Study type

Study topic

Human medicinal product

Study type

Non-interventional study

Scope of the study

Effectiveness study (incl. comparative)

Data collection methods

Secondary use of data
Non-interventional study

Non-interventional study design

Cohort
Study drug and medical condition

Name of medicine, other

Perindopril, Amlodipine, Bisoprolol

Study drug International non-proprietary name (INN) or common name

AMLODIPINE
PERINDOPRIL ARGININE

Medical condition to be studied

Hypertension
Population studied

Short description of the study population

Adult hypertensive patients uncontrolled on two-drug combination therapy identified in CPRD :
- Aged 18 years or over
- With at least one diagnosis record of primary hypertension
- Who have been prescribed concomitantly with two drugs (in free or fixed combination) among Bisoprolol, Perindopril, and Amlodipine at a stable dose for at least 4 weeks
- With uncontrolled blood pressure defined as SBP ≥140mmHg using the most recent BP record in the 2 weeks before or at index date
- With no other antihypertensive treatment received in the 4 weeks before index date
- Who have no prescription of the third drug (the component that is not part of the dual therapy) within 365 days before index date
- Who have been registered for at least one year in CPRD
- With Hospital Episode Statistics (HES) and ONS linkage available

Age groups

  • Adult and elderly population (≥18 years)
Study design details

Study design

Retrospective observational cohort study. Patients will be identified in CPRD between January 2005 and September 2019 and followed until March 2020.

Main study objective

The overall objective of the study is to study the effectiveness on blood pressure reduction of Bisoprolol (Biso), Perindopril (Per), Amlodipine (Amlo) and used concomitantly as free combination, compared to respective dual combination(s) of these 3 drugs in real life conditions, in order to confirm the contribution of all the active substances to the desired therapeutic effect on BP.

Primary objective: To compare the systolic blood pressure (SBP) change at 8 weeks between patients who started the combination of Biso/Per/Amlo (triple therapy) to those treated with the free or fixed combination of two drugs out of the three molecules (dual therapy) in hypertensive uncontrolled patients.
Secondary objectives
- To compare the diastolic blood pressure (DBP) change at 8 weeks between the patients who started the triple therapy to patients treated with the dual therapy.
- To compare the blood pressure control rate at 8 weeks between the patients who started the triple therapy to patients treated with the dual therapy.
- To estimate and compare incidence of adverse events (AEs) during follow-up between patients who started the triple therapy to those treated with the dual therapy.
- To describe treatment patterns of the three drugs taken concomitantly during follow-up and the adherence to treatment.
- To describe healthcare resource use in patients who started the triple therapy
Exploratory objective
- To estimate and compare incidence of cardiovascular events including cardiovascular death during follow-up

Setting

The source population for this study will be all patients identified in CPRD who meet inclusion and exclusion criteria , during the study inclusion period - January 2005 to September 2019. The latest data available at the time of application will be used to maximize the sample size, taking into account the latest linked data.

Comparators

This study will compare the uncontrolled hypertensive patients on triple therapy to those on dual therapy.
- The treatment group will be the triple therapy group i.e., patients on dual therapy who start the third mono-component among the three targeted drugs (Biso, Per and Amlo) during the inclusion period of the study. This group will include patients on either Per+Amlo who add Biso, or Per+Biso who add Amlo, or Amlo+Biso who add Per.
- The control group will be the dual therapy group and will include patients on either Per+Amlo or Per+Biso or Amlo+Biso

Comparison of triple therapy users to dual therapy users will be done by creating exposure sets based on index date and dual-therapy components and then matching using propensity score (PS) method to minimize the effect of confounding factors.

Outcomes

Primary outcome
The primary outcome will be change in SBP between ID and 8 weeks. We will identify an index value defined as the most recent SBP recorded in the two weeks preceding or at the ID, used for patient eligibility.

Post index measurements will be all SBP records reported (on distinct dates) within the time window of interest, from 4 weeks to 24 weeks after the ID and the change from index to week 8 will be estimated with a Mixed Model of Repeated Measures (MMRM) and compared between treatment groups.

Secondary effectiveness outcomes
Change in DBP between ID and 8 weeks:
The change in DBP between index and post-index DBP values will be calculated and compared between treatment groups. The same period assessment used for SBP will be applied for DBP.

Secondary safety outcome
The AEs to be studied are relevant safety events retrieved from the summary of product characteristics of each drug of interest (Biso, Per, Amlo); and from post-marketing safety data reported in the safety database among patient cases where bisoprolol, perindopril and amlodipine were co-administered.

Data analysis plan

Exposure sets will be created by index date and dual-therapy components and patients will be matched using propensity score to ensure comparability between treatment groups in these exposure sets. Missing outcomes due to change in treatment during outcome assessment period will be handled using Baseline Mean Carried Forward imputation method.
The primary outcome will be estimated on the matched cohort and with a Mixed Model of Repeated Measures.