The Cost Effectiveness of Statin Therapies in Spain in 2010, after the Introduction of Generics and Reference Prices

Background

HMG-CoA reductase inhibitors (statins) are the first-line drugs for use in the reduction of low-density lipoprotein cholesterol (LDL-C) levels and prevention of coronary heart disease (CHD) in patients with hypercholesterolemia. Generic statins could change the cost effectiveness of statin therapies in Spain, and more population groups could be included in the recommendations for reduction of cholesterol levels based on cost effectiveness.

Objectives

The objectives of this study were: (i) to assess the cost effectiveness of available statins for the reduction of LDL-C levels in Spain in 2010, after the introduction of generics and reference prices; (ii) to assess the cost effectiveness of combination therapy using a statin plus cholestyramine or ezetimibe; and (iii) to estimate the mean cost per patient to achieve National Cholesterol Education Program (Adult Treatment Panel-III) therapeutic objectives.

Methods

The following treatments were evaluated: rosuvastatin 5–20mg/day; atorvastatin, simvastatin, and pravastatin 10–40mg/day; lovastatin and fluvastatin 20–80mg/day; and combination therapy with a statin plus either cholestyramine 12–24g/day or ezetimibe 10mg/day. The cost effectiveness was evaluated in terms of cost per percentage point reduction in LDL-C, comparing the annual treatment costs with the effectiveness in reducing LDL-C. Treatment costs included those for medications (2010 wholesale prices), control measures, and treatment of adverse drug effects. The effectiveness of statins was estimated by developing a meta-analysis of clinical trials published between 1993 and 2005 that met several inclusion criteria. Average and incremental cost-effectiveness ratios were calculated to assess the efficiency of individual statin and combination therapies in reducing LDL-C levels.

Results

The effectiveness in terms of percentage reduction in LDL-C ranged from 19% for pravastatin 10mg/day to 55% for atorvastatin 80mg/day. Annual treatment costs ranged from €189.7 for simvastatin 10mg/day to €759.3 for atorvastatin 80mg/day. The cost-effectiveness ratios, in terms of cost per percentage point reduction in LDL-C, were: €6 for simvastatin, €10–12 for rosuvastatin, €10 for lovastatin, €13–16 for atorvastatin, €13–14 for fluvastatin, and €14–20 for pravastatin. Rosuvastatin + ezetimibe, simvastatin + ezetimibe, and atorvastatin + ezetimibe were the most cost-effective combination therapies for reducing LDL-C levels. Rosuvastatin was the most cost-effective statin for achieving the LDL-C therapeutic goal in patients at high risk for CHD, with a mean cost per patient of €516. Simvastatin was the most cost-effective statin to achieve the LDL-C goal in patients with moderate or low CHD risk, with a cost per patient of €217 and €190, respectively.

Conclusion

Rosuvastatin should be the first-choice agent in patients with high CHD risk, while simvastatin should be the first choice in patients with moderate or low risk. The addition of ezetimibe to rosuvastatin, simvastatin, or atorvastatin should be the preferred combination therapies when greater LDL-C reductions are required. The cost effectiveness of all statin therapies has increased in Spain after the introduction of generic statins and reference prices.     

Reaching goal in hypercholesterolaemia: dual inhibition of cholesterol synthesis and absorption with simvastatin plus ezetimibe

ABSTRACT

Lowering serum cholesterol levels reduces the risk of coronary heart disease (CHD)-related events. Statins are commonly prescribed as first-line treatment but many patients at high-risk for CHD still fail to reach their cholesterol or low-density lipoprotein cholesterol (LDL-C) goals with statin monotherapy.

National and international guidelines for the prevention of CHD recommend the modification of lipid profiles and particularly LDL‐C [e.g. the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III; 2001) and Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (2003) Guidelines]. Several recent clinical trials indicated an added benefit from aggressive lowering of LDL‐C levels. Based on these findings, the NCEP ATP III revised the LDL‐C target from < 100?mg/dL (2.6?mmol/L) to < 70?mg/dL (1.8?mmol/L) (optional target) for very high-risk patients and < 130?mg/dL (3.4?mmol/L) to < 100?mg/dL (2.6?mmol/L) for moderately high-risk patients.

For patients who fail to achieve their LDL‐C target, inhibiting the two main sources of cholesterol – synthesis and uptake – can produce more effective lipid lowering, allowing more patients to reach their LDL‐C goal. Ezetimibe is a highly-selective inhibitor of cholesterol absorption and simvastatin is an evidence-based inhibitor of cholesterol synthesis. The LDL‐C-lowering efficacy of targeting both major sources of cholesterol with ezetimibe plus simvastatin was demonstrated in several multicentre, double-blind, placebo-controlled trials in patients with hypercholesterolaemia. For patients who do not reach their cholesterol goal with a statin, adding ezetimibe 10?mg significantly reduces LDL‐C compared with statin monotherapy. Thus, this treatment option may help patients reach the new ‘stricter’ cholesterol goals.

This review, based on a Medline database search from January 2000 to August 2005, considers the LDL‐C-lowering efficacy of ezetimibe and discusses the role of this agent for patients who fail to achieve guideline cholesterol goals with statin monotherapy.     

Efficacy of atorvastatin after LDL-cholesterol-based dose selection in high risk dyslipidaemic patients: results of the target dose study

ABSTRACT

Background: Hypercholesterolaemia is one of the major risk factors for the development of coronary heart disease (CHD). European guidelines emphasize the importance of reducing low-density lipoprotein cholesterol (LDL?C) levels below 115?mg/dL (3.0?mmol/L) in patients with high CHD risk.

Objective: The present study evaluates whether selection of the atorvastatin starting dose based on baseline LDL?C levels and previous statin treatment status would result in an achievement of LDL?C targets without the need for up-titration.

Methods: A multicentre, prospective, open-label study conducted in Belgium. Patients were at high risk defined as either a history of CHD, another atherosclerotic disease, diabetes mellitus Type 2 or an estimated 10?year CHD risk > 20%. The primary endpoint was the proportion of patients achieving the LDL?C goal after 12 weeks of treatment.

Results: Overall, 96.4% of the 195 statin-naïve patients reached the LDL?C target after 12 weeks of treatment. The majority of the patients (95.4%) already reached LDL?C control at Week 6. Mean (SD) LDL?C levels decreased from 159 (25)?mg/dL[(4.1 (0.6)?mmol/L] to 86 (14)?mg/dL [2.2 (0.4)?mmol/L] after 12 weeks of treatment. Only 4.6% of the patients needed an up-titration at Week 6.

Conclusions: Taken together, the results demonstrate that LDL?C based dose selection of atorvastatin is highly efficacious for rapid achievement of target LDL?C levels with a low need for up-titration. Application of this flexible first dosing strategy in general practice will, based on available evidence, increase adherence to atorvastatin treatment in patients with high CHD risk.     

Hypocholesterolemic effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in the guinea pig: atorvastatin versus simvastatin.

Male Hartley guinea pigs were fed a hypercholesterolemic diet rich in lauric and myristic acids with 0, 10, or 20 mg/kg of simvastatin or atorvastatin for 21 days. Atorvastatin and simvastatin resulted in a lowering of plasma low-density lipoprotein (LDL) cholesterol in a dose-dependent manner by an average of 48 and 61% with 10 and 20 mg/kg, respectively. Both statins were equally effective in lowering plasma LDL cholesterol and apolipoprotein B (apo-B) levels. Atorvastatin and simvastatin treatments yielded LDL particles that differed in composition from the control. Due to the relevance of LDL oxidation and cholesteryl ester transfer in plasma to the progression of atherosclerosis, these parameters were analyzed after statin treatment. Atorvastatin and simvastatin treatment decreased the susceptibility of LDL particles to oxidation by 95% as determined by the formation of thiobarbituric acid reactive substances. An 80% decrease in the transfer of cholesteryl ester between high-density lipoprotein (HDL) and the apo-B-containing lipoproteins was observed after simvastatin and atorvastatin treatment. In addition, statin effects on plasma LDL transport were studied. Simvastatin- and atorvastatin-treated guinea pigs exhibited 125 and 175% faster LDL fractional catabolic rates, respectively, compared with control animals. No change in LDL apo-B flux was induced by either treatment; however, LDL apo-B pool size was reduced after statin treatment. Hepatic microsomal free cholesterol was lower in the atorvastatin and simvastatin groups. However, only atorvastatin treatment resulted in an 80% decrease of acyl-CoA:cholesterol acyltransferase activity (P < 0.001). In summary, atorvastatin and simvastatin had similar LDL cholesterol lowering properties, but these drugs modified LDL transport and hepatic cholesterol metabolism differently.     

Topical anti-inflammatory effect of hypocholesterolaemic drugs

Objectives The topical anti‐inflammatory effect of simvastatin, atorvastatin, pravastatin, ezetimibe and combined ezetimibe + simvastatin was investigated, using the croton oil model of ear oedema in mice. Methods Simvastatin, atorvastatin, pravastatin, ezetimibe and ezetimibe + simvastatin combination (dissolved in 20 µl of 70% acetone) were topically applied simultaneously with croton oil (200 µg/ear, dissolved in 20 µl of 70% acetone) at the inner surface of each ear. Ear oedema and myeloperoxidase activity, indicative of polymorphonuclear cell migration, were assessed 6 h after inflammatory stimuli. Key findings It was found that statins can act as topical anti‐inflammatories, but the pharmacological effect is dependent on statin polarity. At 0.3 mg/ear inhibition of ear oedema was 79%, 67% and 40% for simvastatin, atorvastatin and pravastatin, respectively. Simvastatin and atorvastatin also remarkably diminished myeloperoxidase activity, even at low concentrations (0.03 mg/ear). Pravastatin, the most polar statin, however, did not cause any reduction in ear oedema or myeloperoxidase activity at low doses. The order of topical anti‐inflammatory activity was pravastatin < < < atorvastatin ≤ simvastatin. Ezetimibe, another hypocholesterolaemic drug, also presented anti‐inflammatory effects, inhibiting ear oedema by 64% at 0.3 mg/ear. However, when used in combination with simvastatin, no further beneficial effect was observed. Conclusions These results consistently support current evidence showing that statins can be used for treatment of dermatological disorders. Polarity of the molecule, however, is a factor that should be considered before recommending use.     

The efficacy of statin monotherapy uptitration versus switching to ezetimibe/simvastatin: results of the EASEGO study

ABSTRACT

Objective: To assess the incremental low-density lipoprotein-cholesterol (LDL-C) lowering efficacy of doubling the statin dose or switching to the ezetimibe/simvastatin 10/20?mg combination tablet (EZE/SIMVA) in patients on simvastatin 20?mg or atorvastatin 10?mg not at LDL-C target < 2.5?mmol/L.

Study design and methods: Patients with documented coronary heart disease (CHD) and/or type 2 diabetes (DM2) with LDL-C ≥ 2.5 and < 5.0?mmol/L despite treatment with atorvastatin 10?mg or simvastatin 20?mg were randomized to (1) double statin dose or (2) switch to ezetimibe/simvastatin 10/20, according to a PROBE study design. LDL-C, lipoprotein subfractions and safety data were assessed during the study.

Results: 119 of 178 (67%) patients in the EZE/SIMVA group and 49 of 189 (26%) in the doubling statin group reached target LDL-C < 2.5?mmol/L. The odds ratio of success for EZE/SIMVA versus doubling statin treatment in reaching the LDL-C target of < 2.5?mmol/L was 5.7 (95% CI: 3.7–9.0, p < 0.0001). A reduction in total cholesterol (TC), total/high density lipoprotein (HDL) cholesterol ratio and apolipoprotein B was observed in both groups, but this reduction was significantly more pronounced in the EZE/SIMVA group as compared with the doubling statin dose group. Treatment was well tolerated and no difference was observed between the two groups with regard to adverse effects.

Conclusions: In CHD/DM2 patients treated with simvastatin or atorvastatin with LDL-C persistently ≥ 2.5?mmol/L, switching to the EZE/SIMVA was more effective in attaining the LDL-C target of < 2.5?mmol/L than doubling the statin dose.     

Switching statin therapy using a pharmacist-managed therapeutic conversion program versus usual care conversion among indigent patients

STUDY OBJECTIVE. To evaluate the effectiveness of switching statin therapy using a therapeutic conversion program versus usual care conversion among patients enrolled in the Colorado Indigent Care Program when atorvastatin was removed from the formulary. DESIGN: Prospective cohort study. SETTING: Family medicine center and other ambulatory care clinics of a university-based health care system. PATIENTS: One hundred seventeen ambulatory care patients with dyslipidemia who were treated with atorvastatin. INTERVENTION: Clinical pharmacists in the family medicine center implemented a therapeutic conversion program (30 patients), switching atorvastatin to a new formulary regimen of simvastatin, rosuvastatin, or ezetimibe-simvastatin, using an algorithm designed to achieve patient-specific goals for low-density lipoprotein cholesterol (LDL). Usual care occurred in the other ambulatory care clinics without clinical pharmacists (87 patients), where medical providers switched atorvastatin to a formulary regimen based on a suggested (but optional) equipotency conversion algorithm. MEASUREMENTS AND MAIN RESULTS: Primary end points were LDL concentration and LDL goal attainment before and after conversion. Before and after conversion, respectively, mean LDL concentrations were 86.7 and 82.3 mg/dl in the therapeutic conversion group (p=0.44) versus 78.3 and 85.2 mg/dl in the usual care group (p=0.01). Percentages of patients attaining LDL goal were 80% before and 97% after conversion in the therapeutic conversion group (p=0.04) compared with 90% before and 75% after conversion in the usual care group (p=0.01). CONCLUSION: Use of a prospective, therapeutic statin conversion program was associated with increased control of dyslipidemia, whereas usual care statin conversion was associated with decreased control. These data suggest that proactive involvement of clinical pharmacists in converting lipid-lowering drugs results in superior patient care outcomes compared with a less aggressive approach.     

Attaining United Kingdom-European Atherosclerosis Society Low-density Lipoprotein Cholesterol Guideline Target Values in the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study

Summary

The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study compared two standards (structured vs. usual care) of lipid lowering treatment in 1600 patients with coronary heart disease (CHD). Structured care aimed at achieving (with atorvastatin 10-80?mg) the low-density lipoprotein cholesterol (LDL-C) (2.6?mmol/l; 100?mg/dl) goal described in the NCEP ATP II and III guidelines for patients with CHD. Structured care was associated with a significant reduction in overall mortality and coronary events compared to usual care.

In the present brief report we interpret the results of GREACE using the United Kingdom (UK) and European Atherosclerosis Society (EAS) treatment goal for LDL-C in secondary CHD prevention (3.0?mmol/l; 115?mg/dl). The mean dose of atorvastatin decreased from 24?mg to 22?mg/day. More patients achieved the UK and EAS LDL-C target (95.6 vs. 95%) in the structured care arm of the trial; 90% of the patients achieved this target with 10 or 20?mg atorvastatin.

These findings may have cost implications, especially if the LDL-C target for high-risk patients will fall below those described above.     

LDL-C reductions and goal attainment among naive statin users in the Netherlands: real life results*

ABSTRACT

Objective: The effectiveness of statin therapy in a real life setting may differ from that in clinical trials, as physicians make non-randomised treatment decisions for patients with less uniform and possibly different characteristics. We therefore performed a study to compare the effectiveness of different statins and doses in routine clinical practice with respect to total serum cholesterol and LDL-cholesterol (LDL-C) reduction and goal attainment according to European guidelines on the prevention of cardiovascular disease (CVD).

Research design and methods: Naive statin users starting treatment in 2003 and 2004 with LDL-C measurements at baseline and between 30 and 365 days after start of treatment were extracted from the PHARMO database. During treatment with their initial statin dose LDL-C reduction and attainment of cholesterol goals were compared between different statins and doses.

Results: Of 2303 identified naive patients, approximately 30% were allocated to the high CVD-risk group. Average LDL-C reductions were 48%, 42%, 39%, and 32% at mean doses of 11 mg rosuvastatin, 17 mg atorvastatin, 22 mg simvastatin and 35 mg pravastatin, respectively. The proportion of patients attaining cholesterol goals was 75% for rosuvastatin, 68% for atorvastatin, 56% for simvastatin, and 42% for pravastatin. Dose comparisons showed greater LDL-C reduction and increased goal attainment for rosuvastatin 10 mg compared to other statins at most doses (adjusted p < 0.05).

Conclusions: In a real life setting, both LDL-C reduction and the proportion of patients attaining cholesterol goals appear to be significantly increased among users of rosuvastatin compared to other statins. These results confirm and extend reported clinical trial results to a real world setting.     

Cost-efficacy analysis of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors based on results of the STELLAR trial: clinical implications for therapeutic selection

STUDY OBJECTIVE: To compare the cost/1% reduction in low-density lipoprotein cholesterol (LDL) and the cost/patient achieving the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL goal based on the results of the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) trial. DESIGN: Cost-efficacy analysis. INTERVENTION: Investigators in the STELLAR trial evaluated percentage reductions in LDL and achievement of the ATP III LDL goal for various doses of atorvastatin, pravastatin, rosuvastatin, and simvastatin. We derived efficacy estimates for these four statins from the results of this trial. We also derived drug acquisition costs from the average wholesale prices to estimate the cost/1% reduction in LDL levels and the cost/patient achieving the ATP III LDL goal. MEASUREMENTS AND MAIN RESULTS: In the STELLAR trial, doses of rosuvastatin produced reductions in LDL significantly greater than those of equivalent milligram/milligram doses of atorvastatin, simvastatin, or pravastatin. The annual acquisition cost/percentage LDL reduction was lower with rosuvastatin at doses of 10 mg (20.92 dollars), 20 mg (18.28 dollars), and 40 mg (17.42 dollars) than with the other statins analyzed. Rosuvastatin also had a lower average cost/patient achieving the ATP III LDL goal over 6 weeks than that of the other statins. CONCLUSION: Although the long-term clinical benefits and safety data from the increased LDL reduction achieved with rosuvastatin remain uncertain, rosuvastatin may be the most cost-effective statin among those analyzed in terms of acquisition cost/1% reduction in LDL levels and in terms of patients achieving ATP III LDL goals. On the basis of the efficacy estimates from the STELLAR trial in conjunction with acquisition cost, a potential cost savings could be realized from the use of rosuvastatin.     

Attaining United Kingdom-European Atherosclerosis Society low-density lipoprotein cholesterol guideline target values in the Greek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study

The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study compared two standards (structured vs. usual care) of lipid lowering treatment in 1600 patients with coronary heart disease (CHD). Structured care aimed at achieving (with atorvastatin 10-80 mg) the low-density lipoprotein cholesterol (LDL-C) (2.6 mmol/l; 100 mg/dl) goal described in the NCEP ATP II and III guidelines for patients with CHD. Structured care was associated with a significant reduction in overall mortality and coronary events compared to usual care. In the present brief report we interpret the results of GREACE using the United Kingdom (UK) and European Atherosclerosis Society (EAS) treatment goal for LDL-C in secondary CHD prevention (3.0 mmol/l; 115 mg/dl. The mean dose of atorvastatin decreased from 24 mg to 22 mg/day. More patients achieved the UK and EAS LDL-C target (95.6 vs. 95%) in the structured care arm of the trial; 90% of the patients achieved this target with 10 or 20 mg atorvastatin. These findings may have cost implications, especially if the LDL-C target for high-risk patients will fall below those described above.     

Atorvastatin in prevention of stroke and transient ischaemic attack

Besides blood pressure-lowering drugs and, in certain circumstances, antithrombotic agents, statins are among the most effective drugs in reducing the risk of stroke in populations of patients at high vascular risk, as well as the risk of major coronary events. In secondary prevention of stroke, statins clearly reduced the risk of major coronary events. In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, compared with placebo, the patients with a recent stroke or transient ischaemic attack without coronary heart disease randomised to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke and a 35% reduction in the risk of major coronary events. This was obtained despite the fact that 25% of patients allocated to the placebo arm were prescribed a commercially available statin outside the trial. A post-hoc analysis used blinded low-density lipoprotein cholesterol (LDL-C) measurements (taken at study visits during the trial) as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-C (the group adherent to placebo or not taking a statin), the group with ≥ 50% reduction in LDL-C had a significant 31% reduction in the risk of stroke. The next step is to define whether or not achieving a LDL-C of < 70 mg/dl is better than a standard dose of statin (LDL ～ 100 – 110 mg/dl) in the secondary prevention of stroke. Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-C lowering.     

Atorvastatin in prevention of stroke and transient ischaemic attack

Besides blood pressure-lowering drugs and, in certain circumstances, antithrombotic agents, statins are among the most effective drugs in reducing the risk of stroke in populations of patients at high vascular risk, as well as the risk of major coronary events. In secondary prevention of stroke, statins clearly reduced the risk of major coronary events. In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, compared with placebo, the patients with a recent stroke or transient ischaemic attack without coronary heart disease randomised to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke and a 35% reduction in the risk of major coronary events. This was obtained despite the fact that 25% of patients allocated to the placebo arm were prescribed a commercially available statin outside the trial. A post-hoc analysis used blinded low-density lipoprotein cholesterol (LDL-C) measurements (taken at study visits during the trial) as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-C (the group adherent to placebo or not taking a statin), the group with >or= 50% reduction in LDL-C had a significant 31% reduction in the risk of stroke. The next step is to define whether or not achieving a LDL-C of < 70 mg/dl is better than a standard dose of statin (LDL approximately 100 - 110 mg/dl) in the secondary prevention of stroke. Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-C lowering.