Concomitant Angiotensin-converting Enzyme Inhibitors Research Articles

Pharmacovigilance study of the association between dipeptidyl peptidase–4 inhibitors and angioedema using the FDA Adverse Event Reporting System (FAERS)

Dipeptidyl peptidase-4 (DPP-4) plays a minor role in degrading vasoactive peptides that cause angioedema when angiotensin-converting enzyme (ACE) is present and fully functional. This study investigated the association between DPP-4 inhibitors (DPP-4Is) and angioedema, including cases where the concomitant use of ACE inhibitors (ACEIs) was absent. We obtained data from the US Food and Drug Administration Adverse Event Reporting System and performed a disproportionality analysis, using the reporting odds ratio (ROR) and information component (IC) for signal detection in patients aged ≥ 40 years, stratified by age group and sex. No signal was detected for DPP-4Is when the entire dataset was analyzed. However, a signal was detected for the entire female subset group, the three stratified female groups aged ≥ 60 years, and males in their 40 s. After excluding the data of concomitant ACEI users, most ROR and IC values were lower and significant only for females in their 60 s and males aged ≥ 80 years. Regarding individual DPP-4Is signals, those detected for saxagliptin and sitagliptin in some age groups disappeared after excluding the data of ACEI users. Notably, linagliptin was the only DPP-4I where signals were detected in most female groups, regardless of age and without concomitant ACEI use. Our findings suggest that some DPP-4Is were associated with a higher reporting of angioedema as per age and sex, even in the absence of concomitant ACEI use.

RETURN OF NERVE FUNCTION FOLLOWING RENAL DENERVATION IN THE PRESENCE OF ANGIOTENSIN-CONVERTING ENZYME INHIBITION IN SPONTANEOUSLY HYPERTENSIVE RATS

Objective: Regrowth of renal nerves and functional restoration occurs following renal denervation (RDN). There is little information regarding the impact of concomitant anti-hypertensive therapies on the extent of reinnervation following RDN. Angiotensin-II has previously been shown to promote renal vessel innervation. We hypothesised that angiotensin-converting enzyme inhibition (ACEi) prolongs the antihypertensive effects of RDN by delaying renal nerve regrowth. The aim of this study was to examine the effect of ACEi treatment on the return of nerve function at 12-weeks post-RDN in spontaneously hypertensive rats (SHR). Design and method: Male SHRs (∼12 weeks of age, n > 7/group) were implanted with a radiotelemetry probe to record mean arterial pressure (MAP). Rats were infused with enalapril (1 mg/kg/day s.c.) or vehicle for two weeks. Rats then underwent sham or surgical RDN procedures and ACEi/vehicle infusion continued for an additional 12 weeks following RDN. Vascular contraction to perivascular nerve stimulation in renal lobar arteries was assessed using wire myography to determine the extent of renal nerve function return. Results: ACEi and RDN independently caused an immediate and sustained reduction in MAP (ACEi: -12 ± 3 mmHg, RDN: -19 ± 4 mmHg, both P < 0.05) across the 12-week period compared to untreated counterparts. However, the blood pressure-lowering effect of RDN was not enhanced by concomitant ACEi. Heart mass was ∼16% less in ACEi-RDN rats compared to untreated counterparts. Return of neurovascular function was observed in RDN-treated rats, but levels were only partially restored to that of untreated rats (P < 0.001). ACEi alone attenuated the response to perivascular nerve stimulation (P < 0.05) but the effects of ACEi in combination with RDN were not additive. Conclusions: Here we show partial functional reinnervation is evident 12 weeks following RDN in the SHR. This may account for the sustained reduction in MAP following RDN. ACEi infusion alone attenuated neurovascular function, but ACEi combined with RDN did not affect the return of renal neurovascular function. These findings suggest that RDN and ACEi effectively lower blood pressure in the long term and may confer cardioprotective benefits despite the return of nerve function. However, ACE inhibition does not provide additive benefits to delaying renal reinnervation.

439. Iclaprim Use for Acute Bacterial Skin and Skin Structure Infection (ABSSSI) is Not Associated with Hyperkalemia: Phase 3 REVIVE Studies

BackgroundTrimethoprim inhibits sodium channels in the distal portion of the renal tubule, thereby impairing renal potassium excretion. Trimethoprim has been associated with a greater risk of hyperkalemia compared with other antibiotics (amoxicillin, nitrofurantoin, cefalexin, ciprofloxacin). An analysis of Phase 3 studies was conducted to determine whether iclaprim, under development for ABSSSI and also a selective bacterial dihydrofolate reductase inhibitor like trimethoprim, is associated with hyperkalemia, relative to vancomycin, an antibiotic not associated with hyperkalemia.MethodsA post-hoc safety analysis was conducted on pooled results of two Phase 3, double-blind, randomized (1:1), active-controlled trials (REVIVE-1/-2) in patients with ABSSSI. These trials compared iclaprim 80 mg fixed doses with vancomycin 15 mg/kg; both administered intravenously every 12 hours for 5–14 days. Hyperkalemia was defined as serum potassium (K) ≥5.5 mmol/L, if normal at baseline, while on study drug. Hyperkalemia was compared between treatment groups and stratified subgroup comparisons were performed.ResultsDemographics and baseline disease characteristics were similar between the pooled iclaprim and vancomycin groups (table). Hyperkalemia occurred during treatment in 1.5% (9/592) and 2.5% (15/599) of patients treated with iclaprim and vancomycin, respectively. Of the patients with hyperkalemia, one patient in each treatment group had moderate to severe renal impairment (creatinine clearance [CrCl] 15–59 mL/minute). Among patients with moderate to severe renal impairment on any RAS, KSD or K supplements, hyperkalemia occurred in 1/16 and 0/16 patients in the iclaprim and vancomycin groups, respectively, and in 2/83 and 0/46 patients with mild to no renal impairment. No patients with hyperkalemia experienced adverse events of palpitations, chest pain, myalgia, muscular weakness or fatigue.ConclusionNo differences in hyperkalemia were seen between the iclaprim and vancomycin groups in the Phase 3 REVIVE studies. In general, few cases of hyperkalemia occurred among patients with renal impairment treated with concomitant angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers treated with iclaprim. Disclosures All authors: No reported disclosures.

Nursing Assessment of Tissue Plasminogen Activator for Pulmonary Embolism

Nursing Assessment of Tissue Plasminogen Activator for Pulmonary Embolism

Drug-induced angioedema : Focus on bradykinin

On apathophysiological level, angioedema can be differentiated into histamine- and bradykinin-mediated types. The prototype drug-associated, bradykinin-mediated form of angioedema is angiotensin-converting enzyme (ACE) inhibitor-induced angioedema. The hypothesized cause is adecrease in bradykinin degradation via ACE inhibition. In this scenario, other bradykinin-degrading enzymes assume major importance. When the effect of these enzymes is also diminished, e. g., due to genetic variants or external factors, compensation for the inhibition of ACE may be insufficient. An increased risk of angioedema has also been reported for other drugs, particularly when prescribed in combination with ACE inhibitors. Here, the suspected cause also relates to the degradation of bradykinin. When angioedema arises within the context of concomitant ACE inhibitor use, additive bradykinin degradation effects may be implicated.

Optimizing Cardiovascular Care With Mineralocorticoid Receptor Antagonists

Mineralocorticoid receptor antagonists (MRAs) block the action of aldosterone at receptors in the kidneys, causing increased sodium and water excretion in exchange for potassium retention. There are 4 treatment groups in the cardiovascular population that have shown benefit with MRA therapy: resistant hypertension, post–acute coronary syndromes, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction. Serum potassium and kidney function should be monitored closely, especially if a patient is on a concomitant angiotensin-converting enzyme inhibitor, an angiotensin II receptor blocker, or direct renin inhibitor therapy.

Effects of Atorvastatin Dose and Concomitant Use of Angiotensin-Converting Enzyme Inhibitors on Renal Function Changes over Time in Patients with Stable Coronary Artery Disease: A Prospective Observational Study.

Angiotensin-converting enzyme inhibitors (ACEI) and statins are widely used in patients with coronary artery disease (CAD). Our aim was to compare changes in glomerular filtration rate (GFR) over time in subjects with stable CAD according to atorvastatin dose and concomitant use of ACEI. We studied 78 men with stable CAD referred for an elective coronary angiography who attained the then-current guideline-recommended target level of low-density lipoproteins (LDL) cholesterol below 2.5 mmol/L in a routine fasting lipid panel on admission and were receiving atorvastatin at a daily dose of 10–40 mg for ≥3 months preceding the index hospitalization. Due to an observational study design, atorvastatin dosage was not intentionally modified for other reasons. GFR was estimated during index hospitalization and at about one year after discharge from our center. Irrespective of ACEI use, a prevention of kidney function loss was observed only in those treated with the highest atorvastatin dose. In 38 subjects on ACEI, both of the higher atorvastatin doses were associated with increasing beneficial effects on GFR changes (mean ± SEM: −4.2 ± 2.4, 1.1 ± 1.6, 5.2 ± 2.4 mL/min per 1.73 m2 for the 10-mg, 20-mg and 40-mg atorvastatin group, respectively, p = 0.02 by ANOVA; Spearman’s rho = 0.50, p = 0.001 for trend). In sharp contrast, in 40 patients without ACEI, no significant trend effect was observed across increasing atorvastatin dosage (respective GFR changes: −1.3 ± 1.0, −4.7 ± 2.1, 4.8 ± 3.6 mL/min per 1.73 m2, p = 0.02 by ANOVA; rho = 0.08, p = 0.6 for trend). The results were substantially unchanged after adjustment for baseline GFR or time-dependent variations of LDL cholesterol. Thus, concomitant ACEI use appears to facilitate the ability of increasing atorvastatin doses to beneficially modulate time-dependent changes in GFR in men with stable CAD.

Effects of aliskiren in diabetic and non-diabetic patients with coronary artery disease: Insights from AQUARIUS

BackgroundAliskiren previously was found to have potentially harmful effects in diabetic individuals prescribed concomitant angiotensin converting enzyme inhibitors (ACEI) or angiotenisn receptor antagonists (ARB). We explored potential effects of aliskiren on coronary atheroma progression and major adverse cardiovascular events (MACE: death/non-fatal MI/non-fatal stroke/hospitalization for heart failure/hospitalization for ACS/arterial revascularization) in patients with and without diabetes mellitus (DM). MethodsAQUARIUS employed serial intravascular ultrasound measures of coronary atheroma volume in coronary artery disease patients randomized to receive daily aliskiren 300 mg or placebo for 104 weeks. This post hoc analysis compared changes in plaque volume [percent atheroma volume (PAV) and total atheroma volume (TAV)] and MACE in patients with (n = 115) and without (n = 343) DM stratified by treatment allocation. ResultsIn multivariable propensity-weighted analyses, which included controlling for baseline and concomitant ACEI/ARB therapy and duration of aliskiren therapy, aliskiren-treated non-DM patients demonstrated the greatest PAV and TAV regression, whereas aliskiren-treated DM patients demonstrated the greatest TAV progression and greater PAV. Aliskiren-treated non-DM patients appeared at significantly lower risk of MACE compared with their aliskiren-treated DM counterparts [HR 95% CI 0.28 (0.10, 0.80)]. Statistical interactions were noted between DM status and treatment allocation for both changes in PAV (p < 0.001), TAV (p = 0.010) and MACE (p = 0.057). ConclusionsAliskiren appears to be relatively anti-atherosclerotic in non-diabetic patients. Due to the limited number MACE and low numbers of diabetic patients in AQUARIUS, the pro-atherosclerotic effects of aliskiren in this population are inconclusive, and these results should be thus considered hypothesis generating. Further outcome studies are required in non-diabetic patients to confirm the possible favorable effects of aliskiren.

Normal 25-Hydroxyvitamin D Levels Are Associated with Less Proteinuria and Attenuate Renal Failure Progression in Children with CKD.

Angiotensin-converting enzyme inhibitors (ACEi) for renin-angiotensin-aldosterone system (RAAS) blockade are routinely used to slow CKD progression. However, vitamin D may also promote renoprotection by suppressing renin transcription through cross-talk between RAAS and vitamin D-fibroblast growth factor-23 (FGF-23)-Klotho pathways. To determine whether vitamin D levels influence proteinuria and CKD progression in children, we performed a post hoc analysis of the Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of CKD in Pediatric Patients (ESCAPE) cohort. In 167 children (median eGFR 51 ml/min per 1.73 m(2)), serum 25-hydroxyvitamin D (25(OH)D), FGF-23, and Klotho levels were measured at baseline and after a median 8 months on ACEi. Children with lower 25(OH)D levels had higher urinary protein/creatinine ratios at baseline (P=0.03) and at follow-up (P=0.006). Levels of 25(OH)D and serum vitamin D-binding protein were not associated, but 25(OH)D ≤50 nmol/L associated with higher diastolic BP (P=0.004). ACEi therapy also associated with increased Klotho levels (P<0.001). The annualized loss of eGFR was inversely associated with baseline 25(OH)D level (P<0.001, r=0.32). Five-year renal survival was 75% in patients with baseline 25(OH)D ≥50 nmol/L and 50% in those with lower 25(OH)D levels (P<0.001). This renoprotective effect remained significant but attenuated with ACEi therapy (P=0.05). Renal survival increased 8.2% per 10 nmol/L increase in 25(OH)D (P=0.03), independent of eGFR; proteinuria, BP, and FGF-23 levels; and underlying renal diagnosis. In children with CKD, 25(OH)D ≥50 nmol/L was associated with greater preservation of renal function. This effect was present but attenuated with concomitant ACEi therapy.

Effects of Inhibitors of the Renin-Angiotensin System on the Efficacy of Interferon beta-1b: A post hoc Analysis of the BEYOND Study

Background: In experimental autoimmune encephalomyelitis, inhibition of the renin-angiotensin system with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors resulted in a significantly ameliorated disease course. We evaluated the effects of ARBs and ACE inhibitors on the efficacy of interferon beta-1b in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: In this post hoc analysis of the BEYOND (Betaferon Efficacy Yielding Outcomes of a New Dose) study, clinical and MRI end points were compared between patients treated with interferon beta-1b 250 or 500 µg and concomitant ARBs or ACE inhibitors and patients treated with interferon beta-1b 250 or 500 µg only (reference group). Results: Patients in the ARB group (n = 22) tended to have a higher relapse rate (0.48 vs. 0.23, p = 0.051) and a higher number of new gadolinium-enhancing lesions (0.6 vs. 0.3, p = 0.057) than patients in the reference group. Patients in the ACE inhibitor group (n = 49) also tended to have a higher relapse rate (0.29 vs. 0.22, p = 0.357). No differences were observed for the other end points. Conclusion: In the BEYOND study cohort, a concomitant medication with ARBs or ACE inhibitors did not have a beneficial effect in patients with RRMS treated with interferon beta-1b. As patients appeared to have a higher relapse rate, our results warrant further investigation.

Bleeding Events Following Concurrent Use of Warfarin and Oseltamivir by Medicare Beneficiaries

During the 2009 H1N1 influenza pandemic, the UK Medicines and Healthcare Products Regulatory Agency received case reports suggesting a potentiation of warfarin anticoagulation by the antiviral drug oseltamivir. We evaluated this putative interaction using Medicare data. To determine the frequency of bleeding following addition of oseltamivir or comparator drugs among Medicare beneficiaries taking warfarin. This was a retrospective cohort evaluation using Medicare nationwide data. Cohort members were Medicare Parts A, B, and D beneficiaries from June 30, 2006 to October 31, 2010 receiving warfarin for at least 1 month prior to a concomitant drug of interest (oseltamivir, ampicillin, trimethoprim-sulfamethoxazole (TMP-SMX), and angiotensin-converting enzyme (ACE) inhibitors). Bleeding within 14 days of new prescriptions for oseltamivir or comparators was identified using inpatient or emergency department ICD-9 (International Classification of Diseases, ninth revision) discharge diagnosis codes for gastrointestinal hemorrhage, epistaxis, hematuria, and intracranial bleeding. Patients with bleeding within 30 days preceding the prescription concomitant to warfarin were excluded. With concomitant ACE inhibitors as reference, adjusted odds ratios (ORs) for any bleeding events within 14 days were 1.47 (95% confidence interval [CI] = 1.08-1.88), 1.24 (95% CI = 0.97-1.57), and 2.74 (95% CI = 2.53-3.03), for warfarin plus ampicillin, oseltamivir, and TMP-SMX, respectively. In a sensitivity analysis, adjusted ORs over a 7-day period were 1.89 (95% CI = 1.29-2.59), 1.47 (95% CI = 1.06-2.02), and 3.07 (95% CI = 2.76-3.49) for warfarin plus ampicillin, oseltamivir, and TMP-SMX, respectively. Bleeding with oseltamivir plus warfarin was not significantly increased over a 14-day observation period; a sensitivity analysis showed a statistically significant increase over a 7-day period; in contrast, the data consistently showed the known tendency of TMP-SMX to potentiate the effects of warfarin. The results should be interpreted with the limitations of this approach in mind, including the inability to control for unmeasured confounders.

Effects of dual blockade of the renin-angiotensin system on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy and hypertension in the ORIENT: a post-hoc analysis (ORIENT-Hypertension).

Combination therapy with angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors (ACEIs) requires further evaluation in patients with diabetic nephropathy and hypertension. In a post hoc analysis of the Olmesartan Reducing Incidence of Endstage renal disease in diabetic Nephropathy Trial with hypertension, we examined the effects of olmesartan on renal and cardiovascular outcomes in the presence or absence of an ACEI. Among 563 patients randomized to receive either olmesartan (n=280) or placebo (n=283), 73.5% (n=414) received a concomitant ACEI. Compared with placebo, olmesartan significantly reduced proteinuria in both the ACEI-treated and non-ACEI-treated groups. The respective changes in the urinary protein creatinine ratio in the olmesartan-treated and placebo-treated groups were −32.6% and +21.1% without an ACEI (P=0.001) and −17.0% and +2.2% with an ACEI (P=0.028). In the olmesartan group, 115 patients developed primary renal outcomes (41.1%) compared with 129 (45.6%) in the placebo group (hazard ratio (HR): 0.97, P=0.787). The respective HRs in the ACEI-treated and non-ACEI-treated groups were 1.02 (P=0.891) and 0.84 (P=0.450). 40 olmesartan-treated patients (14.3%) and 53 placebo-treated patients (18.7%) developed secondary cardiovascular outcomes (HR: 0.65, P=0.042). The respective HRs in the ACEI-treated and non-ACEI-treated groups were 0.69 (P=0.129) and 0.51 (P=0.129). Olmesartan was well tolerated. Dual blockade treatment caused more hyperkalemia than monotherapy. In patients with diabetic nephropathy and hypertension, olmesartan significantly reduced proteinuria, independent of ACEI treatment and cardiovascular outcome but failed to show additional renal benefit compared with ACEI treatment alone. The cardiovascular benefit of dual treatment requires further evaluation.

A Comparison of Adverse Drug Reactions Between High- and Standard- Dose Trimethoprim-Sulfamethoxazole in the Ambulatory Setting

High-dose trimethoprim-sulfamethoxazole (TMP-SMX) for the empiric treatment of community-acquired methicillin-resistant Staphylococcus aureus skin and soft tissue infections has been evaluated for efficacy, but characterization of adverse reactions is lacking. To describe adverse reactions associated with high-dose TMP-SMX therapy, a retrospective medical record review of outpatients receiving TMP-SMX was conducted. Each episode (case) of a patient receiving high-dose TMP-SMX (at least 4 double-strength tablets per day) was matched by next closest prescription number with a patient (control) receiving standard-dose TMP-SMX. 982 cases were reviewed; 491 in each arm. At least one adverse drug reaction (ADR) occurred in 9.1% of patients. There was a significant difference in the incidence for any ADR between high-dose and standard-dose groups (13.0% vs 5.09%, respectively; p<0.0001). More patients taking high-dose TMP-SMX developed hyperkalemia (3.46% vs 0.81%, p=0.0066), acute renal injury (3.67% vs 1.63%, p=0.044), and rash (1.83% vs 0.20%, p=0.021). Patients receiving high-dose TMP-SMX had significantly higher rates of electrolyte abnormality ADR (5.09% vs 1.63%, p=0.0021), gastrointestinal ADR (5.30% vs 2.24%, p=0.011), renal ADR (3.67% vs 1.63%, p=0.044), central nervous system ADR (2.65% vs 0.81%, p=0.047), and hypersensitivity (2.24% vs 0.41%, p=0.022). Concomitant receipt of an angiotensin-converting enzyme (ACE) inhibitor was a univariate variable associated with hyperkalemia, and advanced age and receipt of high-dose TMP-SMX were independent variables. ADRs such as hyperkalemia are more likely to be associated with the use of high-dose TMP-SMX in the ambulatory setting. Clinicians should use caution when initiating high-dose TMP-SMX and consider laboratory monitoring in patients of advanced age or those receiving concomitant ACE inhibitor therapy.

Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study

Aims/hypothesisThe renal and cardiovascular protective effects of angiotensin receptor blocker (ARB) remain controversial in type 2 diabetic patients treated with a contemporary regimen including an angiotensin converting enzyme inhibitor (ACEI).MethodsWe examined the effects of olmesartan, an ARB, on primary composite outcome of doubling of serum creatinine, endstage renal disease and death in type 2 diabetic patients with overt nephropathy. Secondary outcome included composite cardiovascular outcomes, changes in renal function and proteinuria. Randomisation and allocation to trial group were carried out by a central computer system. Participants, caregivers, the people carrying out examinations and people assessing the outcomes were blinded to group assignment.ResultsFive hundred and seventy-seven (377 Japanese, 200 Chinese) patients treated with antihypertensive therapy (73.5% [n = 424] received concomitant ACEI), were given either once-daily olmesartan (10–40 mg) (n = 288) or placebo (n = 289) over 3.2 ± 0.6 years (mean±SD). In the olmesartan group, 116 developed the primary outcome (41.1%) compared with 129 (45.4%) in the placebo group (HR 0.97, 95% CI 0.75, 1.24; p = 0.791). Olmesartan significantly decreased blood pressure, proteinuria and rate of change of reciprocal serum creatinine. Cardiovascular death was higher in the olmesartan group than the placebo group (ten vs three cases), whereas major adverse cardiovascular events (cardiovascular death plus non-fatal stroke and myocardial infarction) and all-cause death were similar between the two groups (major adverse cardiovascular events 18 vs 21 cases, all-cause deaths; 19 vs 20 cases). Hyperkalaemia was more frequent in the olmesartan group than the placebo group (9.2% vs 5.3%).Conclusions/interpretationOlmesartan was well tolerated but did not improve renal outcome on top of ACEI. Trial registration: ClinicalTrials.gov NCT00141453 Funding: The ORIENT study was supported by a research grant from Daiichi Sankyo.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2325-z) contains peer-reviewed but unedited supplementary material, including a list of the ORIENT study investigators, which is available to authorised users.

Association of Long-term Administration of the Survivin mRNA-Targeted Antisense Oligonucleotide LY2181308 With Reversible Kidney Injury in a Patient With Metastatic Melanoma

A 57-year-old man with metastatic melanoma was treated with the survivin inhibitor and antisense oligonucleotide LY2181308 as part of a First-in-Human Dose trial. After 18 months of treatment, he developed kidney injury and the treatment was discontinued. At 9 months and before the development of kidney injury, LY2181308 concentrations were 8- to 10-fold higher relative to median predicted values, but within the targeted exposure considered to be safe. However, at 17 months, 28 days after stopping LY2181308 therapy, LY2181308 concentration exceeded the predicted range by 38-fold. His decreased kidney function was slow to improve after stopping treatment. A kidney biopsy showed signs of acute tubular injury with regeneration. Complete recovery of kidney function occurred 6 months after treatment was stopped. The relationship between high exposures and slow LY2181308 clearance with the gradual improvement in kidney function after stopping the antisense treatment suggests that the oligonucleotide was related to the kidney injury. Based on this case report, kidney function should be monitored frequently in patients receiving long-term treatment with antisense oligonucleotides that specifically target survivin, particularly when they receive concomitant angiotensin-converting enzyme inhibitors or nonsteroidal anti-inflammatory drugs.

Does the ratio of serum aldosterone to plasma renin activity predict the efficacy of diuretics in hypertension? Results of RENALDO

We hypothesized that the aldosterone: renin ratio (ARR) predicts the antihypertensive response to mineralocorticoid receptor antagonist, spironolactone (SPIRO), when compared with bendroflumethiazide (BFZ). We conducted a randomized, crossover, trial on hypertensive patients with either high ARR (HARR defined as >750 and plasma aldosterone >250 pmol/l) or low ARR (LARR defined as <300 and plasma renin activity <10 ng/ml per h). Each group took SPIRO 50 mg once daily for 12 weeks and BFZ 2.5 mg once daily for 12 weeks in random order separated by 2-week washout. Patients with mean 24-h systolic ambulatory blood pressure (SABP) at least 140 mmHg were included. Primary endpoint was difference in SABP between SPIRO and BFZ in patients with HARR compared with those with LARR. One hundred and eleven patients (60 HARR and 51 LARR) completed the study. SABP at 12 weeks in the HARR group was 129.4 mmHg on SPIRO and 134.4 mmHg on BFZ [difference -5.01; 95% confidence interval (CI) -7.51, -2.52; P < 0.0002]. In the LARR group, SABP was 129.7 mmHg on SPIRO and 133.1 mmHg on BFZ [difference -3.43 (95% CI -6.18, -0.68) P < 0.01]. Difference between groups (HARR vs. LARR) was -1.58 mmHg (95% CI 5.25, -2.08; not significant, P = 0.394). In a secondary analysis of the overall study population of 111 patients, SABP reduction with SPIRO 50 mg was superior to BFZ 2.5 mg [SPIRO -14.8 mmHg, BFZ -10.5 mmHg, difference -4.29 mmHg (95% CI -6.12, -2.46)]. Results were similar for secondary endpoints. Plasma renin activity or aldosterone did not predict blood pressure response to SPIRO. Results were independent of concomitant angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use. The ARR did not predict the blood pressure response to SPIRO. SPIRO 50 mg was significantly more effective than BFZ 2.5 mg in lowering SABP irrespective of baseline ARR, plasma renin activity or aldosterone.

Reduction of amiodarone pulmonary toxicity in patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

Amiodarone (AM) is a widely used anti-arrhythmic medication. Its utility is, however, limited by adverse side effects. The mechanism of amiodarone-induced toxicity (APT) in the lungs is attributed primarily to stimulation of the angiotensin enzyme system leading to lung cell apoptosis and cell death. This mechanism has been demonstrated by in vitro and in vivo experimental animal studies. To date, however, no in vivo human studies have confirmed this mechanism for APT. This study was undertaken to determine whether angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) offer a protective effect against APT in humans. Demonstration of a protective effect of an ACE-I or ARB would suggest that stimulation of the angiotensin enzyme system may be a key process in APT. An 8-year retrospective analysis of all patients on AM therapy at the James H. Quillen Veterans Affairs Medical Center was undertaken. A total of 1000 patients on AM were identified. One-hundred-and-seventeen were excluded from the study. Five-hundred-and-twenty-four patients were simultaneously on an ACE-I or ARB. The remaining 359 patients were not. Pulmonary toxicity attributed to AM was identified in five and 14 patients with and without concomitant ACE-I or ARB therapy, respectively. The APT rate for the entire patient sample was 2.2%. APT occurred in 1% of patients on an ACE-I or ARB and in 3.9% of patients not taking an ACE-I or ARB. This observed difference in percentage of APT was statistically significant. The concomitant use of ACE-I or ARB in patients taking AM appears to offer a protective effect against APT. This observation suggests that the stimulation of the angiotensin enzyme system may play an important role in APT in humans.

Understanding the PRoFESS study for secondary stroke prevention

The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial is the largest secondary stroke prevention study completed to date. It compared extended-release dipyridamole plus aspirin (eDYP-ASA) versus clopidogrel and telmisartan versus antihypertensive regimens excluding angiotensin receptor blockers (ARBs). No statistical differences were found in either arm for the primary outcome of fatal or nonfatal stroke or prespecified secondary end points. eDYP-ASA also was associated with increases in major hemorrhagic events but not with statistical increases in combined rates of stroke recurrence or hemorrhage. Despite PRoFESS, the role of ARBs post stroke remains unclear, as concomitant angiotensin-converting enzyme inhibitor use in PRoFESS obscured whether just blood pressure lowering or renin-angiotensin system blockade is important. The resulting interpretation that eDYP-ASA is "not noninferior" has raised questions about how to interpret noninferiority analyses. Also, although the PRoFESS editorialists suggested that aspirin, the historical bystander control, was the "winner," a review of prior antiplatelet studies suggests that the benefits of aspirin, either as combination or monotherapy, are outweighed by its bleeding hazards. The benefits of clopidogrel or eDYP-ASA, compared with aspirin, are small but real, and both remain preferred agents in secondary stroke prevention.

Conventional therapy with an ACE inhibitor diminishes left ventricular dyssynchrony during the progression of heart failure

Purpose Left ventricular (LV) mechanical dyssynchrony is an important codeterminant of cardiac dysfunction in heart failure (HF) patients exhibiting either a narrow or a wide QRS complex. We hypothesized that an angiotensin converting enzyme (ACE) inhibitor would prevent LV dyssynchrony during the progression of pacing-induced HF through its beneficial effects on hemodynamic change and myocardial fibrosis. Methods Twenty-eight dogs were assigned to the following treatment groups; rapid ventricular pacing (HF group; n = 10), concomitant ACE inhibitor and rapid pacing (enalapril 1.9 mg/kg/day: ACEI group; n = 8), or sham-operated control (control group; n = 10). After 4 weeks of pacing, cardiac function was evaluated using micromanometers and conductance catheters. We used indexes to quantify the temporal and spatial aspects of mechanical dyssynchrony derived from online segmental conductance catheter signals. At each time point, a segmental signal was defined as dyssynchronous if its change was opposite to the simultaneous change in the total LV volume. Mechanical dyssynchrony was calculated as the mean of the segmental dyssynchronies during systole, diastole, and throughout the cardiac cycle. Results In the ACEI group, the LV ejection fraction was preserved, and total systemic resistance and end-diastolic volume were significantly decreased, while stroke volume was significantly increased compared to the HF group. The mechanical dyssynchrony index in the HF group was significantly higher compared to that of the control group, while it was significantly lower in the ACEI group. Thus, conventional therapy with an ACE inhibitor diminished LV dyssynchrony during the progression of pacing-induced HF.

Combination Therapy with the Advanced Glycation End Product Cross-Link Breaker, Alagebrium, and Angiotensin Converting Enzyme Inhibitors in Diabetes: Synergy or Redundancy?

Blockade of advanced glycation end product (AGE) accumulation with alagebrium with concomitant angiotensin converting enzyme inhibition was tested for effects on renal function and on other postulated mediators of diabetic renal disease including the renin-angiotensin system, AGEs, mitochondrial and cytosolic oxidative stress, and intracellular signaling molecules. Sprague Dawley rats were rendered diabetic with streptozocin and followed consecutively for 32 wk with nondiabetic controls. Groups were treated with ramipril (1 mg/kg.d; wk 0-32); alagebrium (10 mg/kg.d; wk 16-32); or a combination of both. Although individual treatments had significant effects on albuminuria, no further improvements were seen with combination therapy. Changes in urinary vascular endothelial growth factor excretion mirrored those seen in albuminuria. Diabetes was associated with suppression of circulating angiotensin II in the context of increased circulating and renal levels of the AGE, carboxymethyllysine. All treatments attenuated circulating but not renal carboxymethyllysine levels. The renal gene expression of AGE receptor 1 and soluble receptor for advanced glycation end products were markedly reduced by diabetes and normalized with alagebrium. Diabetes induced renal mitochondrial oxidative stress, which was reduced with alagebrium. In the cytosol, both therapies were equally effective in reducing reactive oxygen species production. Increases in membranous protein kinase C activity in diabetes were attenuated by all treatments, whereas diabetes-associated increases in nuclear factor-kappaB p65 translocation remained unaltered by any therapy. It is evident that renin-angiotensin system blockade and AGE inhibition have specific effects. However, many of their downstream effects appear to be similar, suggesting that their renoprotective benefits may ultimately involve common pathways and key points of convergence, which could be important targets for new therapies in diabetic nephropathy.