trandolapril and Renal-Insufficiency

Trandolapril/verapamil sustained release (SR) [Tarka] is an oral, fixed-dose combination of the ACE inhibitor trandolapril and the SR formulation of the phenylalkylamine calcium channel antagonist verapamil. It is indicated for the treatment of hypertension in patients who require more than one agent to achieve blood pressure (BP) targets. In the large, randomised, multicentre INVEST (INternational VErapamil SR/trandolapril STudy), a verapamil SR-based treatment strategy that included trandolapril in most patients was as effective as an atenolol-based treatment strategy in reducing the risk of the primary outcome (first occurrence of death [all-cause], nonfatal myocardial infarction [MI] or nonfatal stroke) in patients with hypertension and coronary artery disease (CAD) and was as well tolerated. Trandolapril/verapamil SR is generally more effective at controlling hypertension than either component as monotherapy, and is as effective as a number of other fixed-dose combination therapies. The combination is as well tolerated as trandolapril monotherapy and is at least as well tolerated as verapamil SR monotherapy. In hypertensive patients with type 2 diabetes mellitus in the BENEDICT (BErgamo NEphrologic DIabetes Complications Trial), trandolapril/verapamil SR prolonged the time to the onset of persistent microalbuminuria compared with placebo, as did trandolapril monotherapy. Thus, trandolapril/verapamil SR is an effective option for the treatment of essential hypertension in patients requiring more than one agent to achieve BP targets, including those with compelling indications, such as CAD or type 2 diabetes.

Topics: Adult; Aged; Antihypertensive Agents; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Combinations; Drug Interactions; Humans; Hypertension; Indoles; Liver Failure; Randomized Controlled Trials as Topic; Renal Insufficiency; Verapamil

Evidence suggests that the effectiveness of angiotensin-converting enzyme (ACE) inhibition diminishes with time, resulting in increasing angiotensin II levels, the action of which can be inhibited by the addition of an angiotensin receptor blocker (ARB). In the present study, the renal protective effects of ACE inhibitors and ARBs were compared over a five-year period in a prospective, randomized, open-blind study in 68 nondiabetic Japanese patients with elevated serum creatinine levels.. Japanese patients with renal insufficiency were randomly assigned to receive either an ACE inhibitor (benazepril 1.25 to 5 mg daily or trandolapril 0.5 to 4 mg daily) or ARB (candesartan 2 to 8 mg daily or losartan 25 to 100 mg daily) at the Kidney Disease Center at Saitama Medical School Hospital. The primary study endpoint was a change in glomerular filtration rate (GFR) between the baseline value and the last available value obtained during the five-year treatment period, as estimated by the Cockcraft-Gault equation. Secondary endpoints included the annual changes in GFR, serum creatinine level, urinary protein excretion, and blood pressure, as well as the rate of development of endstage renal disease.. There were no significant differences in the primary endpoint between the two groups. However, after 4 years, the decline in GFR in patients treated with ARBs was significantly greater than that seen in patients treated with an ACE inhibitor (p<0.05). Furthermore, the rate of introduction of dialysis therapy was also significantly greater in the ARB-treated patients (52.7% in ACE inhibitor and 81.2% in ARB group at year 5. p<0.01).. While our data suggested that ARB, like ACE, treatment might slow the progression of renal dysfunction, it also pointed to the necessity to be alerted to the progression to endstage renal disease with longterm medication.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chronic Disease; Creatinine; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Indoles; Losartan; Male; Middle Aged; Prospective Studies; Renal Insufficiency; Tetrazoles

Patients with reduced renal function are at increased risk for adverse cardiovascular outcomes. In the post-myocardial infarction setting, angiotensin-converting enzyme (ACE) inhibitors have been shown to be as effective in patients with impaired renal function as in those with preserved renal function.. We assessed the relation between renal function and outcomes, the influence of ACE inhibition on this relation, and whether renal function modifies the effectiveness of ACE inhibition in patients with stable coronary artery disease and preserved systolic function enrolled in the Prevention of Events with ACE inhibition trial (PEACE). Patients (n=8290) were randomly assigned to receive trandolapril (target, 4 mg/d) or placebo. Clinical creatinine measures were available for 8280 patients before randomization. The estimated glomerular filtration rate (eGFR) was calculated with the 4-point Modification of Diet in Renal Disease equation. Renal function was related to outcomes, and the influence of ACE-inhibitor therapy was assessed with formal interaction modeling. The mean eGFR in PEACE was 77.6+/-19.4, and 1355 (16.3%) patients had reduced renal function (eGFR <60 mg.mL(-1).1.73 m(-2)). We observed a significant interaction between eGFR and treatment group with respect to cardiovascular and all-cause mortality (P=0.02). Trandolapril was associated with a reduction in total mortality in patients with reduced renal function (adjusted HR, 0.73; 95% CI, 0.54 to 1.00) but not in patients with preserved renal function (adjusted HR, 0.94; 95% CI, 0.78 to 1.13).. Although trandolapril did not improve survival in the overall PEACE cohort, in which mean eGFR was relatively high, trandolapril reduced mortality in patients with reduced eGFR. These data suggest that reduced renal function may define a subset of patients most likely to benefit from ACE-inhibitor therapy for cardiovascular protection.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Chronic Disease; Coronary Artery Disease; Female; Glomerular Filtration Rate; Humans; Indoles; Male; Middle Aged; Renal Insufficiency; Survival Analysis; Treatment Outcome

Trandolapril is a newly developed angiotensin converting enzyme inhibitor (ACEI) whose characteristic is that it undergoes hepatic excretion. ACEI appears to have a specific reno-protective and antiproteinuric role in patients with chronic glomerulonephritis(CGN). Although renally excreted ACEI tend to accumulate and cause side-effects in patients with renal dysfunction, the pharmacokinetics of trandolapril were not affected by renal dysfunction. We compared the effect of other renally excreted ACEI with those of trandolapril on serum creatinine (s-Cr), creatinine clearance(Ccr), proteinuria and total protein(TP) in CGN patients who switched from another ACEI to trandolapril. Twelve hypertensive patients with chronic renal failure(nine males and three females, ranging from 30 to 72 years of age) who were treated by other renally excreted ACEIs for long periods(2 to 8 years) with some effects on proteinuria and renal function, were enrolled in the present study. After ACEI therapy, s-Cr had decreased(2.09 to 1.80 mg/dl, p < 0.01) as well as proteinuria(1.65 to 0.71 g/day, p < 0.01). A single daily oral dose of 1 mg of trandolapril was administered to these patients regardless of their blood pressure status and renal functions. After change to trandolapril therapy, s-Cr(2.25 to 2.06 mg/dl, p < 0.01) and urinary protein(1.82 to 1.34 g/day, p < 0.05) significantly decreased. On the contrary, both Ccr and TP significantly increased at the level of 39.4 to 44.4 ml/min(p < 0.05) and 6.80 to 7.02 g/dl (p < 0.01), respectively. No apparent side effects, such as hyperkalemia, hyponatremia, anemia or worsening of the existing renal dysfunction except for coughing, were observed in these patients. Furthermore, none of the 12 patients treated with trandolapril required discontinuation of the compound. In conclusion, it was shown from this study that trandolapril is effective for the treatment of hypertensive patients with renal insufficiency irrespective of the original diseases. Thus, it can be envisaged that trandolapril is one of the most appropriate agents compared to other renally excreted ACEI for these patients with renal insufficiency. We recommend the change from other ACEIs to trandolapril, when renal dysfunction might be due to ACEI accumulation.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chronic Disease; Female; Glomerulonephritis; Humans; Hypertension, Renal; Indoles; Male; Metabolic Clearance Rate; Middle Aged; Proteinuria; Renal Insufficiency

We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the follow-up period was 50 weeks. RAS was blocked using angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arteriovenous Fistula; Benzoates; Drug Evaluation, Preclinical; Drug Therapy, Combination; Epoxide Hydrolases; Female; Heart Failure; Indoles; Male; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renal Insufficiency; Urea