Triple-combination therapy in the treatment of hypertension: a review of the evidence.

Hypertension is a serious public health concern with inadequate control of blood pressure (BP) worldwide. Contributing factors include low efficacy of drugs, underuse of combination therapies, irrational combinations, physicians' therapeutic inertia and poor adherence to treatment. Current guidelines recommend the use of initial (dual) combination therapy in high-risk patients for immediate BP response, better short- and long-term BP control, and continued/improved patient adherence. This article aims to review the existing evidence of triple-combination therapies with respect to efficacy, safety and adherence to treatment. It is estimated that three drugs are required to achieve BP control in approximately one-fourth to one-third of patients. Randomised controlled trials (RCTs) have shown that triple combinations of amlodipine/valsartan/hydrochlorothiazide, amlodipine/olmesartan/hydrochlorothiazide and amlodipine/telmisartan/hydrochlorothiazide produce greater BP reductions, with greater proportions of patients achieving BP control compared with dual therapies. Further evidence also demonstrates that triple-combination therapy is efficacious for moderate to severe hypertension, with substantial additional BP reduction over dual regimens. Both RCTs and post-marketing observational studies have shown consistent and comparable efficacy in both the general population and high-risk hypertensive subgroups. Triple therapies are generally well tolerated with adverse event profiles similar to dual regimens. In addition, fixed-dose combinations used as single pill improve patient adherence leading to better long-term BP control. Depending on regional circumstances, they may also be cost effective. Thus, single-pill triple combinations of different classes of drugs with complementary mechanisms of action help to treat patients to goal with improved efficacy and better adherence to treatment.

Renal denervation: unde venis et quo vadis?

OBJECTIVE AND METHODS: Renal denervation is a minimally invasive, catheter-based option for the treatment of refractory hypertension. Indications and contraindications for renal denervation have been defined in an interdisciplinary manner. The efficacy and safety of the procedure were evaluated. RESULTS: Currently, indication for renal denervation is limited to patients with primary hypertension and a systolic blood pressure of ≥ 160 mm Hg (or ≥ 150 mm Hg in diabetes type 2) despite optimal medical therapy with ≥ 3 different antihypertensive drugs. In this specific patient population, an average blood pressure reduction of 32/14 mmHg was observed in non-randomized/-controlled trials after renal denervation. These results were not confirmed in the first randomized controlled trial with a non-significantly superior blood pressure reduction of 14.1 ±â€Š23.9 mm Hg compared to controls (-11.74 ±â€Š25.94 mm Hg, difference -2.39 mm Hg p = 0.26 for superiority with a margin of 5 mm Hg) who underwent a sham procedure. CONCLUSION: The efficacy and long-term effects of renal denervation need to be re-evaluated in light of the HTN3 study results. To date, renal denervation should not be performed outside of clinical trials. Future trials should also assess if renal denervation can be performed with sufficient safety and efficacy in patients with hypertension-associated diseases. The use of renal denervation as an alternative therapy (e. g. in patients with drug intolerance) can currently not be advocated. KEY POINTS: The indication for renal denervation should be assessed in an interdisciplinary fashion and according to current guidelines with a special focus on ruling out secondary causes for arterial hypertension. 5 - 10 % of patients with hypertension suffer from refractory hypertension, but only about 1 % of patients meet the criteria for a renal denervation. Renal denervation leads to a significant decrease in office blood pressure; however, the impact on 24-hour blood pressure measurements remains unclear. In the first randomized controlled trial on renal denervation with a control group undergoing a sham procedure, blood pressure reduction failed to reach the anticipated level of superiority over best medical treatment. Periprocedural complications are rare, but long-term safety can currently not be appraised due to the limited data available.

Renal denervation: results of a single-center cohort study.

PURPOSE: To investigate the effect of renal denervation on office-based and 24-h ambulatory blood pressure measurements (ABPM) in a highly selective patient population with drug-resistant hypertension. MATERIALS AND METHODS: Patients with drug resistant hypertension eligible for renal denervation were included in the study population. Office blood pressure and ABPM were assessed prior to and after renal denervation. To detect procedure related renal or renal artery damage, magnetic resonance imaging (MRI) and angiography (MRA) were performed pre-interventional, one day post-interventional, and one month after renal denervation. RESULTS: Mean follow-up time between renal denervation and blood pressure re-assessment was 9.5 ±â€Š3.9 months. Between August 2011 and March 2013, 17 patients prospectively underwent renal denervation. Pre-interventional mean office blood pressure and ABPM were 177.3 ±â€Š20.3/103.8 ±â€Š20.4 mmHg and 155.2 ±â€Š20.5/93.7 ±â€Š14.5 mmHg, respectively. Post-interventional, office blood pressure was significantly reduced to 144.7 ±â€Š14.9/89.5 ±â€Š12.1 (p < 0.05). ABPM values remained unchanged (147.9 ±â€Š20.3/90.3 ±â€Š15.6, p > 0.05). The number of prescribed antihypertensive drugs was unchanged after renal denervation (4.7 ±â€Š2.0 vs. 4.2 ±â€Š1.2, p = 0.18). No renovascular complications were detected in follow-up MRI. CONCLUSION: After renal denervation, no significant decrease in ABPM was observed. These results may indicate a limited impact of renal denervation for drug resistant hypertension. KEY POINTS: • Renal denervation showed no significant effects on 24-h ambulatory blood pressure measurements. • A significant decrease in office blood pressure measurements may be explained by a potential detection bias. • Renal artery alterations were not observed on follow-up MRI scans.

[Diuretics in the treatment of hypertension. Efficacy, safety and tolerability]. / Therapie der Hypertonie mit Diuretika. Wirksamkeit, Sicherheit und Verträglichkeit.

In the treatment of hypertension, both the thiazide diuretics hydrochlorothiazide and bendroflumethiazide and the "thiazide-like" diuretics chlorthalidone and indapamide are used. Guidelines refer to these as the class of thiazide diuretics suggesting their interchangeability. However, bendroflumethiazide and hydrochlorothiazide, at least in the commonly used low dose range, are less potent with respect to blood pressure lowering and may also be less effective in preventing morbidity and mortality events. This is of great clinical relevance since hydrochlorothiazide is by far the most widely prescribed diuretic. Increasing the dose of hydrochlorothiazide would further reduce tolerability of treatment due to an increase in dose-dependent side effects. The underlying mechanisms of the suggested superiority of chlorthalidone on cardiovascular morbidity and mortality remain unclear. The half-life of chlorthalidone has been estimated at >50 h thus exceeding the half-life of hydrochlorothiazide by about 5-fold. Given the documented irregular intake of antihypertensive drugs, the prolonged efficacy of chlorthalidone makes this agent a "forgiving drug" with a definite advantage over hydrochlorothiazide. On the basis of the available evidence, whenever diuretic treatment is indicated in a hypertensive patient, a thiazide-like agent, preferably chlorthalidone should be employed.

A Bayesian hierarchical assessment of gastric emptying with the linear, power exponential and modified power exponential models.

BACKGROUND: Many studies assessed gastric retention over time utilizing different models, mostly with scintigraphic measures at varied endpoints from limited number of normal volunteers. With a standardized 4-h gastric emptying (GE) protocol, we compared model fit by the linear, power exponential (PE), and modified power exponential (MPE) models to contrast differences in GE among different groups based on clinical diagnosis and gender. METHODS: We retrospectively collected 320 patient records with four consecutive hourly scintigraphic measures of percent intragastric residual at the Kansas University Medical Center. We obtained parameter estimates with the Bayesian hierarchical models using informative priors from previous research. KEY RESULTS: The PE or MPE model captured the time dependent GE rate better than the linear model. The estimated GE rates more than doubled for those without gastroparesis compared to patients diagnosed with gastroparesis. Males tended to empty gastric content faster but were not significantly different from females at the 5% level. CONCLUSIONS & INFERENCES: The point estimates and 95% credible interval for GE rates obtained with the PE and MPE models may provide an alternative diagnostic tool for clinicians since it utilizes gastric emptying scintigraphy measures at multiple endpoints which may be sensitive to different aspects of the disease. No agreement in lag phases was obtained by the three models based on respective definitions from previous researches, but similar results would be obtained with the PE and MPE models if both defined lag phase by back projecting the regression lines to the same gastric retention level.

Mechanisms of symptomatic improvement after gastric electrical stimulation in gastroparetic patients.

The aims were to investigate the effects of gastric electrical stimulation (GES) on autonomic function, gastric distention and tone, and central control mechanisms in gastroparetic patients. Ten gastroparetic patients refractory to standard medical therapy participated in this study and data were collected at baseline, within two weeks before surgery for implantation of GES system, and at follow-up sessions between 6 and 12 weeks after GES therapy was initiated. In each session, electrocardiogram, electrogastrogram (EGG) and gastric barostat measurements were conducted before and after a caloric liquid meal. Positron Emission Tomography (PET) brain scans were performed on a separate day. During GES therapy there was a significant increase in the discomfort threshold for mean pressure from 21 mmHg at baseline to 25 mmHg at follow-up, and for mean volume from 561 mL to 713 mL. A significant increase in the postprandial EGG power (amplitude) was observed between baseline and follow up. The sympathovagal balance was significantly decreased after GES therapy, indicating a significant increase in vagal activity. The cumulative PET data showed an increase in quantitative radioactive counts relative to the standardized data base in both the thalamic and caudate nuclei after chronic GES therapy. We conclude that our data suggest that the symptomatic improvement achieved by GES in gastroparesis is best explained by activation of vagal afferent pathways to influence CNS control mechanisms for nausea and vomiting accompanied by enhanced vagal efferent autonomic function and decreased gastric sensitivity to volume distention which enhances postprandial gastric accommodation.

["Soft" and "hard" end points in the example of hypertension]. / "Weiche" und "harte" Endpunkte am Beispiel der Hypertonie.

Hypertension is a disease with a long latency. Those afflicted will, if untreated, die earlier than an age-matched cohort within the general population. In a first phase of intervention trials it was demonstrated that anti-hypertensive treatment, in comparison with placebo, results in a reduction of so-called hard end points (death, stroke, myocardial infarction). In a second phase of clinical trials, which is still continuing, active treatment strategies are being compared. The problem in this phase is that differences in these hard end points are smaller than in placebo-controlled trials. For this reason signs of organ damage that occur in the time between the diagnosis of high blood pressure and the occurrence of hard end points (e.g. left ventricular hypertrophy, microalbuminuria, intima/media thickness) are used as additional end points. According to epidemiological data, these intermediate or surrogate end points are more or less predictive of hard end points. Systematic inclusion of such surrogates in large trials has been tried for some years in an attempt to raise the predictive power of these parameters. Another patient-relevant endpoint of antihypertensive treatment is the new occurrence of diabetes mellitus.

[The modified Bonn Malmö protocol (MBMP) in the treatment of acquired haemophilia A]. / Das modifizierte Bonn-Malmö-Protokoll in der Behandlung der erworbenen Hemmkörperhämophilie -- Eine multimodale Therapiestrategie.

BACKGROUND AND OBJECTIVE: Autoantibodies directed against clotting factors can induce life threatening bleeding with a mortality rate up to 22%. Although the incidence of the disease is low (1-4 x 10(-6)), costs of treatment due to long-term clotting factor substitution can be enormous. Aim of an optimal treatment strategy should be to control bleedings by a rapid and safe elimination of the inhibitor and reinducing long-term immune tolerance. PATIENTS AND METHODS: Treatment of 48 patients with acquired haemophilia A (m=20, f =28, age 61.3 (SD 16.4)), the largest patient collective world-wide, was monitored for a mean of 48 months. Three patients received only conservative treatment. 45 patients were treated intensively by a multimodal strategy including: 1. immunoadsorption for antibody elimination; 2. FVIII substitution; 3. intravenous immunoglobulin substitution and 4. immunosuppression. The times required for inhibitor elimination, factor VIII substitution and the duration of the MBMP were documented. RESULTS: In 45 patients with a high titre critical bleeding was controlled immediately after the initiation of MBMP. There were no deaths from bleeding or the treatment. Inhibitor levels decreased to undetectable levels within a median of 3 days (95% CI, 3-7 days), factor substitution was terminated within a median of 13 days (95% CI, 10-16 days) and the treatment was completed within a median of 15 days (95% CI, 13-17 days). The overall response rate for complete remission (CR) was 91%. When cancer patients were excluded, the CR rate was 97%. CONCLUSION: Considering the short duration and amount of factor VIII substitution, the short time of hospitalization and the long-term median follow up of 48 months without bleeding events, the MBMP appears to have a modifying effect on the immunological response.

[Initial combination treatment of hypertension]. / Initiale Kombinationsbehandlung der Hypertonie. Therapieturbulenzen mit Zweierkombinationen vorbeugen.

Today, European professional associations favor initial treatment of hypertension with low-dose monotherapy or combination treatment. The aim of combination treatment is to reduce side effects through the application of subtherapeutic doses. In the meantime, American experts have abandoned the use of the term low-dose. For certain patients, for example, those with severe hypertension or with a high associated cardiovascular risk, combination treatment with hypertensive agents employing normal doses of the individual substances is now approved in the USA for first-line treatment. The advantages are assumed to be rapid lowering of the blood pressure and improved patient compliance.

Switch from ABCD pretreatment to A-II-A treatment: a multinational, open, centrally randomized, prospective parallel group comparison.

The aim of this trial was to evaluate the efficacy and safety of switching antihypertensive monotherapy from a non-angiotensin II receptor blocker treatment, i.e., angiotensin-converting enzyme (ACE) inhibitor, beta-blocker, calcium (Ca2+) channel blocker or diuretic, to monotherapy with candesartan cilexetil 8 or 16 mg once daily. Patients (age 18-74 years) with mild to moderate essential hypertension were enrolled in this multinational, open-label, centrally randomized, prospective parallel group study. Previous antihypertensive treatment, with either an ACE inhibitor, a beta-blocker, a Ca2+ channel blocker or a diuretic, was maintained for a run-in period of 4 weeks and was then substituted at the baseline visit where patients were randomized into two groups to receive either candesartan cilexetil 8 mg (n = 985) or 16 mg (n = 982) once daily for an 8-week treatment period. Blood pressure (BP) reduction was the primary endpoint after 4 weeks of therapy and the secondary endpoint after 8 weeks of therapy. Results of the first 4 weeks of therapy are presented here. A total of 1,967 patients were included: 985 received candesartan cilexetil 8 mg and 982 candesartan cilexetil 16 mg once daily; 1,879 patients were included in the intention-to-treat analysis. The percentages of patients receiving an ACE inhibitor, a beta-blocker, a Ca2+ channel blocker or a diuretic as previous antihypertensive treatment were 44.7, 18.8, 30.6 and 5.9%, respectively. After 4 weeks of treatment with candesartan cilexetil 8 and 16 mg, sitting diastolic and systolic BP were reduced (mean +/- SD): -7 +/- 10 and -14 +/- 17 mmHg, and -8 +/- 10 and -16 +/- 16 mmHg, respectively. The percentage of patients who were still borderline hypertensive or hypertensive after 4 weeks of substitute treatment was lower in the candesartan cilexetil 16 mg group than in the 8 mg group: 7.1 and 5.3%, respectively, versus 9 and 7.4%, respectively. Reported adverse events were mild or moderate in intensity and in accordance with those reported in the literature. Candesartan cilexetil can be considered an effective and safe alternative to other common antihypertensive monotherapies in a large spectrum of patients with mild and moderate hypertension.