Concurrent Use Of Diuretics Research Articles

Empagliflozin and Risk of Incident Gout: Analysis from the EMPagliflozin Comparative Effectiveness and SafEty (EMPRISE) Cohort Study.

Hyperuricemia is frequently observed in patients with type 2 diabetes (T2D) and is associated with increased risk of gout and cardiovascular disease (CVD). Empagliflozin lowers serum urate levels by enhancing its urinary excretion. To compare initiators of empagliflozin vs dipeptidyl peptidase-4 inhibitor (DPP4i) and initiators of empagliflozin vs glucagon-like peptide-1 receptor agonist (GLP-1RA) with respect to the risk of incident gout events. Using three claims-based datasets from 08/2014 to 09/2019, we generated two cohorts (cohort 1: empagliflozin vs DPP4i; cohort 2: empagliflozin vs GLP-1RA) of adult patients with T2D and without prior history of gout or gout-specific medication dispensing separately in each dataset. To assess the risk of incident gout, we estimated hazard ratios (HR) and rate differences (RD) per 1000 person-years (PY) with their 95% confidence intervals (CI) before and after 1:1 propensity score (PS) matching adjusting for 141 baseline covariates. We identified 102,262 pairs of 1:1 propensity score-matched adults in cohort 1 and 131,216 pairs in cohort 2. Over a mean follow-up period of 8months on treatment, the risk of gout was lower in patients initiating empagliflozin compared to DPP4i (HR = 0.69: 95%CI (0.60-0.79); RD = - 2.27: 95% CI (- 3.08, 1.46)) or GLP-1RA (HR = 0.83: 95%CI (0.73-0.94); RD = - 0.99: 95%CI (- 1.66, - 0.32)). Results were consistent across subgroups (sex, age, body mass index, chronic kidney disease, heart failure, cardiovascular disease, and concurrent diuretic use) and sensitivity analyses. Among adults with T2D, the initiation of empagliflozin vs a DPP4i or GLP-1RA was associated with lower risk of incident gout, complementing results from a post hoc analysis of the EMPA-REG OUTCOME trial and previously published observational research focusing on the sodium-glucose co-transporter-2 inhibitor class in more narrowly defined study populations.

Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure.

Diuretic resistance implies a failure to increase fluid and sodium (Na+) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level (80 mg of furosemide once or twice daily or greater in those with reduced glomerular filtration rate or heart failure). It is a major cause of recurrent hospitalizations in patients with chronic heart failure and predicts death but is difficult to diagnose unequivocally. Pharmacokinetic mechanisms include the low and variable bioavailability of furosemide and the short duration of all loop diuretics that provides time for the kidneys to restore diuretic-induced Na+ losses between doses. Pathophysiological mechanisms of diuretic resistance include an inappropriately high daily salt intake that exceeds the acute diuretic-induced salt loss, hyponatremia or hypokalemic, hypochloremic metabolic alkalosis, and reflex activation of the renal nerves. Nephron mechanisms include tubular tolerance that can develop even during the time that the renal tubules are exposed to a single dose of diuretic, or enhanced reabsorption in the proximal tubule that limits delivery to the loop, or an adaptive increase in reabsorption in the downstream distal tubule and collecting ducts that offsets ongoing blockade of Na+ reabsorption in the loop of Henle. These provide rationales for novel strategies including the concurrent use of diuretics that block these nephron segments and even sequential nephron blockade with multiple diuretics and aquaretics combined in severely diuretic-resistant patients with heart failure.

Determining Risk Factors for Triple Whammy AKI using Computational Models of Long‐ Term Blood Pressure Regulation

Concurrent use of diuretics, angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB), and nonsteroidal anti‐inflammatory drugs (NSAIDs) increases the risk of acute kidney injury (AKI). AKI resulting from use of all three drugs is referred to as “triple whammy”. Diuretics and ACEI/ARB are often prescribed in tandem for the treatment of hypertension while some NSAIDs, such as ibuprofen, are available over the counter. As such, concurrent treatment with all three drugs is common.To address the critical need to better understand the mechanisms behind the increased risk of AKI and to identify potential risk factors, we use computational models of long‐term blood pressure regulation we developed previously. We hypothesize that individual variations in tubuloglomerular feedback, renal sympathetic nervous activity, and vasoactive hormones such as angiotensin II will determine whether or not triple whammy patients develop AKI. Other circumstances that we hypothesize to influence AKI development include hypertension, salt ingestion and sensitivity, and genetic polymorphisms in enzymes (ACE) or receptors (angiotensin type 1).The computational models used include variables describing the heart and circulation, kidney function, sodium and water reabsorption in the nephron, and the renin angiotensin system (RAS) and is fit separately for male and female humans.Support or Funding InformationThis research was supported by the Canada 150 Research Chair program and by the National Institutes of Health: National Institute of Diabetes and Digestive and Kidney Diseases, grant R01DK106102.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A Novel Computational Tool for Mining Real-Life Data: Application in the Metastatic Colorectal Cancer Care Setting.

BackgroundRandomized clinical trials constitute the gold-standard for evaluating new anti-cancer therapies; however, real-life data are key in complementing clinically useful information. We developed a computational tool for real-life data analysis and applied it to the metastatic colorectal cancer (mCRC) setting. This tool addressed the impact of oncology/non-oncology parameters on treatment patterns and clinical outcomes.MethodsThe developed tool enables extraction of any computerized information including comorbidities and use of drugs (oncological/non-oncological) per individual HMO member. The study in which we evaluated this tool was a retrospective cohort study that included Maccabi Healthcare Services members with mCRC receiving bevacizumab with fluoropyrimidines (FP), FP plus oxaliplatin (FP-O), or FP plus irinotecan (FP-I) in the first-line between 9/2006 and 12/2013.ResultsThe analysis included 753 patients of whom 15.4% underwent subsequent metastasectomy (the Surgery group). For the entire cohort, median overall survival (OS) was 20.5 months; in the Surgery group, median duration of bevacizumab-containing therapy (DOT) pre-surgery was 6.1 months; median OS was not reached. In the Non-surgery group, median OS and DOT were 18.7 and 11.4 months, respectively; no significant OS differences were noted between FP-O and FP-I, whereas FP use was associated with shorter OS (12.3 month; p <0.002; notably, these patients were older). Patients who received both FP-O- and FP-I-based regimens achieved numerically longer OS vs. those who received only one of these regimens (22.1 [19.9–24.0] vs. 18.9 [15.5–21.9] months). Among patients assessed for wild-type KRAS and treated with subsequent anti-EGFR agent, OS was 25.4 months and 18.7 months for 124 treated vs. 37 non-treated patients (non-significant). Cox analysis (controlling for age and gender) identified several non-oncology parameters associated with poorer clinical outcomes including concurrent use of diuretics and proton-pump inhibitors.ConclusionsOur tool provided insights that confirmed/complemented information gained from randomized-clinical trials. Prospective tool implementation is warranted.

The Association Between the Concurrent Use of Diuretics and Tenofovir Disoproxil Fumarate on Renal Function Among HIV-Infected Adults in Washington, District of Columbia

The Association Between the Concurrent Use of Diuretics and Tenofovir Disoproxil Fumarate on Renal Function Among HIV-Infected Adults in Washington, District of Columbia

Incidence and Risk Factors for Acute Kidney Injury Following Mannitol Infusion in Patients With Acute Stroke: A Retrospective Cohort Study.

Mannitol, an osmotic diuretic, is commonly used to treat patients with acute brain edema, but its use also increases the risk of developing acute kidney injury (AKI). In this study, we investigated the incidence and risk factors of mannitol-related AKI in acute stroke patients.A total of 432 patients (ischemic stroke 62.3%) >20 years of age who were admitted to the neurocritical care center in a tertiary hospital and received mannitol treatment were enrolled in this study. Clinical parameters including the scores of National Institutes of Health Stroke Scale (NIHSS) at admission, vascular risk factors, laboratory data, and concurrent nephrotoxic medications were registered. Acute kidney injury was defined as an absolute elevation in the serum creatinine (Scr) level of ≥0.3 mg/dL from the baseline or a ≥50% increase in Scr.The incidence of mannitol-related AKI was 6.5% (95% confidence interval, 4.5%–9.3%) in acute stroke patients, 6.3% in patients with ischemic stroke, and 6.7% in patients with intracerebral hemorrhage. Multivariate analysis revealed that diabetes, lower estimated glomerular filtration rate at baseline, higher initial NIHSS score, and concurrent use of diuretics increased the risk of mannitol-related AKI. When present, the combination of these elements displayed an area under the receiver operating characteristic curve of 0.839 (95% confidence interval, 0.770–0.909). In conclusion, mannitol-related AKI is not uncommon in the treatment of acute stroke patients, especially in those with vulnerable risk factors.

Use of diuretics with ACE inhibitors or angiotensin receptor blockers and NSAIDs increases the risk of acute kidney injury

Commentary on: Lapi F, Azoulay L, Yin H, et al. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute...

Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study

Objectives To assess whether a double therapy combination consisting of diuretics, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers with addition of non-steroidal anti-inflammatory drugs (NSAIDs) and the triple therapy...

NEUROHORMONAL FACTORS IN HEART FAILURE

Currently there are 4 to 5 million people with congestive heart failure in the United States. They consume greater than 7% of the total health care dollar of which a significant portion is directly related to hospitalization expenses alone. Most patients with chronic congestive heart failure can be managed efficiently outside the hospital setting by the proper use of nonpharmacologic therapies. Neurohormonal pathways have a significant impact on the progression of congestive heart failure. Medications, which include alpha-blockers, beta-blockers, digoxin, spironolactone, and diuretics, now can block, modify, or manage most of these neurohormonal effects, and therefore, have a stabilizing effect on the patient with congestive heart failure. Understanding the physiology and medications involved for optimal treatment of congestive heart failure is a must to ensure the quality of life that these patients deserve.

Association of Serum Vancomycin Concentration with Renal Dysfunction

Objective: To evaluate the association of vancomycin-related renal dysfunction with age; serum vancomycin trough concentration; baseline serum creatinine concentration; duration of vancomycin treatment; comorbid medical conditions of congestive heart failure, chronic renal failure, diabetes mellitus, and hepatic cirrhosis; and the concurrent use of drugs that can cause impairment of renal function. Design: A retrospective analysis of medical records of hospitalized patients who received intravenous vancomycin was conducted. Setting: This study was conducted in a 125-bed, tertiary care, government teaching hospital. Methods: Data were collected on 122 men, ranging in age from 41 to 95 years, who received vancomycin during a five-year period starting in 1991. Vancomycin-related renal dysfunction, defined as an increase of ≥0.5 mg/dL in serum creatinine concentration from the baseline value, was examined for an association with age; baseline serum creatinine concentration; duration of vancomycin treatment; serum vancomycin trough concentrations &gt;15 μg/mL; and comorbid conditions of congestive heart failure, chronic renal failure, diabetes mellitus, and hepatic cirrhosis. The concurrent use of aminoglycosides, amphotericin B, diuretics, angiotensin-converting enzyme (ACE) inhibitors, Cimetidine, and intravenously administered contrast medium was also analyzed. Results: Stepwise logistic regression and odds ratio analyses failed to identify an association between vancomycin-related renal dysfunction and any factor examined except concurrent use of diuretics and ACE inhibitors. Conclusions: Patients receiving intravenous vancomycin concurrently with diuretics or ACE inhibitors have a higher risk of renal impairment. No incident of renal dysfunction was attributed to vancomycin alone.

Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema.

To study the association of race and other patient characteristics associated with angiotensin converting enzyme (ACE) inhibitor-associated angioedema. This was a retrospective cohort study of participants in the Tennessee Medicaid Program ( >or= 15 years of age) to whom ACE inhibitors had been prescribed from 1986 through 1992. We identified 82 patients with confirmed angioedema during 51,752 person-years of ACE inhibitor use, giving an overall rate of angioedema of 1.6 per 1000 person-years of ACE inhibitor use. After potential confounding factors were controlled for, the adjusted relative risk (RR) of angioedema among black American users of ACE inhibitors was 4.5 (95% confidence interval [CI] 2.9 to 6.8) compared with white subjects. In addition to race, other factors associated with a significantly increased relative risk in the entire population were the first 30 days of ACE inhibitor use (RR, 4.6; 95% CI, 2.5 to 8.5) compared to > 1 year of use, use of either lisinopril (RR, 2.2; 95% CI, 1.2 to 3.9) or enalapril (RR, 2.2; 95% CI, 1.4 to 3.5) compared to captopril, and previous hospitalization for any diagnosis within 30 days (RR, 2.0; 95% CI, 1.1 to 3.6). Neither ACE inhibitor dose nor concurrent diuretic use was associated with the risk of angioedema. These data suggest that black Americans have a substantially increased risk of ACE inhibitor-associated angioedema compared with white subjects and that this increased risk cannot be attributed to an effect of dose, specific ACE inhibitor, or concurrent medications.

Role of renal prostaglandins and the effects of nonsteroidal anti-inflammatory drugs in patients with liver disease

Renal prostaglandins have several key functions in patients with severe liver disease and ascites. Increased activity of vasodilatory prostaglandins counters the underlying impairment in renal perfusion and the effects of vasoactive hormones. Prostaglandins also participate in renin secretion, renal diluting ability, sodium excretion, the action of diuretics, and, possibly, the development of the hepatorenal syndrome. Nonsteroidal anti-inflammatory drugs inhibit these compensatory actions of prostaglandins and cause a functional reduction in glomerular filtration rate and an impairment in sodium and fluid excretion. The severity of these nephrotoxic effects depends on the potency of the drug in inhibiting renal prostaglandins and on patient susceptibility. Patients with ascites and avid sodium retention, sodium-restricted diets, or concurrent diuretic use are most at risk. If nonsteroidal anti-inflammatory drugs must be administered to these patients, the type of drug should be carefully selected and renal function should be closely monitored.

Long-Term Experience with Lofexidine in the Treatment of Mild-To-Moderate Essential Hypertension

This study describes sustained efficacy and safety of lofexidine in hypertensive patients. Twenty-one male patients (mean age 55 +/- 9 yr) who had previously completed a short-term trial of lofexidine entered this open-label trial. The daily dose of lofexidine was titrated over three months to a maximum of 1.6 mg or an erect diastolic blood pressure less than 90 mm Hg. Hydrochlorothiazide was added when necessary. Thereafter, each patient was evaluated for blood pressure (BP) response, compliance, side effects, hepatic, renal, or hematological abnormalities every three months for two years. Sustained BP reduction with lofexidine was achieved but not without concomitant diuretic therapy. There were no clinically important changes in heart rate or hepatic, renal, or hematological profiles. Side effects were frequent but severe enough to warrant discontinuation in only four patients. The side-effect profile was similar to that of clonidine. We recommend concurrent diuretic use to maximize effectiveness of lofexidine.

The changing pattern of toxicity of digoxin.

Toxicity to digoxin was monitored in 437 consecutive recipients in a comprehensive drug surveillance programme, Adverse reactions developed in 19.5% and, in contrast to previous reports, were generally of a relatively benign nature. There were no drug-related deaths, but patients with adverse reactions spent longer in hospital. Low body weight, impaired renal function, old age and concurrent use of diuretics individually did not increase the risk of toxicity. This was attributed to improvements in the prescribing of digoxin. There was a highly significant excess of gastrointestinal reactions in women, which tended to occur early in the course of therapy. This susceptibility is not widely recognized. The use of loading doses may have caused many early reactions and it is suggested that this practice cold be abandoned in all but the most urgent cases.

Influence of metoprolol, alone and in combination with a thiazide diuretic, on blood pressure, plasma volume, extracellular volume and glomerular filtration rate in essential hypertension

In fifteen patients with essential hypertension WHO I–II (eight men and seven; mean age 45 years) blood pressure (BP), plasma volume (PV;125I-Albumin space), extracellular volume (ECV;82Brdistribution space) and glomerular filtration rate (GFR;51Cr-EDTA clearance) were measured before and during long-term antihypertensive therapy with metoprolol, alone, and in combination with thiazide diuretics. Metoprolol given alone to all patients for an average of 5 months (mean dose 230 mg) resulted in a reduction in systolic and diastolic pressure by 11% and 8%, respectively. In eight patients the BP reduction was considered inadequate (non-responders). In the group as a whole, ECV increased significantly by 5%. The increase in ECV in the non-responders was five times larger than in the responders (1.025 ml against 205 ml), which may in part account for the inadequate BP control. Addition of a thiazide diuretic for an average of 3.5 months resulted in reduction of ECV to its pretreatment level and a pronounced additional fall in BP, comparable to that in the responders. No systematic change in PV or GFR could be demonstrated. No difference was found between the two groups regarding sex, pretreatment BP, body fluid volumes or renal function. On average the non-responders were 20 years older than the responders. The clinical importance of the apparent age-related expansion of ECV and the mechanism behind fluid retention during antihypertensive treatment with beta-blocking drugs are discussed. As failure of BP control during treatment with beta-blockers may be due to fluid retention, concurrent use of diuretics is indicated.