Ole Lederballe Pedersen

Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: An analysis of findings from the VALUE trial.

Background In the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial the primary outcome (cardiac morbidity and mortality) did not differ between valsartan and amlodipine-based treatment groups, although systolic blood pressure (SBP) and diastolic blood pressure reductions were significantly more pronounced with amlodipine. Stroke incidence was non-significantly, and myocardial infarction was significantly lower in the amlodipine-based regimen, whereas cardiac failure was non-significantly lower on valsartan. Objectives The study protocol specified additional analyses of the primary endpoint according to: sex; age; race; geographical region; smoking status; type 2 diabetes; total cholesterol; left ventricular hypertrophy; proteinuria; serum creatinine; a history of coronary heart disease; a history of stroke or transient ischemic attack; and a history of peripheral artery disease. Additional subgroups were isolated systolic hypertension and classes of antihypertensive agents used immediately before randomization. Methods The 15 245 hypertensive patients participating in VALUE were divided into subgroups according to baseline characteristics. Treatment by subgroup interaction analyses were carried out by a Cox proportional hazard model. Within each subgroup, treatment effects were assessed by hazard ratios and 95% confidence intervals. Results For cardiac mortality and morbidity, the only significant subgroup by treatment interaction was of sex (P = 0.016), with the hazard ratio indicating a relative excess of cardiac events with valsartan treatment in women but not in men, but SBP differences in favour of amlodipine were distinctly greater in women. No other subgroup showed a significant difference in the composite cardiac outcome between valsartan and amlodipine-based treatments. For secondary endpoints, a sex-related significant interaction was found for heart failure (P < 0.0001), with men but not women having a lower incidence of heart failure with valsartan. Conclusion As in the whole VALUE cohort, in no subgroup of patients were there differences in the incidence of the composite cardiac endpoint with valsartan and amlodipine-based treatments, despite a greater blood pressure decrease in the amlodipine group. The only exception was sex, in which the amlodipine-based regimen was more effective than valsartan in women, but not in men, whereas the valsartan regimen was more effective in preventing cardiac failure in men than in women.

Relation of left ventricular geometry and function to systemic hemodynamics in hypertension: The Life Study

Objectives To clarify the relations of systemic hemodynamics to left ventricular (LV) geometric patterns in patients with moderate hypertension and target organ damage. Background LV geometry stratifies risk in hypertension, but relations of LV geometry to systemic hemodynamic patterns in moderately severe hypertension have not been fully elucidated. Design Cross-sectional case–control study. Setting Baseline findings in the echocardiographic substudy of the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE) and in a normotensive reference group. Patients/participants Nine hundred and sixty-four patients with Stage I–III hypertension and LV hypertrophy by Cornell voltage duration criteria ((SV3 + RaVL [+ 6 mm in women]) × QRS > 2440 mm × ms) or modified Sokolow–Lyon voltage criteria (SV1 + RV5/RV6 > 38 mm), and 366 apparently normal adults. Interventions None. Methods Two-dimensional and Doppler echocardiograms were used to classify hypertensive patients into groups with normal geometry, concentric remodelling and concentric and eccentric hypertrophy, and to measure stroke volume (SV), cardiac output, peripheral resistance and pulse pressure/SV as a measure of arterial stiffness. Comparisons were adjusted for covariates by general linear model with the Sidak post-hoc test. Results Mean SV was higher in patients with eccentric hypertrophy (83 ml/beat) and lower with concentric remodeling (68 ml/beat) than in normal adults (73 ml/beat). Cardiac output was highest in patients with eccentric LV hypertrophy and lower with concentric remodeling than eccentric hypertrophy; mean pressure and peripheral resistance were equally high in all hypertensive subgroups, whereas pulse pressure/SV was most elevated (by a mean of 47% versus reference subjects) with concentric remodeling and least so (mean + 15%) with eccentric hypertrophy. In multivariate analysis (Multiple R + 0.68), LV mass was independently related to higher systolic pressure, older age, SV, male gender and body mass index (all P < 0.001). Relative wall thickness was independently related (Multiple R + 0.50) to older age, higher systolic pressure, lower SV (all P < 0.001) and higher body mass index (P + 0.007). SV and cardiac output were lower in patients with low stress-corrected midwall shortening. Conclusion In patients with moderate hypertension and ECG LV hypertrophy, the levels of SV and pulse pressure/SV, are associated with, and may be stimuli to different LV geometric phenotypes.

Small artery structure during antihypertensive therapy is an independent predictor of cardiovascular events in essential hypertension.

Objective: Structural changes of small resistance arteries occur early in the disease process of essential hypertension and predict cardiovascular events in previously untreated patients. We investigated whether on-treatment small artery structure also identifies patients at elevated risk despite normalization of blood pressure (BP). Methods: We conducted a long-term follow-up survey of cardiovascular events in 134 moderate-risk patients with 9–12 months of well treated essential hypertension. All participants underwent subcutaneous biopsies with determination of small artery structure in terms of media to lumen ratio (M : L) before and during treatment. Results: After 9–12 months of treatment SBP was lowered from 164 ± 15 to 134 ± 14 mmHg (P < 0.01) and M : L reduced from 0.084 ± 0.028 to 0.075 ± 0.024 (P < 0.01). Mean follow-up hereafter was 15 years representing a total of 2035 years for the entire cohort. During this period 47 patients suffered a predefined cardiovascular event. For patients with on-treatment M : L above the mean value of the cohort (≥0.075), the hazard ratio was 2.14 [95% confidence interval (CI) 1.19–3.84, P = 0.01] and also those with M : L above mean +2SD of a normotensive population (≥0.098) had an elevated risk (hazard ratio 2.99, 95% CI 1.60–5.58, P < 0.01). Both results were adjusted for heart score (a 10-year mortality risk estimate integrating age, sex, smoking status, cholesterol level and SBP). Analysis of changes in M : L during treatment showed significantly higher event rates among patients with increased M : L and vice versa (hazard ratio 1.36 per 25% change, 95% CI 1.07–1.73, P = 0.013). Conclusion: On-treatment small artery structure identifies individuals still at increased cardiovascular risk despite long-term BP normalization and may be an additional target for therapy to prevent cardiovascular events.

Long-term effects of isradipine on blood pressure and renal function

The hemodynamic and renal effects of isradipine were investigated in 10 hypertensive patients treated for 3.5 months and in a further nine patients treated for two years. Both groups achieved significant and sustained reductions in systolic blood pressure/diastolic blood pressure (-15 percent/-12 percent and -15 percent/-20 percent, respectively; p less than 0.001). Renal parameters were investigated two to three hours after the morning dose of isradipine, using a water-loading procedure. After 3.5 months of treatment, the glomerular filtration rate and renal plasma flow showed small increases (+6 percent and +9 percent, respectively, p less than 0.05), whereas, after two years, these changes were no longer present (+4 percent and 0 percent). Clearance of sodium and uric acid was increased by 40 percent (p less than 0.01) and 21 percent (p less than 0.01), respectively, after 3.5 months, and by 45 percent (p less than 0.05) and 23 percent (p less than 0.01), respectively, after two years. Lithium clearance studies revealed the natriuretic effect to be located in the proximal tubule. After 3.5 months, a significant relationship was found between the blood pressure response and the change in sodium excretion, but this relationship also was no longer present after two years. In conclusion, because of a maintained blood pressure-lowering effect while preserving renal function, and sustained natriuretic and uricosuric actions, isradipine can be considered a promising agent in the long-term treatment of arterial hypertension.

Ambulatory blood pressure monitoring after 1 year on valsartan or amlodipine-based treatment: a VALUE substudy.

Objective The ambulatory blood pressure (ABP) monitoring substudy of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was carried out in a subset of patients from USA, Italy and Denmark. ABP was measured after 1 year in the trial, with the aim of evaluating comparability of ABP levels on valsartan (VAL) and amlodipine (AML)-based regimens. Methods ABP was measured every 20 min during a 25-h period after morning administration of medicine; 659 patients were available for intention-to-treat analysis. Results Office blood pressure (BP) differences were smaller than in the main study and mean ABP levels also showed only minor differences between the two regimens (VAL, 132.5/74.8 mmHg; AML, 131.5/75.2 mmHg). However, during the first 7 h after dosing, ABP was lower on VAL, whereas AML exerted a significantly stronger effect during the last 4 h of the dosing interval – possibly influencing the differences in office BP found in the main study. Mean heart rate (HR) was higher on AML (72.3 bpm) than on VAL (70.5 bpm) (P = 0.013), suggesting a sustained difference in sympathetic activation. Correlation analysis showed a close relationship between treated ABP levels and the occurrence of combined cardiovascular endpoints – superior to the relationship to office BP. Conclusions In these elderly high-risk patients, diastolic ABP levels tended to be less predictive than systolic, and daytime less predictive than night-time for all cardiovascular endpoints. The findings underline the importance of ABP substudies in comparative trials for elucidating significant differences in pharmacodynamics, and stresses the superior predictive power of ABP.

The quantitative aspect of photoplethysmography revised

SummaryThe overall transfer function of a photoplethysmograph (PPG) converting changes in intravascular volume to changes in recorder pen deflection was investigated. The specifications of the apparatus working as a red cell densitometer were assessed in vitro, and it was found that PPG output is a logarithmic function of red cell density roughly in accordance with the Lambert-Beer theorem. In an in vivo experiment it was found that PPG output is also a logarithmic function of digital intravascular volume as assessed by means of air plethysmography. It is suggested that the equation for this in vivo function is different because of a dual action of stasis, producing increases in both intravascular volume and haematocrit. Although the relative contributions of the two disparate phenomena are not assessed further, it is concluded that their joint action on PPG output can be described by a monologarithmic function. In the Appendix, sources of non-linearity in the electronics of PPG are pointed out and instructions for the use of an exponential amplifier which will linearize the overall transfer function are given.

Acute natriuresis induced by inhibition of proximal tubular reabsorption of sodium and water in hypertensives following acute calcium entry blockade with nifedipine.

To elucidate the renal effects and especially the natriuretic properties of calcium entry blockers, we studied the effect of sublingual nifedipine 20 mg in 16 patients with mild to moderate essential hypertension. The lithium clearance technique was utilized and constant infusion technique was employed to measure glomerular filtration rate (GFR) and renal plasma flow (RPF). Nifedipine induced a significant reduction of systolic and diastolic blood pressure and an increase in heart rate. RPF increased and renal vascular resistance fell significantly, whereas GFR was unchanged. A significant increase in diuresis and in clearance of sodium and lithium was seen. The absolute and fractional proximal reabsorption of sodium and water was reduced. The absolute distal reabsorption increased significantly. The results indicate that the natriuretic action of nifedipine in hypertensives is a proximal tubular event.

α-Adrenoceptor Blockade in Patients with Mild to Moderate Hypertension: Long-Term Renal Effects of Doxazosin

Summary: Using constant infusion technique and a water-loading procedure, we investigated renal hemodynamic and excretional variables in 15 essential hypertensive patients [diastolic blood pressure (DBP) 102 ± 10 mm Hg] after 3 weeks of placebo and after 16 weeks of treatment with a postjunctional α1-adrenoceptor-antagonist, doxazosin (1–16 mg) once daily. A minor decrease in supine DBP (p < 0.05) but no significant changes in systolic BP (SBP) and heart rate (HR) were observed. No significant changes were noted in glomerular filtration rate (GFR), renal plasma flow (RPF), and renal vascular resistance (RVR). The mean renal excretion rate of sodium, potassium, uric acid, and albumin for the entire group was unaffected by the treatment, but the individual changes in sodium clearance correlated significantly with changes in mean BP (r = 0.64, n = 15, p < 0.05). Six patients showed an increase in sodium excretion after treatment, whereas nine showed a decrease. No decrease in mean body weight was noted, but the BP reduction after 5 months of treatment correlated significantly with the changes in body weight (r = 0.62, n = 15, p < 0.01). The results indicate that long-term treatment with doxazosin had no deleterious effect on renal function, but the effects on BP were rather modest. The individual BP response is probably determined by the degree of fluid retention even if an intact pressure-natriuresis relationship could still be demonstrated during chronic therapy.

Silent Myocardial Ischaemia in Untreated Essential Hypertensives

In hypertension, hypertrophy of the left ventricle might enhance the risk of ischaemia because of an augmented oxygen demand and an insufficient oxygen supply. The aims of the study were to estimate the prevalence of silent ischaemia in a group of untreated hypertensives with Holter monitoring and 3 different stress tests, and to look for a possible association between the presence of ischaemia and the blood pressure level as well as the left ventricular mass. The prevalence of silent ischaemia was tested in a group of 34 untreated hypertensives by Holter monitoring and by bicycle ergometer test, hyperventilation and captopril tests. 68% of the patients exhibited silent ischaemic periods during Holter monitoring. There was a trend towards a higher 24-hour SBP and DBP level in patients with ischaemia (p < 0.05), in addition to a tendency towards a higher catecholamine excretion in patients with ischaemia (p < 0.05), and a higher left ventricular mass (NS). Silent ischaemic episodes during ergometer exercise test were found in 27%. Only 3% had ischaemia during hyperventilation and captopril tests. In conclusion, the prevalence of ischaemia during the various stress tests was low, whereas Holter monitoring revealed signs of silent ischaemia in a substantial proportion of the patients. Patients with ischaemia tended to present more severe degrees of hypertension.

COMPARATIVE STUDIES ON THE EFFECTS OF TOLMESOXIDE (Rx71107), A TOLMESOXIDE METABOLITE (Rx71112) AND NIFEDIPINE IN ISOLATED BLOOD VESSELS

1 The effect was studied of tolmesoxide (Rx71107), a tolmesoxide metabolite (Rx71112) and nifedipine on active tension in human isolated crural veins and in rat thoracic aorta. The effects of tolmesoxide and nifedipine on 22Na and 45Ca net influx in noradrenaline‐induced contractions were investigated in rat thoracic aorta. 2 Tolmesoxide, Rx71112 and nifedipine caused a concentration‐related inhibition of noradrenaline (NA)‐ and potassium (K+)‐induced contractions in human veins. Nifedipine was by far the most potent drug in these respects. Tolmesoxide (4.7μm‐4700 μm) and Rx71112 (22 μm‐220 μm) inhibited the NA‐induced contraction more effectively than the K+‐induced concentration. The reverse was true for nifedipine (0.0023‐3 μm). 3 Nifedipine had a similar potency in inhibiting the NA‐induced contraction in rat aorta and human veins, whereas the inhibitory effect of tolmesoxide was more pronounced in rat aorta than in human veins. 4 Tolmesoxide was a weak antagonist of the contractile effects of the cumulative addition of calcium on human veins. In concentrations up to 470 μm, tolmesoxide was completely devoid of inhibitory effects on 22Na and 45Ca net influx in rat aorta. Rx71112 (220 μm) had an inhibitory effect on 22Na net influx but no significant effect on 45Ca net influx. 5 Nifedipine was an effective antagonist of the contractile effects of cumulative addition of calcium in human veins and had a concentration‐related inhibitory effect on both 22Na and 45Ca uptake in rat aorta. 6 The results indicate that tolmesoxide and Rx71112 cause dilatation of human crural veins in vitro at concentrations that do not interfere with the net transmembranal movements of Ca and are thus clearly different from the effects of nifedipine.