RATIONAL’
Rasilez® - nicht-interventionelle Studie zur Innovation in der Hypertoniebehandlung

RATIONAL’
Rasilez® - nicht-interventionelle Studie zur Innovation in der Hypertoniebehandlung

- Evaluation der therapeutischen Response gemäß den WHO-Kriterien für Hypertonie (WHO/ISH 1999) und die Erreichung des vorab vom behandelnden Arzt definierten Zielblutdruckwertes an Hand der 24-h-Blutdruckmessung. Dabei werden folgende Subkohorten berücksichtigt: Rasilez® als Monotherapie, Rasilez® in Kombinationstherapie gemäß der Zulassung und Subkohorten mit speziellen Risikofaktoren (ältere Patienten, Patienten mit Diabetes mellitus, Niereninsuffizienz, Herzinfarkt und / oder Schlagan-fall in der Vorgeschichte).
- Wirksamkeit und Verträglichkeit im Arzturteil
- Veränderungen der Lebensqualität
- Ermittlung von Inzidenz und Profil der unerwünschten Ereignisse, die unter der Behandlung mit
Rasilez® während der Dauer der NIS beobachtet werden.

Rasilez

600

7000

Müller, Alfons

Phase IV Manager NIS

Novartis Pharma GmbH

Roonstr. 25

90429 Nürnberg

Deutschland

alfons.mueller@novartis.com

Telefon: 0911/273-12897

Telefax: 0911/273-15897

Novartis Pharma GmbH

Roonstr. 25

90429 Nürnberg

Deutschland

07.06.2011

Studie bereits abgeschlossen

This was an open-label, uncontrolled, non-interventional, naturalistic multicenter study including outpatients with hypertension. The study did not include a control group. All patients received aliskiren at the licensed doses of 150 mg or 300 mg/day.

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Patients of both sexes treated with aliskiren for hypertension were observed and documented. Switching treatment to aliskiren only with the objective to include the patient into the NIS was not allowed. Each patient had to be treated with aliskiren in accordance with the labeled aliskiren indication.

15 Monate

9.5.2.1 Efficacy assessments
Office DBP and SBP were measured according to the methods used in the respective study-center. Due to the naturalistic study-design, the protocol did not include any specific requirements.

24-h blood pressure measurements were also performed without specific definitions of the procedure.

9.5.2.2 Appropriateness of efficacy assessments
Measurement of DPB, SBP and 24-h blood pressure are appropriate for the aliskiren efficacy assessment in patients with hypertension. As several guidelines defined target values for DBP and SBP, efficacy can be assessed by comparisons between baseline and endpoint DBP and SBP as well as by determination of the percentage of patients reaching their target values.

9.5.3.1 Safety assessments
Safety assessments consisted of collecting all adverse events (AEs), serious adverse events (SAEs), with their severity and relationship to study drug, and pregnancies. They included the regular routine monitoring of hematology, blood chemistry and urine performed at study center and regular assessments of vital signs, physical condition and body weight.

Figure 9 2 Documentation of renal albumin excretion
.
By definition, SAEs were all adverse events being fatal, life threatening, requiring hospitalization or the prolongation of a hospitalization, resulting in persistent/ significant disability or incapacity (including the inability to work as a result of a significant disability), causing a congenital anomaly or congenital defect or being assessed as medically significant by the investigator. All SAEs had to be reported within 24 hours to the drugs safety department of Novartis Pharma in Nuremberg.

Additionally, the tolerability of the study drug was classified by the investigators at study end with ‘very good’, ‘good’, ‘satisfying’ or’ not satisfying’.
9.5.3.2 Appropriateness of safety assessments
The safety reporting used for this study follows the Novartis standard for non-interventional trials and is compliant with the German guidelines for non-interventional studies. Additionally, results of routine treatment monitoring should be reported by the investigational site.

9.7 Statistical methods
9.7.1 Data analysis
9.7.1.1 Principles of the statistical analysis
The NIS was analyzed using epidemiological approaches and primarily with a descriptive statistically methodology. If inferential statistical methods were used to calculate confidence intervals or to compare parameters or covariates by multivariate approaches, all results had to be interpreted completely descriptive. All p-values were only used for the interpretation of the main study results. Due to the explorative nature of the analysis, no α-adjustments for multiple testing were performed.

The statistical analysis was performed with the SAS® compatible statistical software package STATISTICA® V 8.0
9.7.1.2 Descriptive statistical methods
Variables of at least interval level were presented in tabular form including their sampling characteristics (N, NMISS, MIN, MAX, P5, Q1, MED, Q3, P95, MEAN, SD). Distributions of absolute and relative frequencies (adjusted) were presented for categorical and ordinal variables.
9.7.1.3 Explorative inferential analysis
Stratified analyses adjusted for possible confounding factors (e.g. compliance) were performed inside and between the following subgroups:
 Patients with aliskiren monotherapy
 Patients with aliskiren therapy in combinations with other antihypertensive drugs
 Subgroups with special risks (diabetes mellitus)

Differences of endpoint variables between treatment groups were assessed by non-parametric statistical tests. Categorical variables were analyzed by the Wilcoxon matched pairs signed rank test and interval-scaled data by the Mann-Whitney U test.

All inferential analyses were interpreted completely explorative.

9.7.2 Analysis sets
Two patient populations were analysed:
 Safety population (intention-to-treat): The safety population included all patients with documented intake/prescription of aliskiren and at least one safety follow up during treatment.
 Per protocol population: The Per Protocol-population included all patients with a prescription of aliskiren in accordance with the aliskiren SPC at the discretion of the investigator.

Three subgroups were additionally analyzed:
 Patients on aliskiren monotherapy
 Patients on aliskiren combination-therapy
 Diabetic patients

9.7.3 Patient demographics and other baseline characteristics
See point 9.7.1.1. Analysis and presentation followed the general principles of the statistical analysis.
9.7.4 Treatments (study drug, rescue medication, other concomitant therapies, compliance)
See point 9.7.1.1. Analysis and presentation followed the general principles of the statistical analysis.

9.7.5 Analysis of the primary variable(s)
9.7.5.1 Variable
See point 9.7.1.1. Analysis and presentation followed the general principles of the statistical analysis. Due the characteristic of the NIS, a primary variable were not defined.
9.7.5.2 Statistical hypothesis, model, and method of analysis
Due to the observational nature of the NIS, no statistical hypothesis was formulated. Models and methods of the analysis see point 9.7.1.1. Analysis and presentation followed the general principles of the statistical analysis.

9.7.5.3 Handling of missing values/censoring/discontinuations
Contrary to the analysis of randomized controlled studies, missing data were not regarded as a non-informative category. In a NIS, missing data can deliver important additional information about behavior and treatment in the daily outpatient routine. Therefore, missing data were explicitly presented and not substituted. To limit bias of endpoints estimates by dropouts or lost-to-follow-ups, the last evaluable visits of all patients were summarized and integrated as last-visit into the analysis.
9.7.5.4 Supportive analyses
Not applicable
9.7.6 Analysis of secondary variable(s)
9.7.6.1 Efficacy
See point 9.7.1.1. Analysis and presentation followed the general principles of the statistical analysis. The study did not differ between primary and secondary efficacy results.
9.7.6.2 Safety
Safety analysis was performed in the ITT-population, which included all patients with documented intake/prescription of aliskiren and at least one safety follow up during treatment. Deaths, SAEs, and study discontinuations were presented and discussed separately.
9.7.6.3 Health-related quality of life
Health-related quality of life was measured by SF12 at baseline and after 9 -12 months of study treatment.

Aliskiren treatment resulted in a pronounced and consistent decrease of SBP and DBP during the treatment period of 9 – 12 months. The 24-hour blood pressure decreased in the total population by 19.11/9.41 mmHg and the majority of patients (74.08%) achieved their blood pressure targets. The strong antihypertensive efficacy of aliskiren was also consistently seen in the three analysed subgroups (patients on aliskiren monotherapy, patients on aliskiren combination-therapy, diabetic patients). The investigators classified the efficacy of aliskiren as ‘very good’ or ‘good’ in more than 90% of patients.

147 AEs were reported in 104 patients (2.58%). AEs occurring most frequently were diarrhea (11 AEs, labeled AE), nausea (6 AEs) and light-headedness (6 AEs). 35 of the 147 AEs were classified as serious (SAE). Seven SAEs were cardiac disorders, three were deaths and four were related to therapeutic procedures. Altogether, 10 AEs resulted in the death of the patient (9 cases assessed as not suspected, in one patient the relationship was classified as not assessable). 16 AEs (1 in 252 patients) were classified as definitely related by the investigator, 19 as probably related and 32 as possibly related.
2 SAEs were assessed as definitely related, and 2 as possibly related to the study drug. In 10 SAEs, relation to the the study drug was unlikely, in 11 SAEs not suspected, 2 SAEs were not assessable and in 8 SAEs the corresponding data were not available.
One patient developed a skin rash (labeled AE) and no patient developed angioedema (labeled AE).

Aliskiren is an effective and safe treatment option for patients with hypertension in the daily outpatient routine. Especially in high-risk patients such as diabetics or patients with severe hypertension, aliskiren can be regarded as an excellent approach for the treatment of hypertension.