Impact of a Low-Dose Combination of Isradipine SRO and Spirapril on Left Ventricular Mass and Left Ventricular Performance in Patients with Hypertension and Left Ventricular Hypertrophy
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.
Open, non-randomised preliminary study.
20 patients (11 men and nine women, mean age 62 ± 12 years) with arterial hypertension and LVH were included in the study.
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.
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/m2 (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.
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.
KeywordsLeft Ventricular Hypertrophy Leave Ventricular Mass Index Moderate Hypertension Isradipine Peak Filling Rate
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.[2, 3, 4, 5]
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,[6, 7, 8] 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.[9,10] 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.[11, 12, 13, 14, 15, 16] Antihypertensive drugs inducing a comparable degree of regression again differ in the proportional decrease of muscle to connective tissue.[17,18] In order not to impair ventricular performance any further, it is most desirable to obtain an equivalent reduction in muscle and connective tissue.[19,20] Among the drugs that have been proven to achieve this goal to a satisfactory extent are the ACE inhibitors and the dihydropyridine calcium antagonists.[21, 22, 23]
Currently, the most common approaches to the pharmacological management of hypertension are stepped-care therapy and sequential monotherapy.[24,25] Two studies[26,27] 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.[28,29]
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.[31,32]
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.
Patients and Methods
Outpatients over 18 years of age with sitting systolic BP (SBP) above 140mm Hg and sitting diastolic BP (DBP) between 100 and 114mm Hg after a 2-week placebo period as well as LVH [defined as end-systolic septal thickness ≥15mm in the sagittal axis measured by nuclear magnetic resonance tomography (MRT) imaging] were considered for inclusion in the study. Main exclusion criteria were the use of any antihypertensive medication within 6 months prior to study entry, secondary hypertension, cerebrovascular insult less than 6 weeks previously or known cerebral blood flow disturbances (e.g. transient ischaemic attack), unstable angina pectoris or myocardial infarction in the previous 3 months, heart failure unable to be controlled by digitalis, impaired renal or hepatic function, other serious concomitant diseases, drug or alcohol abuse, and mental impairment.
Study Design and Methods
This open, non-randomised study was approved by the local ethics committee and patients gave their written informed consent to take part. The study consisted of a 2-week placebo run-in phase and a subsequent 12-week treatment period. A fixed combination of isradipine SRO 2.5mg and spirapril 3mg (i.e. half of the conventional monotherapy daily dosages) was administered once daily in the morning. If DBP was not normalised after 6 weeks of therapy (i.e. DBP ≤90mm Hg), the dosage was doubled.
A complete physical examination including a 12-lead electrocardiogram was performed at baseline and after 12 weeks of therapy. Sitting BP was measured with a standard mercury sphygmomanometer according to the American Heart Association guidelines after a 5-minute rest, and the mean value of three measurements used in the calculations. Patient compliance was checked by means of pill counting at each visit. Standard fasting laboratory tests were performed during the placebo phase and at the end of the study. Adverse events were assessed at each visit by recording spontaneous reports. Target measurements (MRT, radioventriculography, echocardiography) were performed at baseline and after 12 weeks.
B-Mode echocardiography was performed according to von Devereux and Reicheck, and included the following parameters: interventricular septum thickness in systole (IVSs) and diastole (IVSd), left posterior wall thickness in end systole (PWTs) and end diastole (PWTd), left ventricular inner diameter in end systole (LVIDs) and end diastole (LVIDd), left ventricular muscle mass (LVMM) and left ventricular mass index (LVMI).
MRT was used to assess IVSs, PWTs and apical thickness. The tomograph (Siemens Magnetom) used a superconduction magnet operating at a field strength of 1.5 Tesla. The Sirecust 404 electrocardiogram (ECG) system had ultrathin copper leads to ensure exact end-systolic and end-diastolic triggering. The repetition rate, or interval between sets of radio frequency pulses, was determined by each subject’s heart rate and ranged from 400 to 1000msec. MRT scans were recorded in four slices and three planes (frontal, transverse and sagittal) with multiple angulations. The imaging sequence was pin-echo with echo delay times of 35, 70 and 105msec and a proton resonance frequency of 15MHz. The selection gradient was 3mT/m. A 256 × 256 reconstruction matrix was used. Angulation was started in the frontal plane to define the correct angle in the transverse plane. This method has been proven to be at least as accurate as echocardiography and permits easy reproduction of the cardiac phase measured, the depth of the level and the angle of determination.
After in vivo marking of erythrocytes by intravenous administration of 10 to 20 μ/kg bodyweight stannous pyrophosphate and 400 to 1100 megabecquerel (MBq) Tc-pertechnetat (99mTcO4−) over an interval of 20 to 30 minutes, a gated pool radionuclide ventriculography was performed. Pictures were taken via an ECG-triggered multigated acquisition with a Na-iodine Crystal camera system (APEX 115) in a modified 30° LAO-projection with a 15° caudal-angled position. For the exercise radionuclide ventriculography we used a stationary cycle ergometer with an induction braking system, exercising the patient up to his maximum steady-state frequency. The following data were derived from this examination: total peripheral resistance [TPR ≈ 60 × 1333 × mean BP/ cardiac output (CO)], systolic wall tension (Tsyst = SBP × 3√ESV2), left ventricular end-diastolic volume (LVED), left ventricular end-systolic volume (LVES), ejection fraction (EF), CO, peak ejection rate (PER), peak filling rate (PFR), left ventricular ejection time (LVET), and RR-interval.
In the statistical analysis, the results of the various measurements were expressed as mean ± SED. The differences (Δ) between baseline and week 12 (Δ) were tested by the Wilcoxon signed rank test, with the level of significance p < 0.05.
Twenty patients (11 men and nine women, mean age 62 ± 12 years) with arterial hypertension were included in our study. SBP ranged from 150 to 190mm Hg and DBP from 98 to 110mm Hg. Mean bodyweight was 78 ± 10kg and did not change significantly throughout the study. On average, arterial hypertension had been diagnosed 3.3 years previously, and LVH 17.3 months previously. Baseline IVSs determined by MRT was 20.1 ± 2.8mm.
Among the 20 patients examined, only one patient had DBP not normalised after 6 weeks’ treatment; this patient responded to the double dosage. During the course of therapy, the mean SBP of all patients declined from 162.6 ± 9.4 to 150.3 ± 14.3mm Hg (−12.3mm Hg; 2p < 0.001) and mean DBP from 98.6 ± 3.8 to 84.1 ± 4.2mm Hg (−14.5mm Hg; 2p < 0.001). There was no significant change in heart rate during the course of therapy.
After 12 weeks’ treatment with isradipine SRO/spirapril, MRT showed reductions in IVSs (from 20.1 to 18.2mm; 2p < 0.001), PWTs (from 19.2 to 17.7mm; 2p < 0.001) and apical thickness (from 22.2 to 19.6mm; 2p < 0.001) [table I]. Echocardiographic measurements confirmed these findings, with IVSs, PWTs, IVSd and PWTd showing significant regression (table II).
We found a highly significant decline in heart muscle mass, with LVMI dropping from 195 ± 31 g/m2 at baseline to 164 ± 31 g/m2 after 12 weeks’ treatment (−31 g/m2, p < 0.001).
There was a high correlation between wall thicknesses measured by MRT and echocardiography. For example, correlations for IVSs before and after treatment were r = 0.83 and r = 0.90, respectively (figure 1 and figure 2). However, there was no correlation between the regression of LVMI and the decline in SBP or DBP (r = 0.03 for LVMI/SBP and r = −0.15 for LVMI/DBP). Neither MRT nor echocardiography showed a correlation between the degree of LVH and the reduction in ventricular muscle mass (r = 0.2). Assumptions that different age subgroups influence the degree of LVH regression were not confirmed by our data (r = −0.508).
Despite the obvious regression of LVH, cardiac output parameters remained largely unchanged at rest as well as during exercise (table III). This is likely to be due to a decrease in afterload arising from a 16% reduction in TPR (from 1470 ± 271 to 1233 ± 175U) and a 14% reduction in systolic wall tension.
PFR (both at rest and during exercise) improved significantly after treatment in the sense of better ventricular compliance, probably because of a reduction in ventricular stiffness (figure 3). Resting PER improved only slightly after treatment, although a significant improvement was seen during exercise (figure 4). This observation is in line with the findings for the other cardiac labour parameters showing that the heart muscle did not achieve a net increase in power during treatment (thus indicating a more efficient ventricular performance).
The combination of isradipine SRO/spirapril was well tolerated; no incompatibilities or serious adverse events were reported and no withdrawals occurred. No significant changes in the ECG or laboratory parameters were noted. At the end of the study, eight patients assessed the tolerability of the medication as ‘very good’, 10 as ‘good’ and two as ‘moderate’.
LVH is recognised as a strong, BP-independent cardiovascular risk factor.[37,38] In fact, LVH predicts complications both in members of the general population and in patients with hypertension more strongly than any other risk factor except advancing age. These observations have provoked great interest in how regression of LVH can be achieved and whether different antihypertensive agents differ in their ability to reduce myocardial hypertrophy in addition to lowering BP.
A meta-analysis of randomised, double-blind studies indicates that ACE inhibitors and, to a lesser extent, calcium channel blockers emerge as the drugs of choice for treating LVH and are superior to diuretics and β-blockers. Dihydropyridine calcium antagonists are functional antagonists to α1- and α2-adrenergic receptors and may therefore cause a regression of LVH. Activation of the renin-angiotensin system has been proved experimentally to act as a trophic stimulus on the myocardial cell and similar observations have been made in humans. As a consequence, blockade of angiotensin II with ACE inhibitors may contribute (independent of any BP-lowering effect) to the reversal of myocardial hypertrophy.
So far, the impact of isradipine and spirapril on LVH has only been investigated in monotherapy studies. In an open study in 15 previously untreated patients with hypertension, 6 months’ treatment with isradipine 2.5 to 10 mg/day caused a significant reduction in mean LVMI of 17%. In another open study in 25 patients with moderate hypertension, 3 months’ treatment with isradipine 2.5 to 5 mg/day (and, if necessary, add-on of hydrochlorothiazide) resulted in a 22% reduction in LVMI. Comparable results were observed after 6 months’ treatment with once daily sustained-release isradipine 5mg in an open pilot study in 12 hypertensive patients with LVH and normal LV diastolic diameter.
Administration of normal to high dosages of spirapril (6 to 24 mg/day) to 11 patients with hypertension for 3 to 36 months effectively reduced parameters of left ventricular hypertrophy, as it did in another study when administered at a dosage of 6 mg/day for 20 weeks to 28 patients with mild to moderate hypertension.
In the present exploratory study both agents in combination, despite the low dosages used, were able to induce a significant regression in LVH. When discussing the results, some methodological considerations have to taken into account. In principle, double-blind, randomised study designs are preferable. The present trial was open and non-randomised and therefore may be prone to bias. In the absence of a control group such as a low-dose combination of a β-blocker and a diuretic it is not possible to assess the relative magnitude of the treatment effect. In addition, substantially higher patient numbers are needed in order to enable us to draw definite conclusions. Our therapeutic endpoint was the DBP level, which is usually the case in day-to-day practice. However, it is well acknowledged that systolic or pulse pressure rather than diastolic pressure determines end-organ damage in hypertensive patients.[24,25]
Bias was reduced by the fact that objective variables with different recognised methods were investigated. In addition to echocardiography, as the most widespread imaging method used for measuring cardiac wall thicknesses, we also used multislice gated multiplanar MRT. Gated MRT can generate excellent morphological contrast and permits easy reproduction of measured cardiac phases, slice thickness and angle of determination. In comparison with echocardiography, MRT provides improved images and permits superior accuracy of measurements. However, it must be said that in a recent study a systematic underestimation of LV mass by MRT was seen.[54,55]
The data derived from both methods indicate that the low-dose combination of a calcium antagonist and an ACE inhibitor is able to induce a substantial regression of LVH in patients with mild to moderate hypertension. Left ventricular mass was reduced by 16% after only 3 months’ treatment and it is likely that the magnitude of the effect increases after longer treatment periods.
These results are in line with other clinical trials showing a 7.8 to 17% reduction in LVH after treatment with ACE inhibitors[21,48,49,52,56,57] and a reduction in left ventricular mass of 11 to 19% with calcium antagonists.[45,56,58,59]
The drug combination used in this study contained half the standard dosage of both isradipine and spirapril, and matched the level of BP control and LVH regression usually achieved with standard dosages of either agent.[45,46,49]
With regard to the haemodynamics, the combination effectively reduced TPR by 16% from baseline and thus lowered the systolic ventricular wall tension by about 14%. The PFR (a measure of ventricular stiffness and LVH) improved at rest and under stress and mean heart rate and PER remained unchanged at rest. The combination therefore did not appear to cause adrenergic stimulation, but maintained cardiac performance and workload on a more efficient and economic level.
According to this pilot study, a once-daily low-dose combination of isradipine SRO and spirapril appears able to induce regression of LVH to a substantial degree and improve ventricular performance in patients with mild to moderate hypertension. Larger-scale studies are warranted to confirm these preliminary findings.
This work was supported by a grant from Novartis Pharma, Nuremberg, Germany. We are indebted to HJ Kaiser, PhD, for his excellent work with the statistical planning and analysis.
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