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Class of 2013 Abstract / Specific Aims: To determine whether concurrent use of a proton pump inhibitor (PPI) and a bisphosphonate represent an additional fracture risk compared with bisphosphonate use alone and to identify an increased risk of any particular fracture type. Methods: This study was a systematic review and meta-analysis of data collected from PubMed, Cochrane, OVID Medline, Google Scholar, and IPA. The authors utilized the search terms: bisphosphonate, fractures and proton pump inhibitors. Studies which met criteria of being English-language with adults 18 years of age and older were included. Main Results: The studies were cohort studies and primarily evaluated older adults. The summary effect was that use of a PPI with a bisphosphonate showed a slight increase in fracture risk when compared to bisphosphonate-only therapy (odds ratio [OR] 1.12, 95% confidence interval [CI], 1.06-1.18). Systematic review of similar studies showed varied results, making difficult any conclusion regarding fracture risk among the treatments. Conclusion: In this analysis, PPI + bisphosphonate demonstrated a slight increase in fracture rate without inference to an increase in any particular fracture type compared with bisphosphonate only. However, there is minimal data on the association or causal effect of this increase. The few studies available offered contradictory results. Additionally, database studies are subject to the possibility of residual confounding. Further research using randomized control trial (RCT) design evaluating long term use of bisphosphonates with or without PPI and their impact on fractures is needed to determine if there is an additional degree of fracture risk from the concurrent use.

Introduction: Proton pump inhibitors (PPI) may impair the biotransformation of clopidogrel leading to increased major adverse cardiac events (MACE). Available studies have focused solely on patients receiving clopidogrel following a cardiac event. Given the widespread use of this combination, (about 64% in a recent study), this represents a major interaction that deserves further study. The objective of this thesis was to determine if the potential interaction between PPIs and clopidogrel leads to an increase in MACE in high-risk atherosclerotic patients receiving clopidogrel and PPIs as compared to clopidogrel alone. Methods: We conducted a retrospective chart review of patients in the University Hospital System who received clopidogrel between January 1, 2007 and April 30, 2009. Patients were included if they were hospitalized for acute coronary syndromes, stroke/TIA, revascularization (coronary, cerebral or peripheral arteries), or aspirin allergy. The primary outcome was the composite of myocardial infarction (MI), stroke/transient ischemic attack (TIA), coronary artery revascularization, or death (all cause) during the first year following discharge. Secondary outcomes included the composite of MI, stroke /TIA, revascularization (coronary, cerebral or peripheral arteries), or death. Bivariate analyses were conducted using Student’s t test, Mann Whitney U and Chi-square tests where appropriate. Multivariate analysis was conducted to adjust for baseline differences. Results: Overall, 1700 charts were reviewed and 572 patients met study criteria. The median follow-up was 332 days. The most common indication for clopidogrel use was coronary artery revascularization (66%). There were 201 patients in the clopidogrel with PPI group and 371 patients in the clopidogrel without PPI group. Baseline characteristics were evenly matched between both groups except for smoking, liver disease, and prior receipt of a PPI. The primary endpoint occurred in 21 patients in the clopidogrel with PPI group and 38 patients in the clopidogrel without PPI group (10% vs. 10%, p = 0.9, OR 1.02, 95% CI 0.58 – 1.80). The primary endpoint was unchanged after multivariate adjustments for baseline differences (adjusted OR 0.98, 95% CI 0.54 – 1.75). Likewise, there was no difference in the secondary endpoint (14% vs. 15%, p = 0.8, OR 1.02; 95% CI 0.58 – 1.80). The secondary endpoint was also unchanged after multivariate adjustments for baseline differences (adjusted OR 1.04, 95% CI (0.61 – 1.75) Conclusion: Patients receiving clopidogrel with a PPI demonstrated similar rates of MACE when compared to patients receiving clopidogrel without a PPI. / text

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This thesis examines strategies to address the inappropriate proton pump inhibitor (PPI) use. A scoping review was conducted to examine patient preferences and values towards PPI initiation and continued treatment, as well as their attitudes towards reducing PPI use (deprescribing). Symptom control (reflux, heartburn) was a driver for patients to seek treatment. Patients were concerned about symptoms returning if they reduced their PPI use but were interested in using less medication if possible. Patients were open to discussing PPI reduction and valued clear communication about rationale and potential benefits/harms. As such, shared and informed decision-making (including eliciting patient values) is important in the choice to continue a PPI or try deprescribing. A decision-support tool for clinicians, aimed at the decision to continue a PPI versus try deprescribing, was implemented over 12 months in one long-term care home in Ottawa. The tool led to a non-statistically significant decrease in PPI use after it was implemented, but PPI usage began to gradually increase after six months. Strategies to sustain use of deprescribing initiatives are needed. Finally, a consult patient decision aid (PtDA) was developed and piloted in three Ottawa area clinics, and aimed to facilitate shared decision-making surrounding the decision to continue or try to reduce a PPI during a healthcare visit. Based on a sample of 12 patients, the consult PtDA increased knowledge about the decision and increased decisional confidence. After receiving the consult PtDA, 8/12 (75%) patients chose to reduce their PPI use and 4/12 (25%) chose to continue their PPI.

Since their introduction in the late 1980s, proton pump inhibitors (PPI) have demonstrated gastric acid suppression superior to that of histamine H2-receptor blockers. This class of drugs has improved the treatment of various acid-peptic disorders, including gastroesophageal reflux disease, peptic ulcer disease, and nonsteroidal anti-inflammatory drug-induced gastropathy. PPIs have minimal side effects and few significant drug interactions. They are generally considered safe for long-term treatment. We present a rare side effect, acute pancreatitis, occurring in a patient who was treated with the proton pump inhibitor omeprazole.

Yes / Introduction As a consequence of the low cost and perceived safety, proton pump inhibitors (PPIs) are widely prescribed but they can cause longterm adverse effects and are often overprescribed. For most patients PPIs should not be continued long-term as patients can become dependent on PPIs and they are rarely stepped down/off treatment. We aimed to measure whether a dyspepsia review service could help patients on PPIs to step down/off treatment whilst still keeping them symptom free. Methods Pharmacists were provided with training on dyspepsia management. Four general practices were selected. Patients taking a PPI for more than two months were included. A list of exclusion criteria (e.g. active ulcers, newly initiated) was applied. Between six and eight dyspepsia review clinics were run at each site. Patients were booked into a 15-minute consultation. A concordance style consultation was held with clinicians providing information on dyspepsia management and exploring the patients’ ideas, concerns and expectations about stepping down or stepping off treatment. A follow-up audit was performed at four months to determine if patients had remained stepped down/off. An economic evaluation of clinic costs and drugs savings was performed. Results A total of 508 patients were invited to a review; 136 did not attend and 58 were excluded due to not meeting the inclusion criteria, leaving 314 patients reviewed for step-down/step-off. Successful step down/step off was achieved in 257 people (82% of those reviewed). The total cost savings of PPIs was £7,100. The additional cost of alginates was £1,207 giving a net saving on medicines of £5,893 per annum. Set-up costs were £1,194 and staff costs £3,524 to £5,156 giving total running costs, which vary dependent on the Agenda for Change (AfC) grade of pharmacist involved, of £4,720 - £6,351. Conclusion A dyspepsia review clinic is cost-neutral to run but, given that many patients are on polypharmacy, PPI step down might best be considered as part of a holistic medication review clinic. / Reckitt Benckiser, National Institute for Health Research, Health Education England

Abstract Background The South African Healthcare landscape has changed dramatically over the last two years with the implementation of mandatory substitution, single exit pricing and prescribed minimum benefits. The private market for medicines is becoming more competitive and commoditized. Between July 2004 and June 2005 there were 119 generic registrations at the Medicines Control Council. In the US and Canada research has been conducted on the change in prescribing behaviour induced through incentive based formularies and the impact of generic medicines on healthcare costs. This research protocol aims to build on this body of knowledge by analysing sales trends within a therapeutic class after the launch of a generic molecule in the same class. This research investigates how the introduction of generics may impact the growth of the innovator molecules and subsequent generics. The therapeutic class Acid Pump Inhibitors has been selected. Method Unit sales of Proton Pump Inhibitors are drawn monthly from sales in the total private market. They are then grouped by molecule and comparisons are drawn between the originator and it’s generic to determine association. This is also done at the aggregate level where the originators form one group and generics the second group. Each aggregate group’s average growth in the therapeutic class is then calculated to determine the aggregate group’s evolution index. Data Analysis Data is analysed through descriptive and interpretative statistics. The descriptive statistics establish a relationship between generisized molecules and the non generisized molecules. A t-test for two independent means is used to test the hypothesis that the non generisized molecules in the therapeutic class have a significant higher growth. Conclusion The results demonstrate that the number of units sold of the generisized molecules increase as they become more affordable, however contrary to intuition the number of iv units sold of the non generisized molecules also increase. The research shows that there is a statistically significant greater growth, albeit on a smaller base, of the non generisized molecules over generisized molecules.

Complex I (NADH:ubiquinone oxidoreductase), located in the mitochondrial inner membrane, is a major electron entry point to the respiratory chain. It couples the energy released from electron transfer (from NADH to ubiquinone) to the concomitant pumping of protons across the membrane, to generate an electrochemical proton motive force. Mammalian complex I is composed of 45 subunits, 14 of which comprise its simpler bacterial homologues. It is encoded by both the mitochondrial and nuclear genomes, and pathological mutations in both sets of subunits result in severe neuromuscular disorders such as Leigh syndrome. Several structures of mammalian complex I from various organisms have been determined, but the limited resolutions of the structures, which typically refer to poorly characterised enzyme states, has hampered detailed analyses of mechanistic features. The first part of this thesis describes development of a method for purifying complex I from the genetically amenable and medically relevant model organism Mus musculus (mouse), in a pure, stable and active state. The enzyme from mouse heart mitochondria was then comprehensively characterised, to ensure the presence of all the expected subunits and co-factors, and to define its kinetic properties. The second part of this thesis describes structural studies by single particle electron cryomicroscopy (cryo-EM) on the purified mouse enzyme in two distinct states, the 'active' and 'de-active' states. The active state was determined to 3.3 Å resolution, the highest resolution structure of a eukaryotic complex I so far. Subsequently, comparison of the two mouse structures, together with previously determined mammalian and bacterial structures, revealed variations in key structural elements in the membrane domain, which may be crucial for the catalytic mechanism. Moreover, in the high-resolution active mouse complex I structure a nucleotide co-factor was observed bound to the nucleoside kinase subunit NDUFA10. Finally, complex I from the Ndufs4 knockout mouse model, which recapitulates the effects of a human mutation that causes Leigh syndrome, was purified and subjected to kinetic and proteomic analyses. Following cross-linking and preliminary structural studies, it was concluded that the detrimental effects of deleting NDUFS4 are due to lack of stability of the mature complex.

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