Impact of chronic kidney disease on hemoglobin among patients with peripheral artery disease treated with P2Y12 inhibitors: Insights from the EUCLID trial.

Patients with chronic kidney disease may develop new or more severe anemia when treated with antiplatelet agents due to blood loss in conjunction with impaired erythropoiesis. Because anemia independently predicts limb amputation and mortality among patients with peripheral artery disease (PAD), we evaluated the relationship between estimated glomerular filtration rate (eGFR) and hemoglobin (Hb) levels in the EUCLID trial in which patients with symptomatic PAD were randomized to ticagrelor or clopidogrel. At baseline, 9025, 1870, and 1000 patients had eGFR ⩾ 60, 45-59, and < 45 mL/min/1.73 m2, respectively. The mean fall in Hb during the trial was 0.46 ± 1.68 g/dL and did not differ by baseline eGFR category, although Hb fall ⩾ 10% was more frequent among patients with lower eGFR (p for trend < 0.0001). On-study treatment with iron, erythropoiesis-stimulating agents, and/or red blood cell transfusion was reported for 479 (5.3%), 165 (8.8%), and 129 (12.9%) patients in the three eGFR categories, respectively (p for trend < 0.0001). After adjustment for baseline and post-randomization effects, those not receiving anemia treatment had a smaller reduction in Hb from baseline than those receiving anemia treatment (p < 0.0001). Other determinants of Hb reduction included absence of on-study myocardial infarction, coronary or peripheral revascularization, residence outside North America, male sex, and baseline eGFR. We conclude that among patients with PAD treated with P2Y12 inhibitors, lower baseline eGFR was associated with a greater reduction in Hb. ClinicalTrials.gov Identifier: NCT01732822.

Chronic kidney disease and risk for cardiovascular and limb outcomes in patients with symptomatic peripheral artery disease: The EUCLID trial.

In patients with symptomatic peripheral artery disease (PAD), the impact of chronic kidney disease (CKD) on major adverse cardiovascular events has not been fully evaluated. The Examining Use of Ticagrelor In PAD (EUCLID) trial randomized 13,885 patients with PAD to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. This post hoc analysis compared the incidence of the primary composite endpoint (cardiovascular death, myocardial infarction (MI), or ischemic stroke) in patients with CKD (eGFR < 60 mL/min/1.73 m2) with those without CKD (eGFR ⩾ 60 mL/min/1.73 m2). The primary safety endpoint was thrombolysis in MI (TIMI) major bleeding. A total of 13,483 patients were included; 3332 (25%) had CKD, of whom 237 had stage 4/5 disease. Median follow-up was approximately 30 months. After statistical adjustment, patients with CKD had a higher rate of the primary endpoint compared with those without CKD (6.75 vs 3.72 events/100 patient-years; adjusted hazard ratio (HR) 1.45, 95% CI 1.30-1.63). CKD was not associated with increased risk of hospitalization for acute limb ischemia (ALI) (adjusted HR 0.96, 95% CI 0.69-1.34) or major amputation (adjusted HR 0.92, 95% CI 0.66-1.28). CKD was not associated with a significantly increased risk of major bleeding (adjusted HR 1.21, 95% CI 0.89-1.64), but minor bleeding was significantly increased (adjusted HR 1.51, 95% CI 1.07-2.15). In conclusion, patients with PAD and CKD had higher rates of cardiovascular death, MI, and ischemic stroke, but similar rates of ALI, major amputation, and TIMI major bleeding when compared with patients without CKD. ClinicalTrials.gov Identifier: NCT01732822.

Glaucoma severity at first presentation to an ophthalmologist and risk factors for late presentation in rural Australia: the S1P study.

CLINICAL RELEVANCE: Well-targeted referrals and timely commencement of treatment are essential to limiting vision loss in glaucoma. Optometrists, primary care providers, and public health policymakers can utilise predictors of late to identify and target at-risk populations. BACKGROUND: This study, which aimed to evaluate glaucoma severity at first presentation to an ophthalmologist in a rural Australian population, is the first of its kind in an Australian population. METHODS: Patient records from a large ophthalmology clinic in Port Macquarie, NSW were retrospectively reviewed using the Fight Glaucoma Blindness registry to identify patients who were first diagnosed with glaucoma at an ophthalmology practice in 2020 or 2021. Associations with glaucoma severity at presentation, measured with visual field index (VFI), were analysed using a beta-regression model. Retinal nerve fibre layer measurements were evaluated as a secondary outcome measure using linear regression. RESULTS: From 3548 new patients seen, 110 cases of glaucoma were diagnosed, 95 of whom met inclusion criteria. These comprised 41.8% primary open-angle glaucoma, 32.7% normal-tension glaucoma, 11.8% secondary open-angle glaucoma, 12.7% primary angle closure glaucoma, and 0.9% secondary angle closure glaucoma. The median VFI at presentation was 94.5%, and 71.9% of patients had a VFI ≥ 90%. However, 6.3% of patients presented with a VFI below 50%. Older age, higher intraocular pressure, and worse visual acuity were significantly associated with severity at presentation. No associations were found for remoteness, sex, family history, or glaucoma type. CONCLUSIONS: Glaucoma appears to be diagnosed relatively early in this population. Severity at presentation was associated with age, intraocular pressure, and visual acuity, but not influenced by the social determinants assessed. These findings underscore the importance of frequent comprehensive eye examinations in older patients. Replication in other Australian populations is recommended as the generalisability of these findings is limited.

Impact of the CYP2C8 *3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone.

AIM: The objective of this study was to determine the extent to which the CYP2C8*3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate). METHODS: In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on CYP2C8*3 genotype (n = 15, CYP2C8*1/*1; n = 15, CYP2C8*3 carriers). Subjects received a single 15 mg dose of pioglitazone or gemfibrozil 600 mg every 12 h for 4 days with a single 15 mg dose of pioglitazone administered on the morning of day 3. A 48 h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period. RESULTS: Gemfibrozil significantly increased mean pioglitazone AUC(0,∞) by 4.3-fold (P < 0.001) and there was interindividual variability in the magnitude of this interaction (range, 1.8- to 12.1-fold). When pioglitazone was administered alone, the mean AUC(0,∞) was 29.7% lower (P = 0.01) in CYP2C8*3 carriers compared with CYP2C8*1 homozygotes. The relative change in pioglitazone plasma exposure following gemfibrozil administration was significantly influenced by CYP2C8 genotype. Specifically, CYP2C8*3 carriers had a 5.2-fold mean increase in pioglitazone AUC(0,∞) compared with a 3.3-fold mean increase in CYP2C8*1 homozygotes (P = 0.02). CONCLUSION: CYP2C8*3 is associated with decreased pioglitazone plasma exposure in vivo and significantly influences the pharmacokinetic magnitude of the gemfibrozil-pioglitazone drug-drug interaction. Additional studies are needed to evaluate the impact of CYP2C8 genetics on the pharmacokinetics of other CYP2C8-mediated drug-drug interactions.

Association of Hypertension and Arterial Blood Pressure on Limb and Cardiovascular Outcomes in Symptomatic Peripheral Artery Disease: The EUCLID Trial.

BACKGROUND: Current guidelines recommend aggressive management of hypertension. Recent evidence suggested potential harm with low blood pressure targets in patients with peripheral artery disease. We investigated the association of a history of hypertension and office systolic blood pressure (SBP) with major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs). METHODS AND RESULTS: The EUCLID trial (Examining the Use of Ticagrelor in Peripheral Artery Disease) included 13 885 participants with symptomatic peripheral artery disease; median follow-up was 30 months. Cox proportional hazards regression was used to calculate hazard ratios (HRs) for any MACE, MALE, and MALE including lower extremity revascularization. A clinical history of arterial hypertension was present in 10 857 (78%) participants, and these participants were older and more likely to be female when compared with the 3026 (22%) patients without hypertension. In patients with a history of hypertension, the adjusted hazard ratio for MACE was 0.94, 95% CI, 0.82-1.08; P=0.39, and the adjusted hazard ratio for MALE was 1.08, 95% CI, 0.96-1.23; P=0.21. During follow-up, average SBP was 135 mm Hg (125-145). Every 10 mmHg increase in SBP>125 mmHg was associated with an increased risk of MACE (HR, 1.10 [95% CI, 1.06-1.14]; P<0.001), a marginally increased risk of MALE (HR, 1.07 [95% CI, 1.00-1.15]; P=0.062), and an increased risk of MALE/lower extremity revascularization (HR, 1.08 [95% CI, 1.04-1.11]; P<0.001). Every decrease in 10 mmHg SBP ≤125 mmHg was associated with an increased risk of MACE (HR, 1.19 [95% CI, 1.09-1.31]; P<0.001) but not MALE or MALE/lower extremity revascularization (HR, 1.02 [95% CI, 0.84-1.23], P=0.824; HR, 1.04 [95% CI, 0.95-1.13], P=0.392, respectively). CONCLUSIONS: History of hypertension was not associated with higher hazard for MACE or MALE in patients with peripheral artery disease. In contrast, there was a higher hazard of MACE in patients with out-of-target low and high SBP. High but not low SBP was associated with an increased risk of ischemic limb events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

Evaluating the feasibility of a pharmacist-guided patient-driven intervention to improve blood pressure control in patients with CKD.

BACKGROUND: Self-titration of blood pressure (BP) medications and lifestyle modifications are effective and safe strategies to lower BP. We assessed the feasibility of implementing a pharmacist-guided, patient-driven self-titration protocol and standardized dietary counseling to improve BP in the chronic kidney disease (CKD) clinic. METHODS: Adult patients seen in the CKD clinic were identified via registry screening. Inclusion criteria were as follows: a diagnosis of hypertension, average of the last 3 office BP > 150/90 mmHg, and prescribed 3 or fewer BP medications. Patients with severe hypertension were excluded. BP goals were established and patients were referred to the clinical pharmacist who provided them a BP cuff, a BP medication titration plan (based on home BP monitoring), and dietary education. The following outcomes were evaluated: appeal of the program to patients identified by the registry, patient adherence to the protocol and 6-month office BP, and provider attitudes and acceptance of the protocol. RESULTS: Seventeen patients enrolled in the pilot, the majority recruited via clinic schedule screening. Eleven of the 17 patients completed a 6-month office follow-up visit. Three of the 11 patients met their pre-specified office BP goal. There was, however, significant improvement in 6-month office systolic and diastolic BP. Twelve of 17 patients were adherent to entering home BP in EMR. Provider satisfaction with the protocol was high. CONCLUSION: Our preliminary data suggest that patient-driven self-titration of BP medications is feasible and well received by providers. Future studies are needed to validate these findings and to evaluate the safety and efficacy of this approach.

Interindividual variability in oral antidiabetic drug disposition and response: the role of drug transporter polymorphisms.

BACKGROUND: Numerous effective oral pharmacologic therapies are available to treat type 2 diabetes. However, a substantial number of patients do not achieve the expected glucose-lowering response, or may be predisposed to adverse effects, from these agents. The application of pharmacogenetics to the field of type 2 diabetes is one step towards the goal of improved pharmacotherapeutic management of this progressive disease. METHODS: A PubMed literature search was conducted to identify clinical studies that have examined the extent to which drug-transporter gene polymorphisms influence interindividual variability in oral antidiabetic drug disposition and response in humans. RESULTS/CONCLUSION: Available data suggest that drug transporters play an important role in the disposition of some oral antidiabetic drugs in the body, particularly the meglitinides and metformin. Moreover, polymorphisms in genes encoding drug transport proteins may alter the pharmacodynamic profile of these agents. Drug transporters, drug-metabolizing enzymes, and drug targets each play a distinct and important role in the disposition and action of many oral antidiabetic agents. Thus, future studies may need to take a pharmacogenomic (i.e., multiple gene) approach in order to comprehensively understand the extent to which genetic variation contributes to interindividual differences in oral antidiabetic drug clinical pharmacology.

Corneal perforation during scleral indentation in a patient with pellucid marginal degeneration.

An observational case report of corneal perforation following scleral indentation in a patient with previously undiagnosed pellucid marginal degeneration is presented. Clinical examination, investigations, and subsequent management of this unwarranted and rare complication are described and discussed. The case highlights the need for thorough anterior segment examination before indirect ophthalmoscopy particularly in the presence of ectatic corneal pathology in which case scleral indentation should be avoided.

Water-mediated lysis of lens epithelial cells attached to lens capsule.

PURPOSE: To investigate the effect of distilled deionized water (DDW) on lens epithelial cells (LECs) attached to the lens capsule. SETTING: Wound Healing Research Laboratory, Center for Vision Research, Westmead Hospital, Sydney, NSW, Australia. METHODS: Anterior capsulotomy specimens taken during routine cataract surgery were divided in half. One half was immersed in DDW and the other half in culture medium (control) for 1 to 5 minutes and photographed at intervals by phase-contrast microscopy. In further experiments, the capsules were exposed to DDW for 1 or 2 minutes and placed in culture for 1 week to determine whether LECs survive treatment and are capable of repopulating the lens capsule. RESULTS: Distilled-deionized water induced marked swelling of the cytoplasm within 60 seconds of treatment. At 120 seconds, there was disruption of the plasma membranes, with few intact cells remaining. In the control capsules, confluent monolayers of LECs covered the entire capsule surface with a halo of LECs growing on the surrounding plastic well. Viable LECs were observed in 1 of 3 capsules treated for 1 minute with DDW. These did not reach confluence or grow off the capsule onto the surrounding well. No viable LECs were seen on capsules exposed to DDW for 2 minutes. CONCLUSIONS: Short exposure of LECs to DDW induced extensive and rapid cell lysis. Distilled-deonized water may be a useful agent for instillation in the capsular bag during sealed-capsule irrigation to prevent posterior capsule opacification.

Influence of SLCO1B1 polymorphisms on the drug-drug interaction between darunavir/ritonavir and pravastatin.

The authors investigated whether SLCO1B1 polymorphisms contribute to variability in pravastatin pharmacokinetics when pravastatin is administered alone versus with darunavir/ritonavir. HIV-negative healthy participants were prospectively enrolled on the basis of SLCO1B1 diplotype: group 1 (*1A/*1A, n = 9); group 2 (*1A/*1B, n = 10; or *1B/*1B, n = 2); and group 3 (*1A/*15, n = 1; *1B/*15, n = 5; or *1B/*17, n = 1). Participants received pravastatin (40 mg) daily on days 1 through 4, washout on days 5 through 11, darunavir/ritonavir (600/100 mg) twice daily on days 12 through 18, with pravastatin 40 mg added back on days 15 through 18. Pharmacokinetic studies were conducted on day 4 (pravastatin alone) and day 18 (pravastatin + darunavir/ritonavir). Pravastatin area under the plasma concentration-time curve (AUC(tau)) was 21% higher during administration with darunavir/ritonavir compared with pravastatin alone; however, this difference was not statistically significant (P = .11). Group 3 variants had 96% higher pravastatin AUC(tau) on day 4 and 113% higher pravastatin AUC(tau) on day 18 compared with group 1. The relative change in pravastatin pharmacokinetics was largest in group 3 but did not differ significantly between diplotype groups. In sum, the influence of SLCO1B1*15 and *17 haplotypes on pravastatin pharmacokinetics was maintained in the presence of darunavir/ritonavir. Because OATP1B1 inhibition would be expected to be greater in carriers of normal or high-functioning SLCO1B1 haplotypes, these findings suggest that darunavir/ritonavir is not a potent inhibitor of OATP1B1-mediated pravastatin transport in vivo.

Wound healing and functional outcomes after infrainguinal bypass with reversed saphenous vein for critical limb ischemia.

OBJECTIVE: To examine wound healing and the functional natural history of patients undergoing infrainguinal bypass with reversed saphenous vein for critical limb ischemia (CLI). METHODS: Consecutive patients undergoing infrainguinal bypass for CLI were retrospectively entered into a technical and functional outcomes database. The patients were enrolled from the tertiary referral vascular surgery practices at the University of Colorado Health Sciences Center and Southern Illinois University Medical School. Main outcome variables included wound healing, self-assessed degree of ambulation (outdoors, indoors only, or nonambulatory), and living status (community or structured) after a mean follow up of 30 +/- 23 months. These outcome variables were assessed relative to the preoperative clinical characteristics (symptom duration before vascular consultation, lesion severity, and serum albumin level) and graft patency. RESULTS: From August 1997 through December 2004, 334 patients (253 men; median age, 68 years) underwent 409 infrainguinal bypasses (157 popliteal, 235 tibial, and 17 pedal) for CLI (159 Fontaine III and 250 Fontaine IV). Perioperative mortality was 1.2%. At 1 and 3 years, respectively, the primary patency was 63% and 50%, assisted primary patency was 80% and 70%, limb salvage was 85% and 79%, and survival was 89% and 74%. Complete wound healing at 6 and 12 months was 42% and 75%, respectively. Thirty-four patients (10%) died before all wounds were healed. Multivariate analysis indicated that extensive pedal necrosis at presentation independently predicted delayed wound healing (P < or = .01). At baseline (defined as the level of function within 30 days before the onset of CLI), 91% of patients were ambulatory outdoors, and this decreased to 72% at 6 months (P < or = .01). Similarly, 96% of patients lived independently at baseline, and this decreased to 91% at 6 months (P < or = .01) Graft patency was associated with better ambulatory status at 6 months. A longer duration of symptoms before vascular consultation was associated with a worse living status at 6 months. CONCLUSIONS: Despite achieving the anticipated graft patency and limb salvage results, 25% of patients did not realize wound healing at 1 year of follow-up, 19% had lost ambulatory function, and 5% had lost independent living status. Prospective natural history studies are needed to further define the functional outcomes and their predictors after infrainguinal bypass for CLI.

Measurement of the economic impact of visual impairment from age-related macular degeneration in Australia.

The purpose of this report was to: (i) outline the potential value of health economic studies into age-related macular degeneration (AMD); (ii) provide an overview of health economic studies pertinent to AMD; and (iii) outline the basic frame work of cost-of-illness studies (a useful first step in applying economic methods). The detection and management of sensory loss in the elderly plays a key role in the Australian Government's Healthy Ageing Strategy. Age-related macular degeneration is currently the leading cause of blindness in elderly Australians. Although a large proportion of AMD cases remain untreatable, the introduction of photo-dynamic therapy provides a relatively expensive and possibly cost-effective innovation for others. Antioxidant therapy has also been proven effective in reducing progression of early to late disease. The discipline of economics can contribute to an understanding of AMD prevention and treatment through: (i) describing the current burden of disease; (ii) predicting the changes in the burden of disease over time, and (iii) evaluating the efficiency of different interventions. Cost-of-illness studies have been performed in many fields of medicine. Little work, however, has been done on describing the economic impact from AMD. A number of different economic evaluation methods can be used in judging the efficiency of possible interventions to reduce the disease burden of AMD. Although complementary in nature, each has specific uses and limitations. Studies of the economic impact of eye diseases are both feasible and necessary for informed health care decision-making.