Quality and efficiency of statin prescribing across countries with a special focus on South Africa : findings and future implications

Statins are recommended first-line treatment for hyperlipidemia, with published studies suggesting limited differences between them. However, there are reports of under-dosing. South Africa has introduced measures to enhance generic utilization. Part one documents prescribed doses of statins in 2011. Part two determines the extent of generics versus originator and single-sourced statins in 2011 and their costs. Results: Underdosing of simvastatin in 2011 with average prescribed dose of 23.7 mg; however, not for atorvastatin (20.91 mg) or rosuvastatin (15.02 mg). High utilization of generics versus originators at 93–99% for atorvastatin and simvastatin, with limited utilization of single-sourced statins (22% of total statins – defined daily dose basis), mirroring Netherlands, Sweden and UK. Generics priced 33–51% below originator prices. Discussion: Opportunity to increase simvastatin dosing through education, prescribing targets and incentives. Opportunity to lower generic prices with generic simvastatin 96–98% below single-sourced prices in some European countries

Did we see it coming? An evaluation of the Swedish early awareness and alert system

Early awareness and alert (EAA) systems have been established in many countries but evidence on their ability to accurately prioritize new medicines (for early assessment) is limited. The purpose of this study is to assess whether the Swedish EAA System identified and prioritized (i.e. produced early assessment reports for) new medicines that would go on to have a substantial economic impact. Methods We adapted a study design commonly used in the assessment of diagnostic test accuracy. The prioritization made by the Swedish EAA System prior to marketing authorization comprised the index test and national drug sales data in the second year post-authorization served as the reference standard. All initial marketing authorization applications for medicinal products processed by the European Medicines Agency (EMA) between 2010 and 2015 (study population) were classified using the index test and the reference standard. Results Two hundred and fifty-three new medicinal products processed by EMA comprised the study population. Of these, 71 were prioritized by the Swedish EAA System and 21 were classified as having a substantial economic impact. The sensitivity and positive predictive value were 76.2% and 22.5%, respectively. Subgroup analyses showed that the accuracy of prioritization, in terms of sensitivity, was 100% for antineoplastic/immunomodulating agents. Conclusions The Swedish EAA System identified all new medicines that would go on to have a substantial economic impact and prioritized most of these medicines. Our findings provide reassurance to decision makers who rely on the outputs of the Swedish EAA System to keep informed about new medicines. Moreover, this study also provides valuable insights to stakeholders willing to establish and/or evaluate their own EAA activities and systems

Measures to enhance angiotensin-receptor blocker prescribing efficiency in Belgium following generic losartan: impact and implications for the future

Objective: Compare the utilisation of losartan before and after the availability of generics in Belgium and its inclusion in the reference price system, which changed its reimbursement status. Determine the impact of reforms on expenditure/defined daily dose (DDD) for losartan and overall reimbursed expenditure for the angiotensin-receptor blockers (ARBs). Methods: Interrupted time-series analysis of monthly reimbursed prescriptions was used for all patients in Belgium covered by the social health insurance system prescribed an ARB alone or in combination between January 2007 and August 2011; that is, 42 months before generic losartan was included in the reference price system (July 2010) to 13 months after. Key findings: A significant increase in losartan utilisation was seen following its change in reimbursement status whereas all other ARBs still required prior approval for reimbursement. Losartan utilisation increased from 18% of all single ARBs on a moving annual total (MAT) DDD basis just before the inclusion of losartan in the reference price system to 24% on a MAT basis 12 months after this. During this period, total ARB utilisation increased by 1%, consequently representing both new and switched patients. Reimbursed expenditure for losartan decreased 40% 12 months after its inclusion in the reference price system despite a 22% increase in utilisation. Total ARB expenditure reduced by 15% during this period. Conclusion: The reforms, including altering the prescribing regulations for losartan, significantly enhanced its utilisation, reduced its expenditure/DDD and reduced overall ARB expenditure in Belgium. No further measures are suggested for Belgium with more ARBs losing or about to lose their patents. There has been no change in the utilisation patterns of losartan in countries following generic availability where there are no specific demand-side measures. These findings confirm that multiple measures are needed to change physician prescribing patterns

Improving the managed introduction of new medicines : sharing experiences to aid authorities across Europe

The 3-day course on the managed introduction of new drugs was organised by the Piperska group together with the Agency for Health Technology Assessment and Tariff System (AOTMiT) and WHO Europe to share experiences and case histories among health authority and health insurance company personnel, academics and those from commercial organisations from across Europe on potential ways to optimise the managed entry of new medicines. This starts pre-launch with horizon scanning and budgeting, then peri-launch including critical drug evaluation, and finally post launch including monitoring prescribing of new medicines against agreed guidance and indicators. There were also discussions on issues regarding managed entry schemes and procurement strategies including biosimilars

Policies to Enhance Prescribing Efficiency in Europe: Findings and Future Implications

Introduction: European countries need to learn from each other to address unsustainable increases in pharmaceutical expenditures. Objective: To assess the influence of the many supply and demand-side initiatives introduced across Europe to enhance prescribing efficiency in ambulatory care. As a result provide future guidance to countries. Methods: Cross national retrospective observational study of utilization (DDDs – defined daily doses) and expenditure (Euros and local currency) of proton pump inhibitors (PPIs) and statins among 19 European countries and regions principally from 2001 to 2007. Demand-side measures categorized under the “4Es” – education engineering, economics, and enforcement. Results: Instigating supply side initiatives to lower the price of generics combined with demand-side measures to enhance their prescribing is important to maximize prescribing efficiency. Just addressing one component will limit potential efficiency gains. The influence of demand-side reforms appears additive, with multiple initiatives typically having a greater influence on increasing prescribing efficiency than single measures apart from potentially “enforcement.” There are also appreciable differences in expenditure (€/1000 inhabitants/year) between countries. Countries that have not introduced multiple demand side measures to counteract commercial pressures to enhance the prescribing of generics have seen considerably higher expenditures than those that have instigated a range of measures. Conclusions: There are considerable opportunities for European countries to enhance their prescribing efficiency, with countries already learning from each other. The 4E methodology allows European countries to concisely capture the range of current demand-side measures and plan for the future knowing that initiatives can be additive to further enhance their prescribing efficiency

Are new models needed to optimize the utilization of new medicines to sustain healthcare systems?

Medicines have made an appreciable contribution to improving health. However, even high-income countries are struggling to fund new premium-priced medicines. This will grow necessitating the development of new models to optimize their use. The objective is to review case histories among health authorities to improve the utilization and expenditure on new medicines. Subsequently, use these to develop exemplar models and outline their implications. A number of issues and challenges were identified from the case histories. These included the low number of new medicines seen as innovative alongside increasing requested prices for their reimbursement, especially for oncology, orphan diseases, diabetes and HCV. Proposed models center on the three pillars of pre-, peri- and post-launch including critical drug evaluation, as well as multi-criteria models for valuing medicines for orphan diseases alongside potentially capping pharmaceutical expenditure. In conclusion, the proposed models involving all key stakeholder groups are critical for the sustainability of healthcare systems or enhancing universal access. The models should help stimulate debate as well as restore trust between key stakeholder groups

Generic pregabalin : current situation and implications for health authorities, generics and biosimilars manufacturers in the future

The manufacturer of pregabalin has a second use patent covering prescribing for neuropathic pain: its principal indication. The manufacturer has threatened legal action in the UK if generic pregabalin rather than Lyrica is prescribed for this indication. No problems exist for practitioners who prescribe pregabalin for epilepsy or generalized anxiety disorder. This has serious implications for health authorities. In Germany, however, generics could be legally prescribed for any approved indication once one indication loses its patent. We aim to establish the current situation with pregabalin among principally European countries. Personnel from 33 regional and national health authorities mainly from Europe, and nine from universities across Europe working as advisers to health authorities or with insight into their activities, were surveyed regarding four specific questions via email to shed light on the current situation with Lyrica and pregabalin in their country. The information collated from each country was subsequently checked for accuracy with each co-author by email and face-to-face contact and collated into five tables. The scenarios ranged from extending the patent life of Lyrica (e.g. France), endorsing the prescribing of Lyrica for neuropathic pain (e.g. Catalonia and South Korea), and current prescribing of pregabablin for all indications (e.g. Serbia and Germany). Little activity has taken place in European countries in which generic pregabalin is not yet reimbursed. The availability of generic pregabalin has prompted a number of different activities to be undertaken among the 33 countries and regions surveyed. The situation in Serbia and the historic situation in Germany provide examples of ways to maximize savings once a product loses its patent for at least one indication

Neuropeptide Y Y1 receptor mechanisms in sympathetic vascular control

Neuropeptide Y Yl receptor mechanisms in sympathetic vascular control. By Rickard E. Malmström, 1997. Department of Physiology and Pharmacology, Karolinska Institute, S- 17177 Stockholm, Sweden. It was demonstrated that the Y1 receptor was the predominant vascular neuropeptide Y (NPY) receptor in pig kidney and hind limb as exogenous and endogenous NPY evoked vasoconstrictor responses that were almost or totally abolished by the selective non-peptide Y1 receptor antagonist, BIBP 3226. Furthermore, renal vasoeonstriction was evoked by NPY and a peptide Y1 agonist, but not by a Y 2 agonist, and these responses were strongly reduced by another non-peptide Y, receptor antagonist, SR 120107A. Moreover, expression of Y1 receptors in pig kidney and renal arteries was indicated by reverse transcriptase-polymerase chain reaction (RT PCR) and mRNA for Y1 receptors was detected in small intrarenal arteries with in situ hybridization. The NPY receptor population in the pig spleen seems to consist of both Y1 and Y2 receptors, since peptide agonists with preference for either subtype evoked splenic vasoeonstriction. Splenic vasoconstriction evoked by the Y1 agonist was markedly reduced by SR 120107A. RT-PCR indicated expression of both Y1 and Y2 receptors in pig spleen and the existence of splenic Y2 receptors was also demonstrated with membrane and autoradiograpbic receptor binding. The predominant NPY receptor in both dog spleen and kidney is the Y1 receptor as demonstrated by in vivo studies, RT-PCR and reeeptor binding. The Y1-selectivity of SR 120107A was demonstrated by the fact that the compound displaced binding of an iodinated Y1, but not Y2, reeeptor ligand from membranes and sections of pig and dog spleen. Moreover, both SR 120107A and BIBP 3226 potently displaced tritiated BIBP 3226 binding from Y1 receptors in dog spleen. Increasing concentrations of BIBP 3226 caused a rightward shift in the concentration-response curves to NPY without influencing the maximal NPY-evoked contraction in guinea-pig vena cava. The antagonism appeared competitive as the slope (0.84) of the Schild plot was not significantly different from unity, with a pA2 value of 8.0. SR 120107A appeared as effective as BIBP 3226 in antagonizing NPY-evoked contractions in this vessel. SR 120107A potently inhibited Y1 receptor mediated vasoconstriction in the pig in vivo, without influencing vascular responses exerted via Y2, a, P2X1 and angiotensin II reeeptors. In addition, the Y, receptor antagonism of SR 120107A was of long (>3h) duration in vivo. BIBP 3226 exerted dose-dependent and equal antagonism on vascular responses to both endogenous and exogenous NPY in the pig in vivo. The elimination of BIBP 3226 from plasma fit a two-compartment model with half-lives of 2 and 20 min for the A- and B- phase, respectively. The final pharmacological evidenee for NPY as a mediator of sympathetic vasoeonstrietion was presented. Thus, neurogenically released NPY mediates long-lasting contraction of the guinea-pig caval vein in vitro, as shown by the inhibitory effects of both BIBP 3226 and SR 120107A. In the presence of either antagonist, only an initial rapid adrenergic phase of contraction remained upon high frequency transmural electrical field stimulation in this vessel. The neurogenic contractions were largely unaffected by the S-enantiomer to BIBP 3226, BIBP 3435, which is virtually inactive on Y1 receptors. Evidence was also presented for the involvement of NPY in nonadrenergic sympathetic vasoconstriction evoked in the reserpine-treated pig in vivo. Thus, SR 120107A strongly reduced the long-lasting phase of vasoconstriction evoked in nasal mucosa and hind limb by high frequency sympathetic nerve stimulation, leaving merely an initial rapid phase of constnction. Furthermore, the reserpine-resistant sympathetic vasoconstrietion in pig kidney was almost abolished by SR 120107A, whereas both the peak and duration of this response were redueed in the spleen. In eontrast, the role of NPY in sympathetie vaseular control is less obvious in the control pig, in which noradrenaline (NA) levels are intact and the NPY release is smaller due to prejunctional a2-reeeptor regulation. Reperfusion after two h of renal isehaemia was associated with venous overflow of NA, but not of NPY-like immunoreaetivhy (Ll). In addition, the renal sympathetic nerve-evoked overflow of NA, but not of NPY-LI, was reduced in parallel with reduced renal vasoconstnctor responses to nerve activation and exogenous agonists. The vascular responses as well as the nerve-evoked overflow of NA were partially restored a further two h after reperfusion. No overflow of either NA or NPY-LI was seen upon reperfusion after 15 min of renal ischaemia but an enhanced overflow of NPY-LI, but not NA, was observed upon sympathetic nerve stimulation and this was paralleled by an augmented vasoconstnctor response that in turn was significantly inhibited by BIBP 3226. Furthermore, the renal vasoconstrictor response to Y, receptor activation by exogenous agonists was markedly prolonged after 15 min ischaemia and this prolonged response was nearly abolished by BIBP 3226. These results suggest that, presumably due to an impaired local degradation, the role of neurogenically released NPY in renal sympathetic vasoconstriction is enhanced after short-term ischaemia compared to control conditions. It is concluded that NPY may serve as a sympathetic mediator of vasoconstriction, preferentially acting on the Y1 receptor. The role of NPY in sympathetic vascular control is enhanced after reserpine treatment and short-term ischaemia, but is less obvious in the control situation. Furthermore, BIBP 3226 and SR 120107A are selective Y, receptor antagonists both in vitro and in vivo. Key words: Sympathetic vasoconstriction, neuropeptide Y1 Y, receptor antagonists, BIBP 3226, SR 120107A, ischaemia, pig. ISBN 91-628-2527-

Biological Variation in Rotational Thromboelastometry in Patients with Atrial Fibrillation Receiving Rivaroxaban

Rotational thromboelastometry (ROTEM) is a viscoelastic hemostasis test used primarily in the management of bleeding after trauma or in cardiac surgery. To allow safe and valid clinical interpretation of test results, objective specifications for analytical performance are needed, which are generally based on biological variation within (CVI) and between (CVG) individuals. The aim of this study was to evaluate biological variation in ROTEM in patients receiving rivaroxaban. Sixty patients with atrial fibrillation on stable rivaroxaban therapy were included, from whom blood was collected on six occasions: three times at trough and three at peak rivaroxaban concentrations. ROTEM® Extem and LowTF were measured as well as rivaroxaban concentration, PT, APTT, and anti-Xa. Within- (CVI) and between-subject (CVG) biological estimates were calculated. Knowledge of these biological variation components will help to establish the appropriate objective analytical performance specifications for ROTEM analysis