fumarates and Hyperkalemia

There have been few major breakthroughs in heart failure (HF) drug therapies in recent years yet HF morbidity and mortality remain high, and there is a clear need for further research. Several newer agents that appear promising in Phase I and II trials do not progress to show clinical benefit in later trials. Part of the failure to find new therapies may lie in flawed trial design compounded by the need for ever-increasing patient numbers in order to prove outcome benefit. We summarize some of the most recent and promising medical therapies for HF.

Topics: Amides; Cardiotonic Agents; Chronic Disease; Diuretics; Forecasting; Fumarates; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Myocardial Contraction; Naphthyridines; Oligopeptides; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Vasodilator Agents

To examine the safety of using aliskiren combined with agents used to block the renin-angiotensin system.. Systematic review and meta-analysis of randomised controlled trials.. Medline, Embase, the Cochrane Library, and two trial registries, published up to 7 May 2011.. Published and unpublished randomised controlled trials that compared combined treatment using aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers with monotherapy using these agents for at least four weeks and that provided numerical data on the adverse event outcomes of hyperkalaemia and acute kidney injury. A random effects model was used to calculate pooled risk ratios and 95% confidence intervals for these outcomes.. 10 randomised controlled studies (4814 participants) were included in the analysis. Combination therapy with aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers significantly increased the risk of hyperkalaemia compared with monotherapy using angiotensin converting enzymes or angiotensin receptor blockers (relative risk 1.58, 95% confidence interval 1.24 to 2.02) or aliskiren alone (1.67, 1.01 to 2.79). The risk of acute kidney injury did not differ significantly between the combined therapy and monotherapy groups (1.14, 0.68 to 1.89).. Use of aliskerin in combination with angiotensin converting enzyme inhibitors or angiotensin receptor blockers is associated with an increased risk for hyperkalaemia. The combined use of these agents warrants careful monitoring of serum potassium levels.

Topics: Acute Kidney Injury; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hyperkalemia; Randomized Controlled Trials as Topic

Angiotensin (Ang) II plays important roles in the development of hypertension and cardiovascular and renal injury. Pharmaceutical approaches to block its activity led to the development of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Numerous trials have documented their efficacy in controlling blood pressure, minimising left ventricular remodelling, preventing progression to heart failure, ameliorating proteinuria and retarding renal disease progression. Although they are considered safe in general, there remain concerns about the potential for adverse events in certain target populations. Recently, several novel, low molecular weight renin inhibitors without the extended peptide-like backbone of previous renin inhibitors were developed with favourable pharmacokinetic properties. They have been shown to successfully reduce Ang II levels in normal volunteers and to lower blood pressure in patients with mild-to-moderate hypertension. In this review, the authors summarise current knowledge about these renin inhibitors.

Topics: Abnormalities, Drug-Induced; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Clinical Trials as Topic; Fumarates; Humans; Hyperkalemia; Hypertension; Hypotension; Inappropriate ADH Syndrome; Male; Mice; Renin

This is a report of a clinical trial on the therapeutic efficacy and safety of combined aliskiren and losartan (an angiotensin II receptor blocker (ARB)) versus aliskiren alone and ARB alone in non-diabetic chronic kidney disease (CKD) over a 3-year period.. This was a randomised trial in 155 patients with non-diabetic CKD comparing aliskiren (150 mg/day) (n=52) versus losartan (100 mg/day) (n=52) and the third group aliskiren (150 mg/day) combined with losartan (100 mg/day) (n=51). The trial utilised primary renal end points of eGFR <15 ml/min or end-stage renal failure.. All three groups had significant reduction of proteinuria (p<0.001 for all). The changes in eGFR, total urinary protein from baseline to each year were not significantly different between the three therapeutic groups.. This study in non-diabetic CKD patients showed that combination therapy with aliskiren and ARB was as efficacious as aliskiren alone and ARB alone. There was one patient who developed a non-fatal stroke in the combined aliskiren and ARB group while the other two groups had none.

Topics: Amides; Blood Pressure; Comorbidity; Demography; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fumarates; Glomerular Filtration Rate; Humans; Hyperkalemia; Losartan; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Systole

Laboratory research and previous study suggest that aliskiren, a direct renin inhibitor, has anti-proteinuric effects. We conducted a randomized crossover study to evaluate the anti-proteinuric effect of aliskiren in patients with immunoglobulin A (IgA) nephropathy.. We studied 22 patients with biopsy-proven IgA nephropathy and persistent proteinuria despite angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Patients were randomized to either oral aliskiren 300 mg/day or placebo for 16 weeks and then crossed over to the other treatment arm after a washout period. Proteinuria, estimated glomerular filtration rate (eGFR), blood pressure, and serum potassium were monitored.. After aliskiren treatment, there was a significant reduction in proteinuria in 4 weeks (1.76±0.95 to 1.03±0.69 g:g-Cr, p<0.0001), which remained at a low level throughout the treatment period. There was a significant difference in proteinuria between the aliskiren and placebo groups from 4 to 16 weeks after treatment (p<0.01 for all comparisons). After aliskiren treatment, there were modest but statistically significant reductions in eGFR (57.2±29.1 to 54.8±29.3 ml/min/1.73 m(2), p = 0.013) and diastolic blood pressure (72.6±12.3 to 66.2±11.2 mmHg, p<0.0001). None of the patient developed severe hyperkalemia (serum potassium ≥6.0 mmol/l) during the study period.. Aliskiren has anti-proteinuric effect in patients with IgA nephropathy and persistent proteinuria despite ACE inhibitor or ARB. Further studies are needed to confirm the renal protecting effect of direct renin inhibition in chronic proteinuric kidney diseases.. ClinicalTrials.gov NCT00870493.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Female; Fumarates; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Hyperkalemia; Male; Middle Aged; Proteinuria; Renin; Treatment Outcome

This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both.. In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level.. The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons).. The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).

Topics: Aged; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Fumarates; Humans; Hyperkalemia; Hypokalemia; Kidney Diseases; Male; Middle Aged; Patient Dropouts; Renin; Treatment Failure

The long-term clinical outcomes in biopsy proven IgAN patients treated with aliskiren on top of a maximally tolerated dose of ACEi/ARB remain unknown.. Patients with IgAN treated with a direct renin inhibitor and ACEi/ARB for at least 6 months were compared with a 1:1 propensityscore-matched cohort (including MEST-C score and the 12-months pre-exposure slope of eGFR matching) who received ACEi/ARB without aliskiren exposure to compute the hazard ratio of reaching the primary endpoint of a composite of 40% reduction in eGFR, initiation of KRT and all-cause mortality. Secondary outcome measures included changes in mean UPCR, blood pressure, eGFR, incidence of hyperkalemia and other adverse events during follow-up.. Among patients with IgAN, add-on aliskiren was associated with less favorable long-term kidney outcomes despite an initial anti-proteinuric effect.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cohort Studies; Fumarates; Glomerulonephritis, IGA; Humans; Hyperkalemia; Propensity Score; Renin

Topics: Acute Kidney Injury; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Female; Fumarates; Humans; Hyperkalemia; Male; Stroke

Some evidence suggests that the direct renin inhibitor aliskiren may increase the risk of severe hyperkalemia, stroke, or acute kidney injury (AKI) when prescribed with angiotensin-converting enzyme inhibitors (ACEi's) or angiotensin-receptor blockers (ARBs). The extent to which concomitant treatment increases the risk of these outcomes in routine clinical practice is unknown. We addressed this issue with the use of administrative databases.. We established a cohort of Ontarians treated with an ACEi or an ARB. Within this cohort, we conducted 3 case-control studies. Cases were patients hospitalized with 1 of 3 outcomes (hyperkalemia, AKI, or stroke). In each analysis, we identified up to 5 matched control subjects for each case. Conditional logistic regression was used to examine the association between hospitalization for each outcome and the use of aliskiren in the preceding 60 days.. Among 903,346 patients aged 66 years and older treated with an ACEi or ARB during the 28-month study period, we identified 4235 hospitalized with hyperkalemia, 18,231 hospitalized with AKI, and 8283 hospitalized with stroke. After extensive multivariable adjustment, aliskiren therapy was not associated with a significant increase in the risk of hospitalization for hyperkalemia, AKI, or stroke. We found similar results in stratified analyses of patients with and without a history of chronic kidney disease, diabetes, or heart failure.. Among community-dwelling patients aged 66 years and older receiving therapy with an ACEi or an ARB, aliskiren use was not associated with hospitalization for hyperkalemia, AKI, or stroke.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Case-Control Studies; Cohort Studies; Drug Therapy, Combination; Female; Fumarates; Hospitalization; Humans; Hyperkalemia; Logistic Models; Male; Ontario; Renin; Risk Factors; Stroke

Topics: Acute Kidney Injury; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Fumarates; Humans; Hyperkalemia

Aliskiren combined with other inhibitors of the renin–angiotensin system increases the risk of hyperkalemia. This risk does not translate into an increased incidence of acute kidney injury, suggest the results of a meta-analysis. However, further research is needed to fully evaluate the safety of combination therapy with aliskiren.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Glomerular Filtration Rate; Humans; Hyperkalemia; Renin; Renin-Angiotensin System

We report the first case of acute renal failure with hyperkalemia associated with the recently marketed direct renin inhibitor aliskiren. To optimize blood pressure control, the antihypertensive medication of a 76-year-old hypertensive female patient was changed from the angiotensin II receptor antagonist irbesartan to aliskiren. Spironolactone was continued, as serum creatinine and potassium levels were initially normal. Two weeks later the patient presented with acute oliguric renal failure, symptomatic hyperkalemia and metabolic acidosis, necessitating emergency dialytic treatment. Unrecognized pre-existing renal insufficiency (CKD Stage 2 - 3) and the continuation of spironolactone were identified as predisposing risk factors.

Topics: Acute Kidney Injury; Aged; Amides; Antihypertensive Agents; Female; Fumarates; Humans; Hyperkalemia; Hypertension; Renal Dialysis

Renin-angiotensin system (RAS) blockade with ACE inhibitor and/or angiotensin receptor blocker therapy can lead to increased potassium levels, hence the need to assess dual blockade involving a direct renin inhibitor. Here we report the results of a pre-planned 6-month interim analysis of a long-term, open-label study examining the safety, tolerability and efficacy of the aliskiren/valsartan 300/320-mg combination in patients with hypertension.. A total of 601 patients with hypertension (msDBP > or = 90 and < 110 mmHg) received a combination of aliskiren/valsartan 150/160 mg for 2 weeks followed by forced titration to aliskiren/valsartan 300/320 mg once daily for a targeted duration of 52 weeks. Optional hydrochlorothiazide (HCTZ) addition was allowed from week 8 for inadequate BP control (> or = 140/90 mmHg). The primary objective was to assess the safety of combination therapy; potassium elevations were a predefined safety outcome. BP was measured at regular intervals during the study.. At the 6-month cut-off date, 512 patients (85.2%) were still ongoing with study treatment, and 192 patients had received at least one dose of HCTZ add-on during this period. Combination therapy was generally well-tolerated; the most commonly reported adverse events were headache (7.5%), dizziness (7.3%) and nasopharyngitis (7.2%). Ten patients (2.5%) receiving aliskiren/valsartan and two patients (1.0%) receiving aliskiren/valsartan/HCTZ had serum potassium elevations > 5.5 mmol/L. Only one patient (0.2%) exhibited potassium levels > or = 6.0 mmol/L during this period and the patient was treated with aliskiren/valsartan. Mean msSBP/DBP reductions of 22.3/14.4 mmHg were observed at 6-month endpoint (LOCF analysis) and 73.4% of patients achieved BP control (< 140/90 mmHg; LOCF).. Although lack of an active comparator group is a limitation of the study, our findings show that long-term treatment with the aliskiren/valsartan 300/320-mg combination provided clinically significant BP lowering, was well-tolerated and was associated with a very low rate of potassium elevations in patients with hypertension.

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Female; Fumarates; Humans; Hydrochlorothiazide; Hyperkalemia; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System; Risk Factors; Tetrazoles; Time Factors; Valine; Valsartan

Topics: Amides; Antihypertensive Agents; Drug Therapy, Combination; Fumarates; Humans; Hyperkalemia; Hypertension; Renin; Tetrazoles; Valine; Valsartan

The patients affected by vitamin B12-unresponsive methylmalonic acidemia (MMA) on the long run develop chronic renal disease with interstitial nephropathy and progressive renal insufficiency. The mechanism of nephrotoxicity in vitamin B12-unresponsive MMA is not yet known. Chronic hyporeninemic hypoaldosteronism has been found in many cases of methylmalonic acidemia, hyperkalemia and renal tubular acidosis type 4. We report 2 patients affected by B12-unresponsive methylmalonic acidemia diagnosed at the age of 23 months and 5 years, respectively, with normal glomerular filtration and function. They showed hyporeninemic hypoaldosteronism and significant hyperkalemia requiring sodium potassium exchange resin (Kayexalate) therapy after an episode of metabolic decompensation leading to diagnosis of MMA. In both children, hyporeninemic hypoaldosteronism and hyperkalemia disappeared after 6 months of good metabolic control.

Topics: Child, Preschool; Female; Fumarates; Humans; Hyperkalemia; Hypoaldosteronism; Infant; Kidney; Male; Maleates; Metabolism, Inborn Errors; Vitamin B 12