choose to switch to an appropriate dose of a more effective statin or as suggested by NICE s draft guidance, co-prescribe ezetimibe with simvastatin. Table 1 shows that the decision to add ezetimibe either as the free or fixed dose combination is not the cheapest second-line treatment option. Further, Table 2 demonstrates that the equivalent LDL-C lowering efficacy of ezetimibe + simvastatin 40mg can be achieved at a reduced cost to the NHS by titrating up the statin treatment pathway. Page 1 of 8
Table 1: Costs of second line LDL-C lowering treatments 2, 3 Product(s) LDL-C lowering (%) Monthly cost ( ) Cost ( ) / % LDL-C lowering Rosuvastatin 10mg 45.8 18.03 0.39 Atorvastatin 20mg 42.6 24.64 0.58 Ezetimibe 10mg / generic simvastatin 40mg 52.1 ~30.11* 0.58 Inegy (10/40)** 52.1 38.98 0.75 * Price based on Q2 2007 drug tariff price for simvastatin 40mg ** LDL-C lowering effect of Inegy assumed to be equivalent to co-administration of simvastatin and ezetimibe Table 2: Costs of comparative LDL-C lowering treatments 2,3 Product(s) LDL-C lowering (%) Monthly cost ( ) Cost ( ) / % LDL-C lowering Rosuvastatin 20mg 52.4 26.02 0.50 Atorvastatin 80mg 51.1 28.21 0.55 Ezetimibe 10mg / generic simvastatin 40mg 52.1 ~30.11* 0.58 Inegy (10/40)** 52.1 38.98 0.75 * Price based on Q2 2007 drug tariff price for simvastatin 40mg ** LDL-C lowering effect of Inegy assumed to be equivalent to co-administration of simvastatin and ezetimibe In summary: The benefits of statins on CV events should not be automatically extended to cholesterol absorptions inhibitors It is more clinically appropriate to optimise the statin treatment pathway than use ezetimibe second line Optimisation of the statin treatment pathway minimises expenditure o When additional efficacy is needed after simvastatin 40mg, add-on ezetimibe / Inegy is not the cheapest option o Equivalent LDL-C lowering produced by simvastatin 40mg +ezetimibe can be achieved at a lower cost by titration of more effective statins Budget Implications of using ezetimibe as a second line add on AstraZeneca is concerned that the cost of implementing this recommendation has not been fully considered, particularly when placed in the context of the NICE statin guidance 4 that has increased the number of patients eligible for statin treatment. As outlined in our previous response, using a statin dose titration strategy is more cost-effective than adding ezetimibe to simvastatin, with an annual treatment cost of 118.93 versus 149.49 as shown in Table 3 2,5,6. When these figures are extrapolated to a population of 100,000 with 14,943 patients eligible for statin treatment, the additional cost of adding ezetimibe compared with dose titration is approximately 457,000 (see Table 4 2, 5, 6 ); however, this additional expenditure does not result in more patients reaching treatment goals. The true budget impact of early use of ezetimibe is clearly seen when the results are further extrapolated to include the population of England and Wales with approximately 7.8 million eligible patients. The current preliminary NICE guidance could result in the NHS (England and Wales) paying an aditional 239 million compared to the use of a statin dose titration strategy. Whilst not all patients are prescribed ezetimibe in conjunction with simvastatin 40mg, this example highlights the potential negative budgetary impact of ezetimibe on the NHS as well as the significant resource implications of Page 2 of 8
opting to prescribe ezetimibe with simvastatin 40mg rather than utilising more effective statins. Given the recent push to reduce prescribing costs of lipid-lowering therapy we would expect such savings to be regarded as significant. Furthermore, we are aware that NHS clinicians are under pressure to hit generic statin prescribing targets 7 and at the same time also hit cholesterol lowering targets 8. Whilst adding ezetimibe to generic simvastatin is supported by NICE s (preliminary) recommendations and may seem a suitable approach to meeting both targets, the financial implications as outlined above show the detrimental effect on NHS resources; there is a substantial rise in costs without a corresponding increase in the number of patients reaching their treatment goals. In the context of NICE s statin appraisal (TA 94; endorsing the use of the statin with the lowest acquisition cost), the current preliminary recommendations endorse use of ezetimibe added to simvastatin 40mg. When this strategy does not meet targets (19.7% of patients Table 3) clinicians will need to use a more effective statin in combination with ezetimibe, further increasing prescribing costs. The alternative approach is to appropriately titrate up the statin pathway; the number of patients not meeting their target on an appropriately titrated dose of the most effective statin is substantially less (14.9% of patients Table 3) than the number not meeting their target on the simvastatin /+ ezetimibe strategy (19.7% - Table 3). Table 4 not only demonstrates that switching patients from simvastatin to rosuvastatin is not only considerably less costly, but given the widespread reluctance to prescribe the maximum dose of simvastatin due to the unfavourable risk benefit ratio, it is also more effective at getting more patients to their treatment targets. Page 3 of 8
Table 3: Cost-effectiveness of alternative treatment strategies 2,5 Ezetimibe Strategy Treatment Strategy % of Patients Annual Cost to Target of Treatment (Incremental) per Patient Cost per Patient to Target Start dose: Simvastatin 40mg 63.4% 49.40 77.89 Step 1: Simvastatin 40mg plus ezetimibe 10mg 16.9%* 323.02 402.37 Dose Titration Strategy Target not reached 19.7% 323.02 N/A Overall 80.3% 149.49 186.21 Start dose: Simvastatin 40mg 63.4% 49.40 77.89 Step 1: Rosuvastatin 10mg 11.9%* 197.39 262.14 Step 2: Rosuvastatin 20mg 9.8%* 259.71 305.12 Target not reached 14.9% 259.71 N/A Overall 85.1% 118.93 139.72 Benefits of Dose Titration Strategy: +4.8% - 30.56-46.49 * of the total treated population Table 4: Budget impact of alternative treatment strategies for a 100,000 population with 14,761 patients eligible for statin treatment 2,5 Ezetimibe Strategy Treatment Strategy No of Patients at Each Step % of Patients to Target (Incremental) No of Patients to Target Total Annual Cost Start dose: Simvastatin 40mg 14,943 63.4% 9,477 522,160 Step 1: Simvastatin 40mg plus ezetimibe 10mg 5,466 16.9%* 2,519 1,711,684 Dose Titration Strategy Target not reached 2,947 19.7% Overall 80.3% 11,996 2,233,843 Start dose: Simvastatin 40mg 14,943 63.4% 9,477 522,160 Step 1: Rosuvastatin 10mg 5,466 11.9% 1,775 505,897 Step 2: Rosuvastatin 20mg 3,691 9.8% 1,467 749,091 Target not reached 2,224 14.9% Overall 85.1% 12,719 1,777,148 Benefits of Dose Titration Strategy: 4.8% 723-456,696 * of the total treated population Page 4 of 8
Data for first prescriptions of ezetimibe co-prescribed with a statin Current data (Q1 2007) indicate that in 42% of patients prescribed ezetimibe in conjunction with a statin for the first time, the co-prescribed statin is simvastatin (atorvastatin is the co-prescribed statin in 39% of patients) 9. Figure 1 further illustrates the break down of statins co-prescribed with ezetimibe at first prescription (the key focus being simvastatin and atorvastatin doses). The chart clearly demonstrates that for first prescriptions simvastatin 40mg is the statin / dose used in 28% of patients; (in other words) approximately 70% of co-prescribing does not occur with simvastatin 40mg. Figure 1 also demonstrates that at present about half (49%) of co-prescribing of a statin with ezetimibe in the UK is not with generic statins (e.g. simvastatin 10 40mg and pravastatin); and therefore represents a considerable cost burden that could be minimised through appropriately optimising the statin titration pathway prior to adding ezetimibe (Note: values based on rounded figures). Figure 1: First Ezetimibe Add-on Script by Statin Dose - Q1 2007 Total Fluvastatin 0% Atorvastatin 10mg Total Rosuvastatin 7% 11% Atorvastatin 20mg 7% Total Pravastatin 8% Simvastatin 80mg 2% Simvastatin 40mg 28% 29% Simvastatin 10mg 4% Simvastatin 20mg 8% Atorvastatin 40mg 14% Atorvastatin 80mg 10% Atorvastatin 10mg 26.31 + 18.03 Atorvastatin 20mg 26.31 + 24.64 Atorvastatin 40mg 26.31 + 28.21 Atorvastatin 80mg 26.31 + 28.21 Simvastatin 10mg 26.31 + 1.66 Simvastatin 20mg 26.31 + 2.02 Simvastatin 40mg 26.31 + 3.54 Simvastatin 80mg 26.31 + 12.10 Total Pravastatin 26.31 + 5.07* Total Rosuvastatin 26.31 + 23.07* Total Fluvastatin 26.31 + 15.21* *Aggregated molecule level cost Source: Cegedim Strategic Data. Patient Data, [Mar/07] Page 5 of 8
Data for all prescriptions of ezetimibe co-prescribed with a statin and implications When all ezetimibe prescriptions are taken into account (new and repeat prescriptions), the data (Q1 2007) demonstrates that, when used in conjunction with a statin, ezetimibe is most commonly prescribed with atorvastatin (47%), most frequently at a dose of 40mg (21%). Simvastatin accounts for 30% of statin co-prescriptions with ezetimibe. It appears that the governing factor determining NICE s preliminary recommendations was the incremental cost-effectiveness ratios from the various scenarios produced by the Assessment Group (section 4.3.9 - committee discussions). Given the large pool of patients on atorvastatin and ezetimibe, the premise that the current preliminary recommendations have been based on (simvastatin /+ ezetimibe; acquisition cost ~ 30.11) is misguided. Introducing the current guidance as it stands will further increase the already large pool of patients on atorvastatin 40mg plus ezetimibe (acquisition cost - 54.52), this practice being considerably more expensive than the scenario 3 options. The current status (atorvastatin + ezetimibe) is more accurately reflected by scenario 1, a scenario not recommended by the committee due to the unfavourable ICERs. Given the pressure within the NHS to minimise expenditure through rational prescribing, we strongly recommend that these preliminary recommendations are re-evaluated in the context of current prescribing and that more scenarios are investigated to adequately explore the place of ezetimibe in the lipid-lowering treatment pathway, particularly given its limited clinical data and potential large budget impact. Figure 2: All Ezetimibe Add-on Scripts (New + Repeat) by Statin Dose - Q1 2007 Total Rosuvastatin 15% Total Fluvastatin 2% Atorvastatin 10mg 4% Atorvastatin 20mg 7% Total Pravastatin 7% Simvastatin 80mg 2% Simvastatin 40mg 20% Simvastatin 20mg Simvastatin 10mg 5% 3% Atorvastatin 40mg 20% 21% Atorvastatin 80mg 15% Atorvastatin 10mg 26.31 + 18.03 Atorvastatin 20mg 26.31 + 24.64 Atorvastatin 40mg 26.31 + 28.21 Atorvastatin 80mg 26.31 + 28.21 Simvastatin 10mg 26.31 + 1.66 Simvastatin 20mg 26.31 + 2.02 Simvastatin 40mg 26.31 + 3.54 Simvastatin 80mg 26.31 + 12.10 Total Pravastatin 26.31 + 5.25* Total Rosuvastatin 26.31 + 24.31* Total Fluvastatin 26.31 + 15.40* *Aggregated molecule level cost Source: Cegedim Strategic Data. Patient Data, [Mar/07] In summary: Opting for a simvastatin /+ ezetimibe strategy versus switching to a more effective statin results in a substantial rise in costs despite fewer patients reaching their treatment goals Currently atorvastatin is the statin most commonly prescribed in conjunction with ezetimbe. The atorvastatin +ezetimibe ( 54.52) combination is considerably more expensive than simvastatin + ezetimibe ( 30.11). Thus the basis of the preliminary recommendations is misguided based on current clinical practice in the UK. Page 6 of 8
Cost-effectiveness section We acknowledege that an equivalent scenario 3 for rosuvastatin has not been incorporated into the preliminary guidance. Given that LDL-C lowering has been used to measure effectiveness within the model, it is reasonable to indicate that as rosuvastatin is more effective at LDL-C lowering and less costly than atorvastatin one would expect the incremental cost per QALY of using a simvastatin + ezetimibe strategy to be greater when rosuvastatin is the comparator statin within the health economics model as opposed to atorvastatin, thus reducing the cost-effectiveness of ezetimibe as a second line option. As such, the preliminary guidance currently falls short of fully informing the NHS of the relative cost-effectiveness of all available strategies. If further scenarios are not being explored, we strongly recommend that a statement about this limitation to the cost-effectiveness analysis is incorporated into the final guidance. In summary: Due to a limited exploration of the various treatment scenarios there are important limitations to the cost-effectiveness analysis on which the preliminary recommendations are based Fixed dose combination of ezetimibe and simvastatin (Inegy) We believe that an explicit recommendation with regards to the fixed dose combination needs to be included in the final guidance. Whilst we support the recommendation that when ezetimibe is coadministered with a statin it should be prescribed at the lowest acquistion cost, at present, it is possible that the reference to the lowest acquisition cost (recommendation 1.3) may be interpreted as referring to the use of the statin with the lowest acquisition cost in conjunction with ezetimibe, rather than (as we believe is intended) referring to the use of the fixed combination tablet Inegy. Due to the substantial burden on the NHS that the routine use of Inegy would represent, we strongly recommend that this section be amended so that there is no room for misinterpretation of the guidance, the following wording is offered as an example, The use of the fixed dose combination tablet of ezetimibe and simvastatin (Inegy) is not recommended for use in the NHS. Compliance If implemented, the current NICE recommendations will result in many patients taking two rather than one lipid-lowering tablet(s) per day. As outlined in our previous response, there are likely to be negative implications on patient compliance of increasing the number of tablets 10. There tends to be an inverse relationship between the number of drugs a patient is required to take and their compliance, more importantly, poor compliance may lead to failure to realise the full benefits of lipid lowering therapy 11. Therefore, we suggest that consideration of the potential negative implications on compliance should be incorporated into the NICE guidance. In addition, another factor associated with poor compliance may be the increased cost of two prescription charges for the patient compared to the previous single charge. Widespread use of ezetimibe will not only have an impact on resources in the NHS but also on patients individual resources - particularly with more frequent restrictions on the volume of supply issued on a prescription. We suggest that this additional consideration should be incorporated into the NICE guidance. We ask the Institution to bear in mind that Inegy may confer additional efficacy benefits by virtue of increased compliance when compared to the separate ( free ) co-administration of statin plus ezetimibe, therefore we would caution the inclusion of data pertaining to Inegy in the final guidance. In summary: Adding ezetimibe to a statin may decrease patient compliance due to an increased number of tablets Caution needs to be exercised in extrapolating benefits seen with Inegy to free coadministration of ezetimibe plus statin. Page 7 of 8
Overall conclusion In summary, whilst ezetimibe may be a useful addition to the available lipid lowering therapy options, prescribing it as a second line alternative to switching to a more effective statin will potentially result in a substantial negative budget impact. In addition, a lack of experience with cholesterol absorption inhibitors makes their use preferable only after the optimal use of established, cost-effective second line statins. 1 FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. The Lancet 2005; 366(9500): 1849 1861. 2 Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW, STELLAR Study Grp. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* trial). American Journal of Cardiology 2003; 92(2): 152-60. *STELLLAR = Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin 3 Davidson M H et al. Efficacy and safety of ezetimibe co administered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia. Int J Clin Pract, August 2004, 58, 8, 746-755 4 NICE Guidance. Statins for the prevention of cardiovascular events in patients at increased risk of developing cardiovascular disease or those with established cardiovascular disease TA 94 January 2006. http://www.nice.org.uk 5 Drug Tariff (HMSO) April 2007 6 Health Survey for England. 2003 Department of Health 7 Increasing low cost statin prescribing. Prescribing PCTs Q3 06/07. NHS productivity. London SHA http://www.productivity.nhs.uk/form_pct_4.1_statin.aspx?period=2006- Q3&report=p41&orgCode=5A4&email= (accessed 1 June 2007) 8 NHS employers. Quality and outcomes framework http://www.nhsemployers.org/primary/primary- 890.cfm (accessed 21 May 2007). 9 Cegedim Strategic Data, Patient Data. March 2007 10 Neutel JM, Smith DHG: Improving patient compliance: a major goal in the management of hypertension. Journal of Clinical Hypertension 2003, 5:127-132 11 Penning-van Beest FJ, Termorshuizen F, Goettsch WG, Klungel OH, Kastelein JJ, Herings RM. Adherence to evidence-based statin guidelines reduces the risk of hospitalizations for acute myocardial infarction by 40%: a cohort study. Eur Heart J. 2007 28(2):154-9. Page 8 of 8