Impact of a Low-Dose Combination of Isradipine SRO and Spirapril
Impact of a Low-Dose Combination of Isradipine SRO and Spirapril
Objective: This study investigated the effects of a low-dose fixed combination of the ACE inhibitor isradipine SRO (slow-release oral) and the calcium antagonist spirapril on left ventricular hypertrophy (LVH) in patients with mild to moderate hypertension and LVH.
Design: Open, non-randomised preliminary study.
Subjects: 20 patients (11 men and nine women, mean age 62 ± 12 years) with arterial hypertension and LVH were included in the study.
Methods: ECG-triggered nuclear magnetic resonance tomography (MRT), echocardiography and radionuclide ventriculography were used to measure parameters of left ventricular function at baseline and after 12 weeks' treatment with a fixed combination of isradipine SRO 2.5mg and spirapril 3mg once daily.
Results: Diastolic blood pressure was normalised (≤ 90mm Hg) after 6 weeks in 19 of 20 patients; only one patient required the dosage to be doubled to achieve BP control. Mean blood pressure was reduced from 163/99mm Hg at baseline to 150/84mm Hg at the end of the study (2p < 0.001). Mean end-systolic interventricular septum thickness measured by MRT was reduced from 20.1 to 18.2mm (2p < 0.001) after 12 weeks and end-systolic left ventricular posterior wall thickness from 19.2 to 17.7mm (2p < 0.001). Echocardiographic assessments resulted in similar findings. The left ventricular mass index calculated from echocardiographic data decreased from 195 to 164 g/m (2p < 0.001). A marked drop in total peripheral resistance from 1470 to 1233 units (2p < 0.001) was paralleled by a 14% decrease in systolic wall tension and an improvement in peak ventricular filling rate. Although there was a significant reduction in left ventricular mass, parameters of cardiac work did not change significantly, thus indicating a more efficient ventricular performance during treatment.
Conclusion: In this preliminary study, a low-dose combination of isradipine and spirapril induced a significant regression in LVH and an improvement in haemodynamic parameters in patients with mild to moderate hypertension and LVH. This finding needs to be confirmed in larger-scale, controlled studies.
The main cardiac response to primary hypertension is concentric left ventricular hypertrophy (LVH). Data from the Framingham cohort as well as later studies have indicated that LVH is an important independent risk factor for congestive heart failure, coronary artery disease, stroke, arrhythmia and sudden death.
Hypertensive hypertrophy of the left ventricle is not only based on a mere expansion in muscle cell size due to an increased amount of contractile proteins, but is also accompanied by proliferation and structural changes in fibrous tissue, resulting in impaired ventricular compliance. These structural changes are already beginning in the early course of hypertension and comprise myocardial hypertrophy as well as coronary micro- and macroangiopathy. Antihypertensive therapy thus not only aims to normalise elevated blood pressure (BP) but also to induce regression of cardiac hypertrophy.
Preclinical and clinical studies have indicated that antihypertensive agents from different classes induce regression of LVH to a different extent, which is not strictly correlated to the degree of BP reduction. Antihypertensive drugs inducing a comparable degree of regression again differ in the proportional decrease of muscle to connective tissue. In order not to impair ventricular performance any further, it is most desirable to obtain an equivalent reduction in muscle and connective tissue. Among the drugs that have been proven to achieve this goal to a satisfactory extent are the ACE inhibitors and the dihydropyridine calcium antagonists.
Currently, the most common approaches to the pharmacological management of hypertension are stepped-care therapy and sequential monotherapy. Two studies have recently proposed another approach, namely to initiate treatment with low doses of antihypertensives with different mechanisms of action. The rationale behind this concept is that small doses of drugs with different modes of action used in combination are likely to minimise the dose-dependent adverse experiences that occur when single drugs are titrated to their therapeutic dose levels.
Increased interest has been expressed in the combination of calcium antagonists and ACE inhibitors because the effective management of many patients with hypertension and concomitant risk factors will almost certainly include such combinations.
The dihydropyridine calcium antagonist isradipine SRO (slow-release oral) has a slow onset and long duration of action. In comparison with first-generation calcium channel blockers, it offers the advantage of minimal cardiodepressant activity, selective action on the coronary and skeletal muscle vasculature, and prolonged vasodilatory action.
Spirapril is a new carboxyl-bearing ACE inhibitor. It is a prodrug that is rapidly and extensively metabolised into the pharmacologically active diacid metabolite spiraprilat. The latter has a long elimination half-life allowing once-daily administration. It is subject to balanced biliary and renal elimination and can thus be used in patients with impaired renal function.
Based on the observation that the drug classes to which isradipine and spirapril belong effectively induce LVH regression and improve ventricular function, this single centre study assessed the effects of 12 weeks' treatment with a low-dose fixed combination of isradipine SRO and spirapril on LVH, BP and left ventricular function in patients with mild to moderate hypertension and LVH.
Objective: This study investigated the effects of a low-dose fixed combination of the ACE inhibitor isradipine SRO (slow-release oral) and the calcium antagonist spirapril on left ventricular hypertrophy (LVH) in patients with mild to moderate hypertension and LVH.
Design: Open, non-randomised preliminary study.
Subjects: 20 patients (11 men and nine women, mean age 62 ± 12 years) with arterial hypertension and LVH were included in the study.
Methods: ECG-triggered nuclear magnetic resonance tomography (MRT), echocardiography and radionuclide ventriculography were used to measure parameters of left ventricular function at baseline and after 12 weeks' treatment with a fixed combination of isradipine SRO 2.5mg and spirapril 3mg once daily.
Results: Diastolic blood pressure was normalised (≤ 90mm Hg) after 6 weeks in 19 of 20 patients; only one patient required the dosage to be doubled to achieve BP control. Mean blood pressure was reduced from 163/99mm Hg at baseline to 150/84mm Hg at the end of the study (2p < 0.001). Mean end-systolic interventricular septum thickness measured by MRT was reduced from 20.1 to 18.2mm (2p < 0.001) after 12 weeks and end-systolic left ventricular posterior wall thickness from 19.2 to 17.7mm (2p < 0.001). Echocardiographic assessments resulted in similar findings. The left ventricular mass index calculated from echocardiographic data decreased from 195 to 164 g/m (2p < 0.001). A marked drop in total peripheral resistance from 1470 to 1233 units (2p < 0.001) was paralleled by a 14% decrease in systolic wall tension and an improvement in peak ventricular filling rate. Although there was a significant reduction in left ventricular mass, parameters of cardiac work did not change significantly, thus indicating a more efficient ventricular performance during treatment.
Conclusion: In this preliminary study, a low-dose combination of isradipine and spirapril induced a significant regression in LVH and an improvement in haemodynamic parameters in patients with mild to moderate hypertension and LVH. This finding needs to be confirmed in larger-scale, controlled studies.
The main cardiac response to primary hypertension is concentric left ventricular hypertrophy (LVH). Data from the Framingham cohort as well as later studies have indicated that LVH is an important independent risk factor for congestive heart failure, coronary artery disease, stroke, arrhythmia and sudden death.
Hypertensive hypertrophy of the left ventricle is not only based on a mere expansion in muscle cell size due to an increased amount of contractile proteins, but is also accompanied by proliferation and structural changes in fibrous tissue, resulting in impaired ventricular compliance. These structural changes are already beginning in the early course of hypertension and comprise myocardial hypertrophy as well as coronary micro- and macroangiopathy. Antihypertensive therapy thus not only aims to normalise elevated blood pressure (BP) but also to induce regression of cardiac hypertrophy.
Preclinical and clinical studies have indicated that antihypertensive agents from different classes induce regression of LVH to a different extent, which is not strictly correlated to the degree of BP reduction. Antihypertensive drugs inducing a comparable degree of regression again differ in the proportional decrease of muscle to connective tissue. In order not to impair ventricular performance any further, it is most desirable to obtain an equivalent reduction in muscle and connective tissue. Among the drugs that have been proven to achieve this goal to a satisfactory extent are the ACE inhibitors and the dihydropyridine calcium antagonists.
Currently, the most common approaches to the pharmacological management of hypertension are stepped-care therapy and sequential monotherapy. Two studies have recently proposed another approach, namely to initiate treatment with low doses of antihypertensives with different mechanisms of action. The rationale behind this concept is that small doses of drugs with different modes of action used in combination are likely to minimise the dose-dependent adverse experiences that occur when single drugs are titrated to their therapeutic dose levels.
Increased interest has been expressed in the combination of calcium antagonists and ACE inhibitors because the effective management of many patients with hypertension and concomitant risk factors will almost certainly include such combinations.
The dihydropyridine calcium antagonist isradipine SRO (slow-release oral) has a slow onset and long duration of action. In comparison with first-generation calcium channel blockers, it offers the advantage of minimal cardiodepressant activity, selective action on the coronary and skeletal muscle vasculature, and prolonged vasodilatory action.
Spirapril is a new carboxyl-bearing ACE inhibitor. It is a prodrug that is rapidly and extensively metabolised into the pharmacologically active diacid metabolite spiraprilat. The latter has a long elimination half-life allowing once-daily administration. It is subject to balanced biliary and renal elimination and can thus be used in patients with impaired renal function.
Based on the observation that the drug classes to which isradipine and spirapril belong effectively induce LVH regression and improve ventricular function, this single centre study assessed the effects of 12 weeks' treatment with a low-dose fixed combination of isradipine SRO and spirapril on LVH, BP and left ventricular function in patients with mild to moderate hypertension and LVH.