Clarissa J. Diamantidis

User Profiles of a Smartphone Application to Support Drug Adherence — Experiences from the iNephro Project

Purpose One of the key problems in the drug therapy of patients with chronic conditions is drug adherence. In 2010 the initiative iNephro was launched (www.inephro.de). A software to support regular and correct drug intake was developed for a smartphone platform (iOS). The study investigated whether and how smartphone users deployed such an application. Methods Together with cooperating partners the mobile application “Medikamentenplan” (“Medication Plan”) was developed. Users are able to keep and alter a list of their regular medication. A memory function supports regular intake. The application can be downloaded free of charge from the App Store™ by Apple™. After individual consent of users from December 2010 to April 2012 2042338 actions were recorded and analysed from the downloaded applications. Demographic data were collected from 2279 users with a questionnaire. Results Overall the application was used by 11688 smartphone users. 29% (3406/11688) used it at least once a week for at least four weeks. 27% (3209/11688) used the application for at least 84 days. 68% (1554/2279) of users surveyed were male, the stated age of all users was between 6–87 years (mean 44). 74% of individuals (1697) declared to be suffering from cardiovascular disease, 13% (292) had a previous history of transplantation, 9% (205) were suffering from cancer, 7% (168) reported an impaired renal function and 7% (161) suffered from diabetes mellitus. 69% (1568) of users were on <6 different medications, 9% (201) on 6 – 10 and 1% (26) on more than 10. Conclusion A new smartphone application, which supports drug adherence, was used regularly by chronically ill users with a wide range of diseases over a longer period of time. The majority of users so far were middle-aged and male.

Health information technology (IT) to improve the care of patients with chronic kidney disease (CKD).

Several reports show that patients with chronic disease who are empowered with information technology (IT) tools for monitoring, training and self-management have improved outcomes, however there are few such applications employed in kidney disease. This review explores the current and potential uses of health IT platforms to advance kidney disease care by offering innovative solutions to inform, engage and communicate with individuals with CKD.

Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: A systematic review

After its approval by the U.S. Food and Drug Administration (FDA) in 1994, metformin became the recommended initial treatment for type 2 diabetes mellitus in the United States (1). Beyond its glycemic benefits, metformin typically does not cause weight gain or hypoglycemia and may be associated with lower mortality (2, 3). Because of concerns regarding lactic acidosis with use of phenformin, a related biguanide withdrawn from the market in 1977, the FDA applied a boxed warning to metformin concurrent with its approval (4). This warning cautioned against using metformin in the setting of chronic kidney disease (CKD), which may impair excretion of the drug, and recommended caution in patients with conditions that may promote lactate accumulation (such as congestive heart failure [CHF] and chronic liver disease [CLD]) (5). Despite this warning, recent estimates suggest that 20% to 30% of persons receiving metformin have historical contraindications or precautions regarding its use (6, 7). These findings reflect that many prescribers believe the FDA boxed warning is too restrictive (8, 9). Literature reviews indicate no clear association between metformin use and lactic acidosis (10) and suggest that the drug is safe for patients with moderate CKD or CHF (11, 12). In 2006, the FDA removed CHF as a contraindication to metformin use, although acute or unstable CHF remains a precaution (13, 14). In April 2016, the FDA revised its warning regarding metformin use in patients with CKD, switching from a serum creatininebased definition of renal impairment to more-inclusive criteria based on estimated glomerular filtration rate (eGFR) (15). With this change, an estimated 1 million additional patients with moderate CKD (eGFR, 30 to <60 mL/min/1.73 m2) became eligible to receive metformin, although severe CKD (eGFR, <30 mL/min/1.73 m2) remains a contraindication (16). In the wake of these changes, metformin use will continue to increase in populations with historical contraindications and precautions. Prescribers therefore must fully understand the consequences of metformin use in these groups. To promote informed prescribing, we systematically reviewed the literature regarding the benefits and harms of metformin use (beyond lactic acidosis) among patients with common chronic diseases historically identified by the FDAs boxed warning as contraindications or precautions: moderate to severe CKD, CHF, and CLD with impaired hepatic function. Methods Study Design This work was part of a Veterans Health Administration (VHA)-funded report. Additional details are available online (www.hsrd.research.va.gov/publications/esp). The present analysis focuses on the following question: For patients with type 2 diabetes and a historical contraindication or precaution regarding metformin use, what are the benefits and harms (beyond lactic acidosis) of metformin treatment? This review followed a published protocol (PROSPERO: CRD42016027708), and each step was pilot-tested to train and calibrate investigators. Data Sources and Study Selection In consultation with an expert medical librarian, we searched PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, and the International Pharmaceutical Abstracts in November 2015; we subsequently updated our PubMed search through September 2016. We also searched ClinicalTrials.gov for relevant completed and ongoing studies. Appendix Table 1 presents our search strategies. We also screened reference lists of published reviews and queried Bristol-Myers Squibb, the manufacturer of the branded metformin formulation, for other relevant studies. Appendix Table 1. Search Strategies for Online Databases, With Date of Search and Specific Terms Our prespecified inclusion and exclusion criteria are listed in Appendix Table 2. We included English-language clinical trials and observational cohort studies that examined adults with type 2 diabetes and a metformin contraindication or precaution of interest (moderate to severe CKD [eGFR, <60 mL/min/1.73 m2], CHF, or CLD with hepatic impairment); compared antihyperglycemic regimens that included metformin with those that did not; and reported all-cause mortality, major adverse cardiovascular events (MACEs), glycemic control, lipid control, hypoglycemia, weight gain, or vitamin B12 deficiency. Our VHA stakeholders and technical expert panel provided guidance on outcome selection. Appendix Table 2. Inclusion and Exclusion Criteria for Citations Data Extraction and Quality Assessment of Individual Studies Two investigators screened all citations for eligibility, and citations considered relevant by either individual advanced to full-text review. Two investigators reviewed all full-text articles and resolved disagreements through discussion or adjudication by a third investigator. Before excluding any potentially eligible study whose primary analysis did not explicitly address a population with a metformin contraindication or precaution, we examined the full text for relevant subgroup analyses. Two investigators independently assessed study quality, and disagreements were resolved by consensus or through arbitration by a third investigator. Using published quality criteria, we developed a customized risk-of-bias (ROB) assessment tool designed to address selection, performance, attrition, detection, and reporting biases (Appendix Figure 1) (17). We assigned each study an ROB score (low, moderate, or high). Appendix Figure 1. Quality assessment for observational studies. BNP = brain natriuretic peptide; CHF = congestive heart failure; CKD = chronic kidney disease; CT = computed tomography; CV = cardiovascular; DM = diabetes mellitus; DM2 = type 2 diabetes mellitus; eGFR = estimated glomerular filtration rate; FBS = fasting blood sugar; f/u = follow-up; HbA1c = hemoglobin A1c; HTN = hypertension; ICD = International Classification of Diseases; MACEs = major adverse cardiovascular events; MI = myocardial infarction; NA = not applicable; NR = not reported; PE = physical examination. Appendix Figure 1. Continued Data Abstraction For each included study, an investigator abstracted data by using a customized DistillerSR database (Evidence Partners); a second investigator independently reviewed these data for accuracy. Relevant data included demographics, study setting, contraindication or precaution definitions, metformin dosage, other antihyperglycemic agents, comparators, and outcomes. We treated multiple publications from a single study as a single data point, prioritizing the longest-term and most complete results. If critical data were missing or unclear in a published report, we contacted the manuscript authors. Data Synthesis We developed summary tables to characterize all included studies for each metformin contraindication or precaution of interest. Of note, 2 studies (18, 19) separately compared distinct groups of metformin usersthose receiving metformin monotherapy and those receiving metforminsulfonylurea combination therapywith patients receiving sulfonylurea monotherapy. In each case, we derived a pooled, weighted hazard ratio (HR) for all metformin users, incorporating an approximation of the correlation resulting from the shared sulfonylurea monotherapy reference group (Appendix). For another study (20), we estimated the HR and variance from the reported frequencies and the odds ratio (OR) by using an established approach (21, 22) (Appendix). If 3 or more studies were conceptually similar in terms of design, population, intervention, and outcomes, we performed quantitative synthesis by using a random-effects model to generate summary HRs. For analyses with fewer than 20 studies, we used the KnappHartung approach to adjust the SEs of the estimated coefficients (23, 24). If appropriate, we conducted sensitivity analyses by omitting subgroups with more severe contraindications or precautions (such as an eGFR <30 mL/min/1.73 m2), studies with shorter follow-up (<2 years), and studies not using propensity-score adjustment. We evaluated statistical heterogeneity by using Cochran Q and I 2 statistics; for analyses including 10 or more studies, we assessed publication bias by using funnel plots and Begg and Egger tests (25, 26). For cases with too few studies to warrant meta-analysis, we performed qualitative synthesis. We conducted all quantitative analyses by using R (version 3.1.2) (The R Foundation), including the metafor package (version 1.9-7), for meta-analysis. Strength of Evidence We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to evaluate the overall strength of evidence (SOE) for outcomes with sufficient data. Using the domains of ROB, directness, and consistency or precision of treatment effects, an investigator (J.W.W.) rated the SOE as high, moderate, low, or insufficient. We considered the effect of residual confounders, magnitude of effect, and publication bias (27, 28). Role of the Funding Source This review was funded by the U.S. Department of Veterans Affairs. The funding source had no role in the study design, data collection, analysis, preparation of the manuscript, or decision to submit the manuscript for publication. Results From 4910 screened citations, we reviewed 532 full-text articles and identified 17 eligible studies (Figure 1). All were observational and addressed populations with moderate to severe CKD (n= 5), CHF (n= 11), or CLD with hepatic impairment (n= 3); 3 studies addressed both CKD and CHF. Appendix Table 3 provides details on the included studies. Of note, we identified no ongoing studies in ClinicalTrials.gov that met our inclusion criteria. Figure 1. Flow of articles through the literature search and screening process. CHF = congestive heart failure; CKD = chronic kidney disease; CLD = chronic liver disease; OECD = Organization for Economic Cooperation and Development. * Search results are from EMBASE (n = 2512), PubMed (n = 2381), and Cochrane (n = 17). Three references

Erythropoiesis-stimulating agents increase the risk of acute stroke in patients with chronic kidney disease.

Erythropoiesis-stimulating agents (ESAs) are effective in ameliorating anemia in chronic kidney disease (CKD). A recent trial in diabetic patients with CKD, however, suggested a greater risk of stroke associated with full correction of anemia with ESAs. Using national Veterans Affairs data we performed a case-control study examining the association of incident ESA use with acute stroke in patients with estimated glomerular filtration rate < 60 cm³/min per 1.73 m² and outpatient hemoglobin <12 g/dl. Using diagnosis codes, we identified 2071 acute hospitalized stroke cases and matched them 1:5 with controls without stroke, resulting in 12,426 total patients for analysis. Conditional logistic regression was used to estimate the association of ESA use with stroke, adjusting for potential confounders. After multivariate adjustment, ESA use in 1026 patients was associated with greater odds of stroke (odds ratio 1.30). There was significant interaction between ESA use and cancer, with greater odds of stroke among ESA-treated cancer patients (odds ratio 1.85), but not in ESA-treated patients without cancer (odds ratio 1.07). ESA-treated patients with cancer received a median initial dose 2.5-4 times greater than ESA-treated patients without cancer, but pre-ESA hemoglobin and its rate of change did not differ between these groups. Hence, in a large national sample of anemic patients with CKD, ESA treatment was associated with an increased risk of acute stroke with the greatest effect among patients with cancer.

Limited health literacy is associated with low glomerular filtration in the Chronic Renal Insufficiency Cohort (CRIC) study.

Background: Low health literacy in the general population is associated with increased risk of death and hospitalization. The evaluation of health literacy in individuals with predialysis chronic kidney disease (CKD) is limited. Methods: We conducted a cross-sectional study to evaluate the associations of limited health literacy with kidney function and cardiovascular disease (CVD) risk factors in 2,340 non-Hispanic (NH) Whites and Blacks aged 21 – 74 years with mild-to-moderate CKD. Limited health literacy was defined as a Short Test of Functional Health Literacy in Adults (STOFHLA) score ≤ 22. Outcomes evaluated included estimated glomerular filtration rate (eGFR), 24-hour urine protein excretion, and CVD risk factors. Results: The prevalence of limited health literacy was 28% in NH-Blacks and 5% in NH-Whites. Compared with participants with adequate health literacy, those with limited health literacy were more likely to have lower eGFR (34 vs. 42 mL/min/1.73 m2); higher urine protein/24-hours (0.31 vs. 0.15 g); and higher self-reported CVD (61 vs. 37%); and were less likely to have BP < 130/80 mmHg (51 vs. 58%); p ≤ 0.01 for each comparison. After adjustment, limited health literacy was associated with self-reported CVD (OR 1.51, 95% CI 1.13 – 2.03) and lower eGFR (β –2.47, p = 0.03). Conclusion: In this CKD cohort, limited health literacy was highly prevalent, especially among NH-Blacks, and it was associated with lower eGFR and a less favorable CVD risk factor profile. Further studies are needed to better understand these associations and inform the development of health literacy interventions among individuals with CKD.

Usability of a CKD Educational Website Targeted to Patients and Their Family Members

BACKGROUND AND OBJECTIVES Web-based technology is critical to the future of healthcare. As part of the Safe Kidney Care cohort study evaluating patient safety in CKD, this study determined how effectively a representative sample of patients with CKD or family members could interpret and use the Safe Kidney Care website (www.safekidneycare.org), an informational website on safety in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Between November of 2011 and January of 2012, persons with CKD or their family members underwent formal usability testing administered by a single interviewer with a second recording observer. Each participant was independently provided a list of 21 tasks to complete, with each task rated as either easily completed/noncritical error or critical error (user cannot complete the task without significant interviewer intervention). RESULTS Twelve participants completed formal usability testing. Median completion time for all tasks was 17.5 minutes (range=10-44 minutes). In total, 10 participants had greater than or equal to one critical error. There were 55 critical errors in 252 tasks (22%), with the highest proportion of critical errors occurring when participants were asked to find information on treatments that may damage kidneys, find the website on the internet, increase font size, and scroll to the bottom of the webpage. Participants were generally satisfied with the content and usability of the website. CONCLUSIONS Web-based educational materials for patients with CKD should target a wide range of computer literacy levels and anticipate variability in competency in use of the computer and internet.

Directed use of the internet for health information by patients with chronic kidney disease: prospective cohort study.

Background Health information technology has become common in the care of patients with chronic diseases; however, there are few such applications employed in kidney disease. Objective The aim of the study was to evaluate the use of a website providing disease-specific safety information by patients with predialysis chronic kidney disease. Methods As part of the Safe Kidney Care (SKC) study, an educational website was designed to provide information on safety concerns in chronic kidney disease. Phase I study participants were provided a medical alert accessory with a unique ID number, the Safe Kidney Care website, and an in-person tutorial on the use of the Internet and accessing the SKC website at baseline. Participants were asked to visit the website and enter their unique ID as frequently as they desired over the next 365 days or until their annual follow-up visit, whichever occurred first. Participants’ visits and dwell times on specific safety modules were tracked using embedded webpage PHP scripts linked to a MySQL database, enabling the collection of website usage statistics. Results Of 108 Phase I participants, 28.7% (31/108) visited the website from 1-6 times during the observation period (median follow-up 365 days). Median access time was 7 minutes per visit (range <1-46) and 13 minutes per person (range <1-123). The three most frequently visited pages were “Renal function calculator”, “Pills to avoid”, and “Foods to avoid”. High school education and frequent Internet use were significantly associated with website entry (P=.02 and P=.03, respectively). Conclusions Preliminary results show general interest in a Web-based platform designed to improve patient safety in chronic kidney disease. Trial Registration Clinicaltrials.gov NCT01407367; http://clinicaltrials.gov/show/NCT01407367 (Archived by WebCite at http://www.webcitation.org/6KvxFKA6M).

Influence of Creatinine versus Glomerular Filtration Rate on Non-Steroidal Anti-Inflammatory Drug Prescriptions in Chronic Kidney Disease

Background: Non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, are generally contraindicated in chronic kidney disease (CKD). This investigation sought to identify the frequency of NSAID/COX-2 prescription and to determine the influence of serum creatinine (Cr) versus estimated glomerular filtration rate (eGFR) on this practice pattern. Methods: An established Veterans Health Administration CKD safety cohort (n = 70,154) was examined to determine the frequency of NSAID/COX-2 in fiscal year 2005 (FY05) for up to 30 days preceding the index hospitalization and as many as 365 days during that year. Binomial regression was used to determine adjusted prevalence ratios for prescription of NSAID/COX-2 with respect to continuous eGFR measurement and serum Cr categories. CKD was defined as eGFR <60 ml/min/1.73 m2. Results: 15.4% of the subjects had an NSAID/COX-2 prescription during the observation period. The proportion of these prescribed agents decreased with declining renal function, but remained significant at any stage of CKD given the renal harm related to these medications. At specific GFR estimates, serum Cr remained a significant predictor of NSAID/COX-2 prescription. At GFR set at 42 ml/min/1.73 m2, the predicted proportion of prescribed NSAID/COX-2 was 0.29 (95% CI 0.24, 0.36), 0.23 (95% CI 0.22, 0.26), 0.20 (95% CI 0.19, 0.22), and 0.12 (95% CI 0.10, 0.14) for Cr strata of ≤1.3, 1.4–1.6, 1.7–2.1, and ≥2.2 mg/dl, respectively (all p < 0.05). Conclusion: A significant proportion of individuals with CKD continue to be prescribed NSAID/COX-2 and serum Cr remains an influential guide to NSAID/COX-2 prescription, even in GFR ranges where these agents are ill advised.

A varying patient safety profile between black and nonblack adults with decreased estimated GFR.

BACKGROUND Chronic kidney disease is a high-risk condition for a variety of adverse safety events, yet little is known about differential rates of safety events across racial groups with decreased kidney function. We sought to examine the incidence of an array of disease-specific adverse safety events in black versus nonblack patients with decreased estimated glomerular filtration rate (eGFR). STUDY DESIGN Retrospective observational study of a national US Veterans Affairs cohort. SETTINGS & PARTICIPANTS Veterans with eGFR <60 mL/min/1.73 m(2) and one or more hospitalization during federal fiscal year 2005 (n = 70,154). PREDICTOR Self-reported race/ethnicity dichotomized as black or nonblack. OUTCOMES Hospital discharge coding for Agency for Healthcare Research and Quality (AHRQ) patient safety indicators (PSIs), laboratory records for detection of hyperkalemia and hypoglycemia, and pharmacy records to determine dosing of 4 selected medications. MEASUREMENTS Relationship between race and disease-specific patient safety events. RESULTS Black veterans were more likely than nonblack veterans to experience one type of safety event (33% vs 32%, respectively) and multiple types of safety events (32% vs 23%, respectively; both P < 0.001). After adjustment, black veterans were 11% and 36% more likely to have at least one episode of hyperkalemia and hypoglycemia, respectively, than nonblack veterans, but were 14% less likely to experience a medication error (all P < 0.001). There was no association between the occurrence of AHRQ PSIs and race after adjustment. LIMITATIONS Use of administrative data has a risk of imprecision in coding; Veterans Affairs cohort may limit generalizability. CONCLUSIONS Black veterans with decreased eGFR are more likely to experience a broad array of safety events than nonblacks with decreased eGFR, with a preponderance of metabolic disturbances rather than medication errors or AHRQ PSIs. The differential safety phenotype in blacks versus nonblacks may have implications for preventive strategies to improve patient safety in an integrated health care system.

A mobile application improves therapy-adherence rates in elderly patients undergoing rehabilitation: A crossover design study comparing documentation via iPad with paper-based control.

AbstractMedication adherence is crucial for success in the management of patients with chronic conditions. This study analyzes whether a mobile application on a tablet aimed at supporting drug intake and vital sign parameter documentation affects adherence in elderly patients.Patients with coronary heart disease and no prior knowledge of tablet computers were recruited. They received a personal introduction to the mobile application Medication Plan, installed on an Apple iPad. The study was conducted using a crossover design with 3 sequences: initial phase, interventional phase (28 days of using the app system), and comparative phase (28 days of using a paper diary). Users experienced the interventional and comparative phases alternately.A total of 24 patients (12 males; mean age 73.8 years) were enrolled in the study. The mean for subjectively assessed adherence (A14-scale; 5-point Likert scale, from “never” to “very often” which results in a score from 0 to 56) before the study was 50.0 (SD = 3.44). After both interventions there was a significant increase, which was more pronounced after the interventional phase (54.0; SD = 2.01) than after the comparative phase (52.6; SD = 2.49) (for all pairs after both interventions, P <0.001). Neither medical conditions nor the number of drug intake (amount and frequency of drug taking) per day affected subjective adherence. Logging data showed a significantly stronger adherence for the medication app than the paper system for both blood pressure recordings (P <0.001) and medication intake (P = 0.033). The majority of participants (n = 22) stated that they would like to use the medication app in their daily lives and would not need further assistance with the app.A mobile app for medication adherence increased objectively and subjectively measured adherence in elderly users undergoing rehabilitation. The findings have promising clinical implications: digital tools can assist chronic disease patients achieve adherence to medication and to blood pressure measurement. Although this requires initial offline training, it can reduce complications and clinical overload because of nonadherence.