Differences between statins on clinical endpoints: a population-based cohort study

OBJECTIVE: Many studies have shown differences between statins based on surrogate endpoints, but few have studied differences in reaching clinical endpoints.This study compares the risk of cardiovascular and cerebrovascular events between atorvastatin users and other statin users in daily general practice. RESEARCH DESIGN AND METHODS: A cohort study was performed in the Integrated Primary Care Information project database, a longitudinal general practice research database with electronic patient records of more than 500,000 individuals in The Netherlands. All new statin users in the period 1st September 1999 to 31st December 2002 were included. Multivariate Cox-regression analysis was used to compare the occurrence of the primary endpoint between atorvastatin users and other statin users. MAIN OUTCOME MEASURES: The primary endpoint was the composite outcome of fatal or non-fatal myocardial infarction, admission for unstable angina pectoris, fatal or non-fatal cerebrovascular accidents, or transient ischaemic events. RESULTS: 3499 new statin users were identified, including 797 patients with a history of cardiovascular disease. 1341 persons started with simvastatin (38.3%), 1154 with atorvastatin (33.0%), 811 with pravastatin (23.2%) and 193 with other statins (5.5%). The median follow-up was 1.9 years. Two hundred and thirty three patients (6.7%) experienced a primary endpoint. Atorvastatin users had a significantly lower risk of cardiovascular and cerebrovascular events than users of other statins (relative risk [RR]: 0.70, 95% confidence interval [CI]: 0.55-0.96). The relative risks of atorvastatin users compared to simvastatin and pravastatin users individually were 0.70 (95% CI: 0.48-1.02) and 0.78 (95% CI: 0.52-1.16), respectively. The protective effect of atorvastatin was more pronounced in persons without a history of cardiovascular or cerebrovascular events. CONCLUSION: Atorvastatin showed a more favourable effect on fatal and non-fatal cardiovascular and cerebrovascular events in the general population than other statins.     

Changes to the Statin Prescribing Policy in Belgium

Background and Objective New policies in Belgium encourage prescribing of generic HMG-CoA reductase inhibitors (statins), but may lead to non-equivalent switching of patients from more potent second generation statins, as has occurred elsewhere. We sought to assess the potential health economic impact of the new policies. Design This was a cost-effectiveness analysis Methods A Markov model was constructed to simulate the onset of cardiovascular disease (CVD) and death among a representative cohort of 80 Belgian patients initially free of CVD and taking atorvastatin. Cardiovascular risks were estimated from calibrated Framingham equations, and utilities and costs from published data. Decision analysis assessed the potential impact of switching all 80 patients to simvastatin. Changes in lipid levels expected to arise from switching were based on a published meta-analysis. Results If the 80 patients remained on atorvastatin, the model predicted that 23 (29%) would develop CVD over 20 years. If they were switched to simvastatin, the predicted number was 25 (31%), equating to a ‘number needed to harm’ of 52. Switching would lead to a net cost saving of € 131 (2012) per subject, but also a loss of 0.03 quality-adjusted life-years (QALYs) per subject. These equated to a decremental cost-effectiveness ratio of €4777 per QALY lost. Sensitivity analyses indicated this result to be robust. Conclusion Recently introduced statin prescribing policies in Belgium are likely, as intended, to reduce statin costs, but also increase the burden of CVD due to non-equivalent switching. It would be cost effective to maintain patients on atorvastatin for primary prevention rather than switch them to simvastatin.     

Persistence of atorvastatin and simvastatin among patients with and without prior cardiovascular diseases: a US managed care study

ABSTRACT

Background: In clinical practice, persistence with statin therapy is poor. While little is known about relative persistence to specific statins, previous studies have observed greater persistence in patients who achieve greater degrees of lipid lowering. Identification of statin therapies which improve patient persistence has the potential to improve the quality of patient care and clinical outcomes. Therefore, we assessed patient persistence with atorvastatin and simvastatin in primary and secondary prevention patients enrolled in managed care.

Methods: New statin users aged ≥18 years, both with and without prior cardiovascular (CV) events within the 12 month pre-treatment period, were identified from a large national database of managed care patients. Patients initiated atorvastatin or simvastatin therapy from January 1, 2003 to September 30, 2005 and were continuously enrolled in a covered plan for at least 12 months before and after initiation of statin therapy. Subanalyses of patients ≥65 years were also conducted. Measures of interest included demographic and clinical characteristics of the study samples and persistence of statin utilization over the 1-year follow-up period. Persistence was defined as the number of days a patient remained on treatment in the first year following their index date, measured from the date of first fill to study end or the date of discontinuation.

Results: A total of 129 764 atorvastatin users and 45 558 simvastatin users without prior CV events were included in the study. For those patients with prior CV events, a total of 6888 atorvastatin users and 4443 simvastatin users were included in the study. Median persistence in patients without prior CV events was 50 days longer for patients initiating therapy with atorvastatin than simvastatin (207 vs. 157 days, p < 0.0001) and after adjusting for confounding factors, those treated with atorvastatin were 15% less likely to discontinue therapy during the first year than those treated with simvastatin (HR = 0.85; 95% CI 0.84, 0.86; p < 0.001). In secondary prevention patients median persistence was 85 days longer in atorvastatin patients than simvastatin patients (266 vs. 181 days, p < 0.0001) and atorvastatin patients were 22% less likely to discontinue therapy (HR = 0.78; 95% CI 0.75, 0.82; p < 0.001). Persistence was worse in the elderly patients, but the relative difference between atorvastatin and simvastatin was similar to the overall patient population.

Conclusions: In patients with and without prior CV disease, persistence is generally poor, even worse in the elderly, but significantly better for atorvastatin patients than simvastatin patients (p < 0.001). Further studies are required to determine whether this is due to differences in cost, effectiveness, side-effects, or other attributes of the statins.

Study limitations: Differences in persistence could be, in part, due to unmeasured confounders although all available variables were adjusted in multivariate analyses. Additionally, the claims database lacks some clinical data such as lipid levels, limiting assessments of statin efficacy, and does not include any reasons for discontinuation of therapy.     

Suboptimal choices and dosing of statins at start of therapy

AIM: To assess dosing and determinants of the choice of statins among starters of statins. METHODS: Data were obtained from the PHARMO database comprising pharmacy and linked hospital discharge records of approximately 300 000 subjects in the Netherlands. All new users of statins in 1998 were selected. Patient characteristics and drug regimens were compared between starters of different statins. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using polytomous logistic regression modelling, using the start of simvastatin therapy as reference category. RESULTS: In 1998, 1738 patients started using simvastatin (41.1%), pravastatin (23.1%), fluvastatin (11.9%), atorvastatin (22.8%) or cerivastatin (1.0%). Compared with starters with simvastatin [mean dose 1.02 +/- 0.39 defined daily doses (DDDs)], starters with pravastatin (1.27 +/- 0.56 DDDs) and atorvastatin (1.43 +/- 0.59 DDDs) received higher doses (P < 0.001), whereas users of fluvastatin (0.78 +/- 0.37 DDDs) and cerivastatin (0.81 +/- 0.30 DDDs) received lower doses (P < 0.001). Patients already using CYP3A4 inhibitors more frequently received fluvastatin (OR = 1.80; 95% CI 1.11, 2.94), metabolized by non-CYP3A4 pathways, and atorvastatin (OR = 1.62; 95% CI 1.06, 2.47), which is metabolized by CYP3A4, than simvastatin. Statin doses were not adjusted when prescribed to patients using CYP3A4 inhibitors. CONCLUSIONS: Many patients starting statin therapy did not receive a statin of first choice. The coadministration of potentially interacting drugs may have led to a change in statin choice, but not in dosage lowering. These findings suggest that the quality of statin therapy could be improved.     

Differences between statins on clinical endpoints: a population-based cohort study

ABSTRACT

Objective: Many studies have shown differences between statins based on surrogate endpoints, but few have studied differences in reaching clinical endpoints.

This study compares the risk of cardiovascular and cerebrovascular events between atorvastatin users and other statin users in daily general practice.

Research design and methods: A cohort study was performed in the Integrated Primary Care Information project database, a longitudinal general practice research database with electronic patient records of more than 500?000 individuals in the Netherlands. All new statin users in the period 1st September 1999 to 31st December 2002 were included. Multivariate Cox-regression analysis was used to compare the occurrence of the primary endpoint between atorvastatin users and other statin users.

Main outcome measures: The primary endpoint was the composite outcome of fatal or non-fatal myocardial infarction, admission for unstable angina pectoris, fatal or non-fatal cerebrovascular accidents, or transient ischaemic events.

Results: 3499 new statin users were identified, including 797 patients with a history of cardiovascular disease. 1341 persons started with simvastatin (38.3%), 1154 with atorvastatin (33.0%), 811 with pravastatin (23.2%) and 193 with other statins (5.5%). The median follow-up was 1.9 years. Two hundred and thirty three patients (6.7%) experienced a primary endpoint. Atorvastatin users had a significantly lower risk of cardiovascular and cerebrovascular events than users of other statins (relative risk [RR]: 0.70, 95% confidence interval [CI]: 0.55–0.96). The relative risks of atorvastatin users compared to simvastatin and pravastatin users individually were 0.70 (95% CI: 0.48–1.02) and 0.78 (95% CI: 0.52–1.16), respectively. The protective effect of atorvastatin was more pronounced in persons without a history of cardiovascular or cerebrovascular events.

Conclusion: Atorvastatin showed a more favourable effect on fatal and non-fatal cardiovascular and cerebrovascular events in the general population than other statins.     

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.     

Society already achieves economic benefits from generic substitution but fails to do the same for therapeutic substitution

AIMS: To assess the potential annual savings due to generic and therapeutic substitution of statin therapy for the general Dutch population, taking the patients medical history into account. METHODS: We conducted a population-based costing study using the PHARMO Record Linkage System (RLS). PHARMO RLS contains drug dispensing records from a representative sample of pharmacies located in more than 50 regions in the Netherlands. We selected all statin users in the database since 2003. The cost-savings of generic substitution of statin therapy for all simvastatin and pravastatin users, and of therapeutic substitution of statin therapy for other statin users were calculated. Substituting current users and new users of statins were considered separately. Therapeutic substitution was based on the medical history of the individual patient. Patients were only substituted if there was an appropriate substitute available. The appropriateness of substitution was based on drug-drug interactions between statins and possible comedication and the availability of an equipotent alternative. RESULTS: Substituting (generic and therapeutic) statin therapy for all current users would lead to potential annual savings of approximately 87 million euros. Substituting (generic and therapeutic) all starters on statin therapy would lead to potential annual savings of around 51 million euros. In the case of generic substitution only, the potential annual savings for all current simvastatin and pravastatin users would be 2.4 million euros and for the new users about 1.8 million euros. CONCLUSIONS: From an economic point of view, society could gain a lot from substituting statin therapy, especially from therapeutic substitution.     

Implementation of a therapeutic-interchange clinic for HMG-CoA reductase inhibitors.

A therapeutic-interchange clinic for statins is described. In 1999, the Department of Defense mandated the use of cerivastatin and simvastatin as the formulary statins in all military health care facilities by April 2000. Cerivastatin was the preferred agent; the goal was to use this agent in 60-65% of all patients. Walter Reed Army Medical Center developed a voluntary therapeutic-interchange clinic for patients receiving statins. Goals included facilitating the rapid switching of patients to the formulary statins, maximizing the use of the preferred agent, maintaining or improving lipid control, monitoring safety, determining costs, educating patients about their treatment, and documenting satisfaction with the clinic. Written educational materials were prepared, an algorithm for statin conversion was created, and laboratory tests were performed, among other measures. Between January and April 2000, 1356 patients were seen by the therapeutic-interchange clinic; of these, 942 agreed to have the efficacy and safety of their therapy monitored by the clinic. Before the formulary change, the most commonly prescribed statins were atorvastatin (44% of patients) and pravastatin (42%). Under the conversion policy, 96% of patients received cerivastatin and 4% simvastatin. The percentage of patients achieving their targeted low-density-lipoprotein cholesterol concentration increased from 65% to 75%. The policy saved an average of $115 per patient in the first year. Most patients were satisfied with the clinic, but only 36% of providers were satisfied. Cerivastatin was withdrawn from the market in August 2001; simvastatin became the only formulary statin. A therapeutic-interchange clinic at a military medical center provided an efficient means of switching a large number of patients to alternative statin therapy, monitoring the outcomes, and individualizing patient care.     

Lipid-lowering drug use in Italian primary care: effects of reimbursement criteria revision

Objective To assess whether the prescribing pattern of lipid-lowering drugs (LLD) changed after reimbursement criteria revision in a general practice in southern Italy. Methods From the Caserta-1 Local Health Service database, 93 general practitioners (GPs) who had consistently sent data about their patients during the years 2003-2005 were recruited. Prevalence of use and incidence of new treatments were calculated for each year, stratified by three drug cohorts: statins, omega-3 fatty acids, and fibrates. Subanalyses by gender, age, and indication of use were performed. Results Overall, 1-year prevalence of LLD use increased from 2003 to 2004. After reimbursement criteria revision (November 2004), a slight decrease was observed for statins, from 41.1 (95% CI: 39.9–42.2) per 1,000 inhabitants in 2004 to 40.3 (39.2–41.5) in 2005, while omega-3 utilization fell markedly: 14.6 (13.9–15.3) vs. 5.4 (5.0–5.8). The use of both statins and omega-3 fatty acids was reduced particularly for primary prevention. On the other hand, utilization of statins increased in diabetic patients and as secondary prevention from 2004 to 2005. Concerning individual molecules, 1-year prevalence of use of any statin declined from 2004 to 2005, except for rosuvastatin. Conclusions Revision of reimbursement criteria led to significant changes in the trend in LLD use in general practice in southern Italy: (1) statin utilization was slightly reduced in 2005, although it increased in certain categories, such as diabetic patients, and (2) omega-3 fatty acid use was strongly reduced even though a higher use in post-infarction cases was reported.     

基于层次分析法合理选择他汀类药物

目的基于最高的性价比选择他汀类药物。方法在调脂强度达标的范围内,基于层次分析法构建评价指标体系,确定减低LDL-C强度和价格为评价指标,设计问卷调查表确定个体化的评价指标权重,使用matlab软件进行矩阵计算,根据结果选择最适合患者长期治疗的性价比最高的他汀类药物。结果根据患者调脂目标及经济能力合理选择他汀,如更关注药物的调脂强度,则依次选择阿托伐他汀40mg,瑞舒伐他汀10mg,阿托伐他汀20mg,辛伐他汀20mg,阿托伐他汀10mg,辛伐他汀40mg,氟伐他汀80mg,普伐他汀80mg及普伐他汀40mg。如更加关注价格,依次选择辛伐他汀20mg,阿托伐他汀10mg,氟伐他汀80mg,辛伐他汀40mg,瑞舒伐他汀10mg,阿托伐他汀20mg,普伐他汀40mg,阿托伐他汀40mg及普伐他汀80mg。如药物的调脂强度和价格同等重要,则依次选择辛伐他汀20mg,阿托伐他汀10mg,氟伐他汀80mg,辛伐他汀40mg,瑞舒伐他汀10mg,阿托伐他汀20mg,阿托伐他汀40mg,普伐他汀40mg及普伐他汀80mg。结论在调脂强度达标的范围内,可以通过层次分析法获得最适合患者的性价比最高的他汀类药物。     

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.     

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.