Opportunities to Improve Awareness of Antimicrobial Resistance Through Social Marketing: A Systematic Review of Interventions Targeting Parents and Children.

Lack of knowledge from parents concerning the appropriate use of antimicrobials leads to poor treatment choices and mismanagement of antimicrobials for their children. Social marketing (SM) strategies have the potential to help parents access useful information on the appropriate use of antimicrobials. Still, its application in interventions targeting antimicrobial/antibiotic resistance awareness is minimal. This study explores the use of SM in antimicrobial/antibiotic awareness campaigns (AACs) to identify opportunities for SM approaches in developing future communication interventions targeting parents and children. We conduct a systematic review of interventions targeting parents and children between 2000 and 2022. Articles meeting the selection criteria were assessed against social marketing benchmark criteria (SMBC). We identified 6978 original records, 16 of which were included in the final review. None of the articles explicitly identified SM as part of their interventions. Twelve interventions (75%) included 1 to 4 (out of 8) benchmark criteria, while four (25%) had 5-8 benchmarks in their interventions. Of the interventions with less than four benchmark criteria, six studies (50%) reported a positive effect direction outcome, and six studies (50%) reported negative/no change direction on the outcome of interests. Meanwhile, all interventions with five or more SMBC resulted in a positive effect direction in their outcomes. In this review, the use of SM has shown promising results, indicating opportunities for future antimicrobial resistance (AMR) interventions that incorporate social marketing benchmark criteria to improve intervention outcomes.

Changes in parental anxiety and intention to demand antibiotics: A longitudinal study among parents during the COVID-19 pandemic.

AIMS: Assessing the effects of the COVID-19 pandemic on parental anxiety and preferences for antibiotic treatment can help inform antibiotic stewardship strategies. Therefore, this study aimed to examine COVID-19 pandemic-related changes in parental anxiety levels, their intentions to demand antibiotics and frequencies of practising preventative behaviours. DESIGN: This longitudinal quantitative study compared two groups of parents, those from Victoria and Western Australia, who experienced high and low COVID-19 risk, respectively. METHODS: Participants were recruited through an online panel to complete three waves of surveys between October 2020 and August 2021. Anxiety scores and frequency of preventative behaviours were analysed using mixed-effects tobit regression, considering time, state, and their interaction as fixed effects predictors. Intention to demand antibiotics was modelled using multinomial logistic regression, with time, state, and their interaction as the predictors. RESULTS: The final longitudinal sample comprised 50 participants from Victoria and 51 from Western Australia. Parental anxiety did not significantly change over time for either state. Intention to demand antibiotics was also stable over time within each state; however, participants from Victoria exhibited stronger intentions to demand antibiotics compared to those from Western Australia. Frequencies of parental preventative behaviours declined from Wave 1 to Wave 2 before increasing again in Wave 3, but only for Western Australia. CONCLUSION: This longitudinal study among Australian parents found stable parental anxiety and intention to demand antibiotics within each state. However, the intention to demand antibiotics and preventative behaviours varied between states as per the COVID-19 risk. Thus, viral pandemics may not affect judicious antibiotic use, though the intention to demand antibiotics may increase in states with high COVID-19 risk. IMPACT: Though parental anxiety may not impact antibiotic stewardship during viral respiratory illness outbreaks, tailored messaging to maintain appropriate antibiotic use may be necessary, especially when the disease risk is high.

Identifying Patients With Cirrhosis Who Might Avoid Screening Endoscopy Based on Serum Albumin and Bilirubin and Platelet Counts.

The presence of gastroesophageal varices is a major complication of portal hypertension associated with significant morbidity and mortality.1 The Baveno VI criteria state that patients with liver stiffness measurement (LSM) <20 kPa by transient elastography (TE) and platelet count >150,000/µL can avoid screening endoscopy for high-risk varix (HRV).2 However, because TE is not widely available, the Baveno VI criteria could not be applied in many clinical settings. As such, we aim to determine a concise clinical criterion as an alternative noninvasive tool to predict absence of HRV among patients with compensated cirrhosis to avoid screening esophagogastroduodenoscopy (EGD).

Durability of glycaemic control with dapagliflozin, an SGLT2 inhibitor, compared with saxagliptin, a DPP4 inhibitor, in patients with inadequately controlled type 2 diabetes.

Dapagliflozin is associated with greater reductions in HbA1c and weight than saxagliptin in management of type 2 diabetes mellitus (T2DM). The present post hoc analyses compared the durability of these effects over short- and long-term follow-up in patients with T2DM who were inadequately controlled with metformin (≥1500 mg/day) and who were receiving either dapagliflozin (10 mg/day) or saxagliptin (5 mg/day). Failure of glycaemiccontrol was assessed using the slope of the change in HbA1c from baseline-over-time regression line (coefficient of failure [CoF]). CoF was compared directly (dapagliflozin vs saxagliptin) over the short term (NCT01606007, 24 weeks) and indirectly (placebo-adjusted) over the long term (NCT00528879 and NCT00121667, 102 weeks). A low CoF value indicated greater durability. CoF was lower for dapagliflozin versus saxagliptin over 18-24 weeks (-1.38%/year; 95% CI, -2.41 to -0.35; P = .009) and 20-102 weeks (-0.37%/year; 95% CI, -0.73 to -0.02; P = .04). Fewer dapagliflozin-treated patients versus saxagliptin-treated patients required rescue medication or discontinued the study because of failure to achieve glycaemic control at 24 weeks (3.4% vs 9.4%; P = .0191). In patients with T2DM who were inadequately controlled with metformin, dapagliflozin was associated with greater durability of glycaemic control than saxagliptin over 18-24 and 20-102 weeks.

Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin and simvastatin acid in Caucasian and Asian subjects: a class effect?

PURPOSE: Systemic exposure to rosuvastatin is approximately double that of Caucasians in Asian subjects. We investigated whether this pattern of increased exposure exists for other statins. METHODS: Plasma exposure following single-dose rosuvastatin 20 mg, atorvastatin 40 mg or simvastatin 40 mg was studied in Chinese, Japanese and Caucasian subjects. Plasma concentrations were determined using LC-MS methods. Impact of polymorphisms in SLCO1B1 (T521>C and A388>G) and in ABCG2 (C421>A) on exposure to rosuvastatin, atorvastatin, simvastatin and simvastatin acid was assessed. RESULTS: Relative to Caucasians, geometric mean area under the curve from time zero to time of last quantifiable concentration was 86 % (90 % confidence interval (CI), 51-130 %) and 55 % (26-91 %) higher for rosuvastatin in Chinese and Japanese subjects, respectively, 53 % (25-88 %) and 69 % (37-108 %) higher for atorvastatin, 23 % (0-52 %) and 12 % (-0.9-39 %) higher for simvastatin and 28 % (5-56 %) and 34 % (10-64 %) higher for simvastatin acid. Geometric mean maximum drug concentration was also proportionally higher for each statin. Polymorphisms in SLCO1B1 T521>C or ABCG2 C421>A were associated with higher exposure to rosuvastatin, atorvastatin and simvastatin acid (but not simvastatin) within a population, but only the ABCG2 C421>A polymorphism contributed towards between-population exposure differences. In individuals carrying wild-type alleles for both SLCO1B1 and ABCG2, area under the plasma concentration-time curve (AUC) still appeared to be higher for rosuvastatin, atorvastatin and simvastatin acid in Chinese and Japanese subjects compared with Caucasians, respectively. CONCLUSION: Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.

Does antibiotic awareness campaigns exposure decrease intention to demand antibiotic treatment? Testing a structural model among parents in Western Australia.

Antimicrobial resistance (AMR) is one of the key public health concerns the world is facing today. The effect of antibiotic awareness campaigns (AACs) on consumer behaviour has been documented in the literature with mixed results. Understanding the mechanism for how AACs affect target populations is vital in designing effective and tailored campaigns. Using structural equation modelling our study examined the relationships among people's exposure to antibiotic awareness campaigns, knowledge of AMR prevention, AMR risk perception, and intention to seek antibiotic treatment. This study also tested the moderating effect of anxiety and societal responsibility on preventing AMR, and on their intention to demand antibiotic treatment mediated by knowledge of AMR prevention and risk-perception. Primary data was generated using an online survey of 250 Western Australian parents. We tested our hypotheses using reliability and validity tests and structural equation modelling. Our results show that exposure to AACs alone may not be enough to change parental intention to demand antibiotic prescription for their children. Parental risk perception of AMR and parental anxiety affect intention to demand antibiotics, and the view that AMR is a social responsibility has a moderating effect on intention to demand antibiotics. These factors could be considered and combine messaging strategies in designing future antibiotic awareness campaigns.

Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study.

BACKGROUND: The antiplatelet effects of the Platelet Inhibition and Patient Outcomes (PLATO) trial dose of ticagrelor in patients nonresponsive to clopidogrel and after they switch agents are unknown. METHODS AND RESULTS: Patients with stable coronary artery disease on aspirin therapy received a 300-mg clopidogrel load; nonresponders were identified by light transmittance aggregometry. In a 2-way crossover design, nonresponders (n=41) and responders (n=57) randomly received clopidogrel (600 mg/75 mg once daily) or ticagrelor (180 mg/90 mg twice daily) for 14 days during period 1. In period 2, all nonresponders switched treatment; half of the responders continued the same treatment, whereas the others switched treatment. Inhibition of platelet aggregation was higher in nonresponders treated with ticagrelor compared with clopidogrel (P<0.05). Treatment with ticagrelor among nonresponders resulted in a >10%, >30%, and >50% decrease in platelet aggregation from baseline in 100%, 75%, and 13% of patients, respectively. Platelet aggregation fell from 59+/-9% to 35+/-11% in patients switched from clopidogrel to ticagrelor and increased from 36+/-14% to 56+/-9% in patients switched from ticagrelor to clopidogrel (P<0.0001 for both). Platelet reactivity was below the cut points previously associated with ischemic risk measured by light transmittance aggregometry, VerifyNow P2Y(12) assay, and vasodilator-stimulated phosphoprotein phosphorylation in 98% to 100% of patients after ticagrelor therapy versus 44% to 76% of patients after clopidogrel therapy. CONCLUSIONS: Ticagrelor therapy overcomes nonresponsiveness to clopidogrel, and its antiplatelet effect is the same in responders and nonresponders. Nearly all clopidogrel nonresponders and responders treated with ticagrelor will have platelet reactivity below the cut points associated with ischemic risk. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00642811.

The effect of ticagrelor versus clopidogrel on high on-treatment platelet reactivity: combined analysis of the ONSET/OFFSET and RESPOND studies.

OBJECTIVES: The objective of the study was to determine the prevalence of high on-treatment platelet reactivity (HPR) in coronary artery disease patients enrolled in the ONSET/OFFSET and RESPOND studies. BACKGROUND: HPR has been linked to the occurrence of adverse events after stenting in patients treated with clopidogrel (C) and aspirin. Prevalence of HPR after treatment with ticagrelor (T), a reversible oral P2Y(12) receptor antagonist developed to overcome the limitations of C, is unknown. METHODS: Patients were treated with T (n = 106) or C (n = 103) on top of aspirin therapy. HPR was defined by published cutoff points associated with post-percutaneous coronary intervention ischemic risk: >59% 20 µM adenosine diphosphate-induced aggregation (light transmittance aggregometry), >235 P2Y12 reaction unit by VerifyNow P2Y(12) assay (VerifyNow, San Diego, CA), and >50% platelet reactivity index by vasodilator-stimulated phosphoprotein phosphorylation assay (VASP-P). Proportion differences for T versus C were analyzed by χ(2) test for each time point. Correlations (R) were analyzed by the Pearson method. RESULTS: Ticagrelor was associated with a significantly lower prevalence of HPR (0%-8%) compared with C (21%-81%) at 2, 4, 8, and 24 hours and ≥2 weeks postdosing (P < .0001, for all assays). The R values between light transmittance aggregometry and VerifyNow/VASP-P were all ≥0.43, P < .0001. CONCLUSIONS: The above data represent the largest serial pharmacodynamic evaluation of the comparative effects of T versus C. Ticagrelor was rapidly and consistently associated with a very low prevalence of HPR compared with C, as determined by multiple established methods to measure platelet reactivity. These results provide a mechanism for the lower ischemic event rate associated with T therapy reported in the PLATO trial.

Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.

BACKGROUND: Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel. METHODS AND RESULTS: In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 micromol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks (P<0.0001 for all); by 2 hours after loading, a greater proportion of patients achieved >50% IPA (98% versus 31%, P<0.0001) and >70% IPA (90% versus 16%, P<0.0001) in the ticagrelor group than in the clopidogrel group, respectively. A faster offset occurred with ticagrelor than with clopidogrel (4-to-72-hour slope [% IPA/h] -1.04 versus -0.48, P<0.0001). At 24 hours after the last dose, mean IPA was 58% for ticagrelor versus 52% for clopidogrel (P=NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo (P=NS). CONCLUSIONS: Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation.

Assessment of Saxagliptin Efficacy: Meta-Analysis of 14 Phase 2 and 3 Clinical Trials.

INTRODUCTION: This meta-analysis of data from 14 phase 2 and 3, double-blind, randomized, controlled 12- and 24-week studies (N = 4632) summarizes saxagliptin efficacy in patients with type 2 diabetes (T2D) across treatment regimens. METHODS: Patients received saxagliptin 5 mg/d or control as either monotherapy (n = 1196 vs placebo), add-on therapy (n = 2139 vs placebo and n = 514 vs uptitrated sulfonylurea), or initial combination therapy (n = 619 vs control monotherapy). Patients with renal impairment received saxagliptin 2.5 mg/d or placebo (n = 164). RESULTS: Mean baseline glycated hemoglobin (A1C) ranged from 8.07% to 9.43% for the saxagliptin and control groups across treatment regimens. A1C reduction from baseline was greater with saxagliptin versus control for all studies combined (mean treatment difference [95% CI]: -0.55% [-0.63%, -0.47%]) and when used as monotherapy (-0.52% [-0.63, -0.40%]), add-on (-0.55% [-0.69%, -0.40%] vs placebo; -0.72% [-0.88%, -0.56%] vs uptitrated sulfonylurea), initial combination therapy (-0.54% [-0.73%, -0.35%] vs control monotherapy), and in patients with renal impairment (-0.42% [-0.75%, -0.09%]). Similar reductions in A1C versus control were noted for patients <65 years (-0.55% [-0.67%, -0.43%]) and ≥65 years (-0.54% [-0.69%, -0.38%]) and for men (-0.54% [-0.69%, -0.40%]) and women (-0.55% [-0.64%, -0.47%]) across treatment regimens. More patients achieved A1C <7% (39% vs 23%) and A1C ≤6.5% (24% vs 14%) with saxagliptin than with placebo or active-control treatment. Saxagliptin versus control was associated with a reduction in glucagon area under the curve (AUC) from baseline and increases in insulin AUC, C-peptide AUC, and the homeostasis model assessment of ß-cell function. CONCLUSION: Results of this meta-analysis demonstrate the consistency of saxagliptin efficacy in different subgroups of patients with T2D across treatment regimens. FUNDING: AstraZeneca.

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial.

OBJECTIVE: Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy. RESEARCH DESIGN AND METHODS: We studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial. RESULTS: At baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g), 4,426 (26.8%) had microalbuminuria (ACR 30-300 mg/g), and 1,638 (9.9%) had macroalbuminuria (ACR >300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was -19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m2 (BSA), -105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and -245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA. Analyzing ACR as a continuous variable showed reduction in ACR with saxagliptin (1 year, P < 0.0001; 2 years, P = 0.0143; and EOT, P = 0.0158). The change in ACR did not correlate with that in HbA1c (r = 0.041, 0.052, and 0.036; 1 year, 2 years, and EOT, respectively). The change in eGFR was similar in the saxagliptin and placebo groups. Safety renal outcomes, including doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar as well. CONCLUSIONS: Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control.

Saxagliptin Efficacy and Safety in Patients With Type 2 Diabetes and Moderate Renal Impairment.

INTRODUCTION: Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD). The recommended dose of the dipeptidyl peptidase-4 inhibitor saxagliptin is 2.5 mg in patients with moderate or severe renal impairment (creatinine clearance ≤50 mL/min). In this post hoc analysis, we assessed the effect of saxagliptin 2.5 and 5 mg/day versus placebo on glycemic measures in patients with T2D and estimated glomerular filtration rate 45-60 mL/min/1.73 m(2). METHODS: Efficacy and safety data were pooled from nine 24-week, randomized, placebo-controlled clinical trials. RESULTS: The majority (56-61%) of patients were women aged <65 years with glycated hemoglobin (A1C) 8.1-8.2%; half of the patients had a T2D duration ≥5 years. Mean change from baseline in A1C was significantly greater with saxagliptin 2.5 (-0.6%, P = 0.036 vs placebo) and 5 mg/day (-0.9%, P < 0.001 vs placebo) compared with placebo (-0.2%). There were numerically greater reductions in fasting plasma glucose and 2-h postprandial glucose, and a significantly greater proportion of patients achieved A1C <7% with saxagliptin 5 mg/day (44.8%) compared with placebo (20.0%, P = 0.004 vs placebo). The incidence of hypoglycemia was not significantly different across groups (16.2% in the saxagliptin 5-mg/day, 12.2% in the saxagliptin 2.5-mg/day, and 11.3% in the placebo groups). CONCLUSION: These results suggest that saxagliptin 2.5 and 5 mg/day improve glycemic control and are generally well tolerated in patients with T2D and moderate CKD. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00121641, NCT00316082, NCT00698932, NCT00918879, NCT00121667, NCT00661362, NCT00313313, NCT00295633, NCT00757588. FUNDING: AstraZeneca, Gaithersburg, MD, USA.

Effects of Glimepiride versus Saxagliptin on ß-Cell Function and Hypoglycemia: A Post Hoc Analysis in Older Patients with Type 2 Diabetes Inadequately Controlled with Metformin.

PURPOSE: The management of hyperglycemia is challenging in older patients with type 2 diabetes owing to excess fragility and risk for adverse outcomes should hypoglycemia episodes occur. We evaluated baseline ß-cell function as a potential risk factor for the development of hypoglycemia when saxagliptin or glimepiride was added in patients aged ≥65 years whose type 2 diabetes was poorly controlled on stable metformin monotherapy. METHODS: A post hoc analysis of data from the GENERATION (Efficacy and Tolerability of Saxagliptin Compared with Glimepiride in Elderly Patients with Type 2 Diabetes: A Randomized, Controlled Study) trial, which enrolled 720 patients aged ≥65 years, was conducted. ß-Cell function was assessed using homeostasis model assessment-2%ß (HOMA-2%ß). FINDINGS: The percentage of patients experiencing any hypoglycemia event (ie, symptomatic event or event of plasma glucose concentration <54 mg/dL regardless of symptoms) was lower with saxagliptin compared with glimepiride (5.8% vs 34.8%). Regardless of treatment, patients with lower (median HOMA-2%ß ≤39.1% [≤median]) versus higher (HOMA-2%ß above median value [>median]) baseline ß-cell function had a higher hypoglycemia event rate (1.27 vs 0.82 events/patient-year; adjusted incidence rate ratio [IRR] = 1.800; 95% CI, 1.501-2.159). In patients receiving glimepiride, the hypoglycemia event rate was higher in patients with baseline HOMA-2%ß ≤median versus >median (2.29 vs 1.60 events/patient-year; adjusted IRR = 1.737; 95% CI, 1.439-2.097); corresponding saxagliptin hypoglycemia event rates were too low to draw meaningful conclusions (0.16 vs 0.09 events/patient-year; adjusted IRR = 2.457; 95% CI, 1.148-5.256). The association between lower ß-cell function at baseline and increased prevalence of hypoglycemia was particularly strong in patients aged ≥75 years (adjusted IRR = 2.409; 95% CI, 1.686-3.442; P < 0.001), although it was also significant in patients aged 65 to <75 years old (adjusted IRR, 1.654; 95% CI, 1.339-2.043; P < 0.001). IMPLICATIONS: In patients with lower ß-cell function, the addition of a sulfonylurea to a metformin regimen was associated with an increased risk for hypoglycemia compared with that in patients with higher ß-cell function; low hypoglycemia event rates with the addition of saxagliptin limited equivalent assessments. These findings in older patients are especially relevant because morbidity associated with hypoglycemia is higher in this age group. ClinicalTrials.gov identifier: NCT01006603 (ClinicalTrials.gov).

Incidence of Fractures in Patients With Type 2 Diabetes in the SAVOR-TIMI 53 Trial.

OBJECTIVE: Patients with type 2 diabetes have an increased risk of bone fractures, the predisposing factors for which are unknown. Treatment with thiazolidinediones (TZDs) further increases the incidence of osteoporotic fractures. In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, fractures were considered an adverse event of special interest, and information regarding fractures was collected. RESEARCH DESIGN AND METHODS: We compared the incidence of fractures among the 8,280 patients who were assigned to treatment with saxagliptin with that in the 8,212 patients who were assigned to placebo. We further analyzed the participants' baseline characteristics and fracture risk. RESULTS: During a median follow-up of 2.1 years, 241 patients (2.9%) in the saxagliptin group and 240 (2.9%) in the placebo group experienced a fracture (hazard ratio [HR] 1.00 [95% CI 0.83-1.19]). Event rates for fractures were the same in both treatment arms: 14.7 per 1,000 patient-years in the entire population and 14.0 in the on-treatment population (first event only). Fracture risk was similar in patients treated with saxagliptin or placebo across different subgroups defined by race, cardiovascular risk, and renal function. A multivariable Cox regression analysis showed that risk of fracture was associated with female sex (P < 0.0001), longer diabetes duration (P < 0.0001), older age (P = 0.002), major hypoglycemic events (P = 0.01), noncompliance with study drug (P = 0.01), and treatment with TZDs (P = 0.03). CONCLUSIONS: In a large population of older patients with type 2 diabetes, treatment with saxagliptin was not associated with an increased risk of fractures. The association between longer diabetes duration and increased risk of bone fracture is an intriguing finding.

Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease: results from the ONSET-OFFSET and RESPOND studies.

BACKGROUND AND OBJECTIVES: Ticagrelor, the first reversibly binding oral P2Y(12) receptor antagonist, improves outcomes in patients with acute coronary syndromes (ACS) compared with clopidogrel. In the ONSET-OFFSET study (parallel group trial) and the RESPOND study (crossover trial), the pharmacodynamic effects of ticagrelor were compared with clopidogrel in patients with coronary artery disease (CAD). We now report the pharmacokinetic analyses of ticagrelor, and the exposure-inhibition of platelet aggregation (IPA) relationships from these studies. PATIENTS AND METHODS: Patients were treated with ticagrelor (180 mg loading dose, 90 mg twice daily maintenance dose) or clopidogrel (600 mg loading dose, 75 mg once daily maintenance dose) in addition to aspirin (acetylsalicylic acid) [75-100 mg once daily]. Ticagrelor administration was for 6 weeks in ONSET-OFFSET. In RESPOND, ticagrelor was given for 14 days before or after 2 weeks of clopidogrel in patients classified as clopidogrel responders or non-responders. Pharmacokinetics and IPA were evaluated following the loading and last maintenance doses. Exposure-IPA relationships were evaluated using a sigmoid maximum effect (E(max)) model. OUTCOME MEASURES: The outcome measures were ticagrelor and AR-C124910XX (active metabolite) pharmacokinetics and exposure-IPA relationships in both trials, including the effect of prior clopidogrel exposure, and effects in clopidogrel responders and non-responders in RESPOND. RESULTS: In ONSET-OFFSET, maximum (peak) plasma concentration (C(max)), time to C(max) (t(max)) and area under the plasma concentration-time curve from time 0 to 8 hours (AUC(8)) for ticagrelor were 733 ng/mL, 2.0 hours and 4130 ng · h/mL, respectively; and for AR-C124910XX were 210 ng/mL, 2.1 hours and 1325 ng · h/mL, respectively. E(max) estimates were IPA >97%. Trough plasma ticagrelor (305 ng/mL) and AR-C124910XX (121 ng/mL) concentrations were 5.2 and 7.7 times higher than respective concentration producing 50% of maximum effect (EC(50)) estimates. In RESPOND, ticagrelor mean C(max) and AUC(8) following 2-week dosing were comparable between clopidogrel responders (724 ng/mL and 3983 ng · h/mL, respectively) and non-responders (764 ng/mL and 3986 ng · h/mL, respectively). Pharmacokinetics of ticagrelor were unaffected by prior clopidogrel dosing. E(max) estimates were IPA >96% for both responders and non-responders. Trough plasma concentrations were sufficient to achieve high IPA. CONCLUSIONS: Ticagrelor pharmacokinetics in stable CAD patients were comparable to previous findings in stable atherosclerotic and ACS patients, and were not affected by prior clopidogrel exposure or clopidogrel responsiveness. Ticagrelor effectively inhibited platelet aggregation, and trough plasma concentrations of ticagrelor and AR-C124910XX were sufficient to result in high IPA in stable CAD patients.

First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies.

BACKGROUND: The influence of cytochrome P450 (CYP) 2C19 genotype on platelet function in patients treated with ticagrelor versus clopidogrel is unknown. METHODS AND RESULTS: CYP2C19 (*1, *2, *3, *4, *5, *6, *7, *8, *17) genotyping was performed in patients with coronary artery disease treated with ticagrelor (180-mg load, 90 mg BID) (n=92) or clopidogrel (600-mg load, 75 mg/d) (n=82). All patients received 75 to 100 mg/d aspirin. Platelet function was measured by aggregometry, VerifyNow P2Y12 assay, and vasodilator-stimulated phosphoprotein-phosphorylation assay at predose, 8 hours postloading, and maintenance. In each treatment group, patients were categorized according to 2C19 genotype carrier status (loss-of-function, gain-of-function) and metabolizer status. Kruskal-Wallis test was used to compare platelet function among these categories for each treatment, and Wilcoxon rank sum test was used to compare platelet function between the clopidogrel and ticagrelor groups for each category. There was no statistically significant influence of genotype on platelet function during aspirin therapy alone. Ticagrelor exhibited lower platelet reactivity than clopidogrel by all assays irrespective of 2C19 genotype or metabolizer status (P<0.01). Loss-of-function carriers had greater platelet reactivity during clopidogrel therapy. The influence of genotype on platelet reactivity was greatest during clopidogrel maintenance and best demonstrated by the VerifyNow P2Y12 assay. CONCLUSIONS: This report is the first to demonstrate the superior pharmacodynamic effect of ticagrelor compared with clopidogrel irrespective of CYP2C19 genotype. Whereas CYP2C19 genotype influenced the antiplatelet effect of clopidogrel, there was no effect of CYP2C19 genotype during ticagrelor therapy.

Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study.

OBJECTIVES: We prospectively assessed cardiac and pulmonary function in patients with stable coronary artery disease (CAD) treated with ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease) study. BACKGROUND: Ticagrelor reduces cardiovascular events more effectively than clopidogrel in patients with acute coronary syndromes. Dyspnea develops in some patients treated with ticagrelor, and it is not known whether this is associated with changes in cardiac or pulmonary function. METHODS: In all, 123 stable aspirin-treated CAD patients randomly received either ticagrelor (180 mg load, then 90 mg twice daily; n=57), clopidogrel (600 mg load, then 75 mg daily; n=54), or placebo (n=12) for 6 weeks in a double-blind, double-dummy design. Electrocardiography, echocardiography, serum N-terminal pro-brain natriuretic peptide, and pulmonary function tests were performed before (baseline) and 6 weeks after drug administration and/or after development of dyspnea. RESULTS: After drug administration, dyspnea was reported by 38.6%, 9.3%, and 8.3% of patients in the ticagrelor, clopidogrel, and placebo groups, respectively (p<0.001). Most instances were mild and/or lasted<24 h, although 3 patients discontinued ticagrelor because of dyspnea. Eight of 22 and 17 of 22 ticagrelor-treated patients experiencing dyspnea did so within 24 h and 1 week, respectively, after drug administration. In all treatment groups, and in ticagrelor-treated patients with dyspnea, there were no significant changes between baseline and 6 weeks in any of the cardiac or pulmonary function parameters. CONCLUSIONS: Dyspnea is commonly associated with ticagrelor therapy, but was not associated in this study with any adverse change in cardiac or pulmonary function. (A Multi-Centre Randomised, Double-Blind, Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease [ONSET/OFFSET]; NCT00528411).