Assessment of the Efficacy, Adherence and Tolerability of the Single Pill Combination Bisoprolol/PerindopRil In Patients With Previous Myocardial Infraction With Arterial Hypertension in the Daily Clinical practicE
Conditions: Coronary Artery Disease, Myocardial Infarction, Arterial Hypertension
Sponsor: Servier Russia

1 
 
 
PRIDE 
 
 
Assessment of the efficacy, adherence and tolerability of the single pill combination 
bisoprolol/PerindopRil  In patients with previous myocardial infraction with arterial 
hypertension in the Daily clinical practicE 
 
Protocol №: №IC4-05150-065-RUS 
 
NCT04656847 
 
 
 
10 March 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

2 
 
INN: bisoprolol + perindopril  
 
Dosages:  
bisoprolol 2.5 mg + perindopril 2.5 mg 1 time per day (1/2 tablet 5+5) 
bisoprolol 5 mg + perindopril 5 mg once daily 
bisoprolol 5 mg + perindopril 10 mg once daily 
bisoprolol 10 mg + perindopril 5 mg once daily 
bisoprolol 10 mg + perindopril 10 mg once daily 
 
Presentation: film-coated tablet.  
 
National coordinator: Professor Kobalava Z.D. MD, PhD  
 
Confidential 
This document is classified by Servier as confidential and is intended only for instructions during 
the observational period. 
The contents of this document should not be disclosed to any persons or institutions not 
participating in this study without the prior written consent of Servier. 
 
 

3 
 
Abbreviations 
ABPM 
ambulatory blood pressure monitoring 
ACE  
ACS 
angiotensin-converting enzyme 
acute coronary syndrome 
ADR 
adverse drug reaction 
AE 
adverse event 
BP 
blood pressure 
CAD 
CCS 
coronary artery disease 
canadian cardiovascular sosiety 
CI 
CRF 
confidence interval 
case report form 
DBP 
diastolic blood pressure 
ECG 
Electrocardiography 
HCP 
HR 
health care professional 
heart rate 
HTN 
(arterial) hypertension 
ISH 
MI 
NYHA 
RAAS 
isolated systolic hypertension 
myocardial infarction 
New York Heart Association 
renin-angiotensin-aldosterone system 
SBP 
SD 
SOC 
SPC 
systolic blood pressure 
standard deviations 
System-Organ-Class 
single pill combination 
SMBP 
self-monitoring of blood pressure 
 

4 
 
/ 
Contents  
1 
Introduction and aims .............................................................................................................. 6 
1.1 
Introduction ....................................................................................................................... 6 
1.2 
Aim ................................................................................................................................... 7 
1.3 
Variables ............................................................... Ошибка! Закладка не определена. 
2 
Methods and documentation .................................................................................................... 9 
2.1 
Study design and substantiation of design choice ............................................................ 9 
2.2 
Calculation of the sample size ........................................................................................ 10 
2.3 
Selection of doctors ........................................................................................................ 10 
2.4 
Selection of patients ........................................................................................................ 11 
2.4.1 
Inclusion criteria .................................................................................................... 11 
2.4.2 
Non-inclusion criteria ............................................................................................ 11 
2.5 
Treatment during the study ............................................................................................. 12 
2.5.1 Treatment with the studied drug ................................................................................... 12 
2.5.2 
Concomitant drugs ................................................................................................. 12 
2.6 
Duration of non-interventional study .............................................................................. 12 
2.7 
Documentation during the non-intervention study ......................................................... 13 
2.7.1. Documentation folder ...................................................................................................... 13 
    2.7.2  Study schedule ....................................................... Ошибка! Закладка не определена. 
2.7.3. Methods and measurements............................................................................................. 13 
2.7.4 Study procedures and data collection  .............................................................................. 13 
    2.7.5  Implementation of non-intervention study ...................................................................... 16 
3 
Pharmacovigilance ................................................................................................................ 17 
3.1 
Definitions ...................................................................................................................... 17 
3.1.1 
Pharmacovigilance information ............................................................................. 17 
3.1.2 
Adverse Event (AE) ............................................................................................... 17 
3.1.3 
Adverse (drug) reaction (ADR) ............................................................................. 17 
3.1.4 
Serious adverse (drug) reaction (SADR) ............................................................... 17 
3.2 
Responsibilities ............................................................................................................... 18 

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3.2.1 
Events to be reported ............................................................................................. 18 
3.2.2 
Responsibilities of the investigator ........................................................................ 18 
3.2.3 
Responsibilities of the Sponsor/Marketing Authorisation Holder ......................... 19 
4 
Data management, quality management, statistics and reporting ......................................... 19 
4.1 
Data management ........................................................................................................... 19 
4.2 
Statistical analysis ........................................................................................................... 19 
4.3 
Report preparation .......................................................................................................... 19 
5 
Ethical considerations ............................................................................................................ 20 
6 
Appendices ............................................................................................................................ 20 
7 
References ............................................................................................................................. 25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

6 
 
 
1 Introduction and aims 
Introduction 
A blood pressure (BP) lowering in the treatment of arterial hypertension (HTN) is associated with 
a reduction in the risk of cardiovascular mortality and the rate of complications (1,2). When 
prescribing antihypertensive drugs, the choice depends largely on the presence of concomitant 
diseases and associated conditions. The prevalence of HTN in patients with coronary artery disease 
(CAD) exceeds 80% (3). The BP control in patients with HTN and CAD is important, as the risk 
of recurring coronary events depends mostly on the BP level (4). For patients with HTN who have 
had a recent myocardial infarction (MI), it is recommended to use beta1-adrenoceptor blocking 
agents and renin-angiotensin-aldosterone system (RAAS) inhibitors (5). 
Monotherapy often does not contribute to achieving the target BP levels. The combination of two 
agents from any two classes of antihypertensive drugs is much more effective than monotherapy 
even at the maximum dose of the agent chosen for monotherapy (1,2). In addition to the higher 
efficacy, combination therapy provides a more potent organ-protective effect and has a better 
tolerance (by minimizing adverse effects and due to the ability to use lower doses) (2,6). The use 
of combination therapy increases patient adherence to treatment. A meta-analysis performed by 
Bangalore S et al. (2007) with the inclusion of data from 68 clinical trials assessing the single pill 
combinations (SPCs) and antihypertensive agents of various groups has demonstrated that 
antihypertensive SPCs increase treatment adherence by 24%, compared with free combinations in 
equivalent doses, and, therefore, provide better control of hypertension (7). 
The studied efficacy and safety of perindopril and bisoprolol both in monotherapy and in free 
combination became the basis for the creation of Prestilol® medicine - a fixed combination of these 
active substances. Bisoprolol, a component of Prestilol®, is one of the long-acting beta1-blockers 
with the highest selectivity. Bisoprolol reduces adrenergic stimulation of the heart muscle and 
pacemakers, which leads to a decrease in stroke volume and heart rate (HR), as well as the 
inhibition of renin secretion by the kidneys (3,6,8). In the BRIGHT study, 96.4% of 2161 patients 
with essential HTN showed significant reductions in systolic blood pressure (SBP), diastolic blood 
pressure (DBP) and HR after 12 weeks of bisoprolol monotherapy. Bisoprolol has demonstrated a 
marked BP-lowering effect and good tolerance. Moderate adverse events (AEs) were observed in 
only 1.9% of patients, and no serious AEs or drug withdrawals were reported (9). 
Perindopril is a highly lipophilic angiotensin-converting-enzyme (ACE) inhibitor, which has a 
proven organ-protective effect and is able to improve outcome in HTN, CAD, and cerebrovascular 
diseases. Like other ACE inhibitors, perindopril inhibits the RAAS by reduction in the formation 
of angiotensin II. The latter is accompanied by a decrease in total peripheral vascular resistance, 
formation of aldosterone and, therefore, sodium and water retention, with a reduction in circulating 
blood volume (6). The EUROPA study assessed the efficacy of perindopril on the top of standard 
therapy with β1-blocker in CAD patients (67% of them had a history of MI, and one third had 

7 
 
concomitant HTN). Combination treatment with perindopril and β-blocker reduced the relative 
risk of the primary endpoint (cardiovascular death, nonfatal MI, and resuscitated cardiac arrest) by 
24% compared with β-blocker monotherapy (HR, 0.76; 95% CI, 0.64-0.91; P = 0.002). Addition 
of perindopril also reduced fatal or nonfatal MI by 28% (HR, 0.72; 95% CI, 0.59-0.88; P = 0.001) 
and hospitalization for heart failure by 45% (HR, 0.55; 95% CI, 0.33-0.93; P = 0.025) (10,11). 
There are other published data from several studies of the bisoprolol/perindopril SPC efficacy in 
hypertensive patients with CAD. 
Korennova O.Yu. et al. (2019) evaluated the efficacy of bisoprolol/perindopril SPC in patients 
with recent acute coronary syndrome (ACS) who underwent endovascular coronary intervention. 
The study has demonstrated an efficient and optimal in time (within the first 4 weeks) achievement 
of target levels of SBP, DBP and HR, as well as persistence of the effects after 12 weeks of 
treatment. Clinical benefits of bisoprolol/perindopril SPC included a significant reduction in the 
severity and rates of manifestations of chronic heart failure and/or angina pectoris (3).  
The data of PRESTOL (2019) study examined the efficacy of bisoprolol/perindopril SPC in 2394 
hypertensive patients with CAD and showed significant reductions in HR (target HR ≤70 beats 
per minute was achieved in 84.9% of patients) and BP (target BP ≤140/90 mm Hg was achieved 
in 86.9% of patients). The treatment was associated with a reduction in the number of angina 
attacks (from 4.4 to 2.6 per week) and an improvement in the treatment adherence level (up to 
66.5% of patients) (8). 
SPC of bisoprolol/perindopril with several doses of 5/5, 5/10, and 10/10 mg in one tablet makes 
possible to individualize therapy and increase treatment compliance, while breakable tablets of 
5/5, 5/10 mg combinations provide additional options for dose titration (12). 
Aim 
This non-interventional, ambispective study was aimed at describing effectiveness, safety, and 
tolerability of bisoprolol and perindopril SPC in patients with HTN and previous myocardial 
infarction treated with the SPC for 12 weeks in the real clinical practice. SPC will be used 
according to the approved instruction for medical use of the medicine. 
Primary objectives 
• To 
describe 
antihypertensive 
effectiveness 
(SBP 
and 
DBP 
reduction) 
of 
bisoprolol/perindopril SPC in hypertensive patients with previous MI at week 12 of 
prospective observation.  
Secondary objectives 
• 
To describe antianginal effectiveness of bisoprolol/perindopril SPC in hypertensive 
patients with a history of MI at week 12 of prospective observation. 
• 
To describe a proportion of patients achieving target systolic and diastolic BP levels among 
hypertensive patients with previous MI during 12 weeks of prospective observation with 
bisoprolol/perindopril SPC according to the age (as stated in the guidelines “2”) 

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• 
To describe mean change in resting HR from BL among study patients at week 12 of 
prospective observation. 
• 
To describe a proportion of patients who achieved resting HR less than 60 bpm at week 12 
of prospective observation.  
• 
To estimate association between the resting HR and achievement of target level of BP at  
week 12 of prospective observation. 
• 
To describe adherence to the treatment with bisoprolol / perindopril in hypertensive patients 
with previous MI during the prospective observational period of 12 weeks. 
• 
To describe the tolerability of treatment with bisoprolol / perindopril in hypertensive 
patients with previous MI during 12 week prospective observation. 
Outcome measures 
Primary outcome measure: 
• Change in the mean systolic and diastolic BP levels at week 12 of prospective observation 
compared to baseline among patients included in the study.  
Secondary outcome measures: 
• Change in mean systolic and diastolic BP levels at week 4 of prospective observation 
compared with baseline.  
• Change in number of angina attacks per week at week 4 of prospective observation 
compared with baseline.  
• Change in number of angina attacks per week at week 12 of prospective observation 
compared with baseline. 
• Proportion of patients who were taking lipid lowering therapy (LLT) at week 12 of 
prospective observation. 
• Proportion of patients receiving LLT who achieved target levels of LDL C at week 12 of 
prospective observation. 
• Proportion of patients who achieved SBP ≤140 mm Hg and DBP ≤90 mm Hg at week 4 of 
prospective observation. 
• Proportion of patients who achieved SBP ≤140 mm Hg and DBP ≤90 mm Hg at week 12 
of prospective observation.  
• Proportion of patients younger than 65 who achieved SBP ≤130 mm Hg and DBP ≤80 mm 
Hg at week 4 of prospective observation . 
• Proportion of patients younger than 65 who achieved SBP ≤130 mm Hg and DBP ≤80 mm 
Hg at week 12 of prospective observation. 
• Proportion of patients older than 65 years who achieved SBP≤140 mm Hg and DBP ≤90 
mm Hg at week 4 of prospective observation.  

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• Proportion of patients older than 65 years who achieved SBP≤140 mm Hg and DBP ≤90 
mm Hg at week 12 of prospective observation .  
• Changes in the mean heart rate (HR) at week 4 of prospective observation compared with 
baseline. 
• Changes in the mean heart rate (HR) at week 12 of prospective observation compared with 
baseline. 
• Proportion of patients who achieved target level of resting HR (55-60 bpm) at week 4 of 
prospective observation. 
• Proportion of patients who achieved target level of resting HR (55-60 bpm) at week 12 of 
prospective observation. 
• Correlation between the resting HR values stratified by groups and achievement of BP 
targets at week 12 of prospective observation . 
• Proportions of patients with high, medium or low adherence to the treatment with SPC of 
bisoprolol/perindopril, assessed by MMAS-8 self-reporting questionnaire at week 4 of 
prospective observation.  
• Proportions of patients with high, medium or low adherence to the treatment with SPC of 
bisoprolol/perindopril, assessed by MMAS-8 self-reporting questionnaire at week 12 of 
prospective observation. 
• Incidence rate of adverse events/ adverse drug reactions and special situations during 12 
week observational period of the study.  
2 Methods and documentation 
 Study design and definitions 
This is a multi-centre, observational, incomparative, ambispective study, which will 
retrospectively and prospectively collect clinical and socio-demographic data from medical 
records of patients with HTN and previous MI initiated with bisoprolol/perindopril SPC in real 
clinical settings.  
Baseline data will be collected retrospectively from medical records of patients with HTN and a 
history of MI. Baseline data are defined as clinical parameters of interest available in medical 
records at the nearest date before or at the date of the initiation of SPC with Bisoprolol/ Perindopril.  
To be included in the study for further prospective observation a patient should have been 
administered bisoprolol/ perindopril SPC within first three months before the Index Date. (Fig.1).  
The Index date is a date when a decision to include a patient in the study for further 12 week 
prospective observation made by a treating physician after evaluation of recorded data to confirm 
patient’s eligibility for the study. 

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Therefore, criteria for non-inclusion or inclusion of patients in the study are to be retrospectively 
evaluated by the treating physician using recorded clinical data available from medical records. 
Once a treating physician makes decision to include a patient in the study and, in particular, on the 
prospective observation for 3 months, a visit 0 (inclusion visit) to the clinic for obtaining signed 
patient’s consent to participate in the study should be appointed and made within 1 month from 
the Index Date.   
Retrospective screening and evaluation of patient’s eligibility to inclusion/ exclusion criteria for 
entering the study allows mitigating a potential risk of deliberative medicine administration within 
the observational program. Such studies are carried out in case of observational programs when 
the studied drug is administered in line with indications according to the instruction for its medical 
use. 
Several multicenter, non-interventional, open, incomparable studies have been performed with 
bisoprolol/perindopril SPC in patients with HTN and coronary heart disease (3,8,13,14). A total 
of 70 general practitioners and cardiologists from primary care facilities will participate in the 
program. Each doctor will include about 7-8 patients. In total, it is planned to include at least 500 
patients. 
Calculation of the sample size 
As the present research has an exploratory nature, the study is not intended to prove any 
hypothesis. In this case, a formal calculation of the sample size is not performed. Moreover, all 
statistical tests will be performed at a level of statistical significance of 0.05 and a power of 80%. 
Given that the study will include patients with any grade HTN, the variability of SBP and DBP 
levels may be high enough. However, assuming that standard deviations (SDs) at baseline does 
not exceed 50 mm Hg, a sample of 500 patients will allow achieving a statistically significant 
difference in BP reduction after 3 months of treatment with bisoprolol/perindopril SPC compared 
with baseline levels, providing it is 6.3 mm Hg or more. 
This non-interventional study has an exploratory nature, so the sample size is not a strict parameter 
and is recommendatory in nature. 
Therefore, in order to obtain a representative population of patients with this particular disease and 
taking into account the practical aspects of conducting research in daily everyday routine practice, 
the total sample should consist of at least 500 patients. 
Selection of doctors 
A total of 70 general practitioners and outpatient cardiologists will participate in this non-
interventional study. 

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Selection of patients 
Inclusion criteria 
 Age from 18 to 79 years. 
 Signed informed consent to participate in the study.  
 Stable arterial hypertension  with concomitant 
stable angina pectoris of class I-III according to the Canadian Cardiovascular Society 
(CCS) classification and a history of myocardial infarction not earlier than 3 months 
before inclusion in the study 
 Bisoprolol/perindopril SPC prescription 1-3 months before screening 
 Bisoprolol/perindopril SPC prescription in accordance with Russian SmPC, based on 
necessity in treatment with bisoprolol/perindopril SPC and separated from the decision to 
include the patient in the study 
 Clinical parameters of interest (Resting HR; SBP and DBP; freaquency of angina attacks 
per week) are available in medical records for the nearest date before or at the date of the 
initiation of SPC with Bisoprolol/ Perindopril. 
 
Non-inclusion criteria 
 Hypersensitivity to bisoprolol, perindopril, excipients of the medicine, or other ACE 
inhibitors. 
2.  Any contraindication for bisoprolol/perindopril's SPC according to the instruction for 
medical use 
3. CAD, angina pectoris of functional class IV according to the CCS classification (Appendix 
1). 
 Chronic heart failure of class III-IV according to the New York Heart Association 
(NYHA) functional classification of heart failure (Appendix 3). 
 Cerebrovascular diseases (ischemic, haemorrhagic stroke, or transient ischemic attack) 
within the past 6 months prior to inclusion in the study. 
 A history of revascularization procedure within 3 months prior to inclusion in the study. 
 Hypertrophic obstructive cardiomyopathy. 
 Office BP ≥ 180/110 mm Hg on treatment 
 Type 1 diabetes mellitus and decompensated type 2 diabetes mellitus. 
 Bradycardia with a heart rate of less than 60 beats per minute. 
 Atrioventricular block (II-III degree), sinoatrial block, or sick sinus syndrome. 
 Severe bronchial asthma or severe chronic obstructive pulmonary disease. 
 Arterial hypotension (BP less than 100/70 mm Hg). 
 Pregnancy, breastfeeding. 
 Secondary hypertension. 
 Severe decompensated diseases of organs and systems requiring continuous treatment. 
 Current participation in another clinical trial and within 30 days prior to signing informed 
consent. 

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Treatment during the study 
Treatment with the studied drug 
bisoprolol 5 mg + perindopril 5 mg once daily 
bisoprolol 5 mg + perindopril 10 mg once daily 
bisoprolol 10 mg + perindopril 5 mg once daily 
bisoprolol 10 mg + perindopril 10 mg once daily  
A minimum dosage may also be prescribed: 
bisoprolol 2.5 mg + perindopril 2.5 mg 1 time per day (1/2 tablet of bisoprolol 5 mg + perindopril 
5 mg) 
If the dose adjustment is required, the treating physician can correct the dosage of the drug at any 
time after the treatment start. The decision on the need to correct the dosage lives upon the treating 
physician. 
In renal failure, it is necessary to adjust the dose depending on the degree of impaired renal function 
(creatinine clearance). 
 Concomitant drugs 
Due to the non-interventional design of the study, it is allowed to use any concomitant treatment 
or drugs if it is considered necessary by the treating physician and not contraindicated according 
to the approved instruction for use. This treatment will be appropriately reflected in the study 
documentation.  
Duration of non-interventional study 
It is planned to complete enrolment of patients in this non-intervention study within 6 month. 
Follow-up period for each patient will be 3 months.  
First patient in is scheduled for Q1 2021 
Last patient in is scheduled for Q3 2021 
Last patient last visit Q4 2021 
Data base lock is scheduled for Q1 2022 
Statistical analysis is scheduled for Q2 2022 
Clinical study report is scheduled for Q2 2022 

13 
 
Documentation during the non-intervention study 
2.7.1. Documentation folder 
Each doctor will be provided with a documentation folder containing a complete set of documents 
for 7-8 patients + 2 extra sets in case of lost or damage of study documentsincluding:  
• 
One protocol of the observation plan; 
• 
Documents for 7-8 patients (Patient Informed Consent Form, Case report form (CRF) with 
7-8 Adverse event/adverse drug reaction/special situation reporting forms). 
• 
2 extra sets in case of lost or damage of study documents (Patient Informed Consent Form, 
CRF; Adverse event/adverse drug reaction/special situation reporting forms) 
2.7.2 Study schedule 
According to the design of multicentre, non-intervention , open-label, incomparative, ambispective 
study in patients with HTN and CAD treated with a bisoprolol/perindopril SPC, three visits will 
be enough to include patients, evaluate the treatment effectiveness and safety, as well as to adjust 
the dose of the study drug* (3,8). 
The following visits are scheduled: 
1. Screening period: will be retrospectively performed to ensure each patient fulfills inclusion/ 
non-inclusion criteria    
2. Inclusion visit (V0): month 0; 
3. Follow-up visit (V1): at 1 month after the V0 visit; 
4. Final visit (V2): at  month 3 after the visit V0 or in case of perindopril/ bisoprolol SPC treatment 
withdrawal. 
* In renal impairment, it is necessary to adjust the dose depending on the degree of impaired renal 
function (creatinine clearance) 
2.7.3. Methods and measurements of clinical parametrs 
Measurement of the clinical BP by Korotkov’s method in the sitting position in the doctor’s office 
at the regular visit. BP will be measured on the same arm of the patient after 5 minutes of the rest. 
BP and HR will be measured thrice with an interval of 1-2 min; the average value of the last two 
measurements will be considered as the BP value measured at the visit; if the differences between 
two consecutive measurements of SBP are ≥ 15 mm Hg, it is necessary to perform the repeated 
BP measurement.  
2.7.4 Study procedures and data collection  
The plan at each visit during the study is presented in Table 1. 

14 
 
Patients will be provided with the self-observation diaries where they will record the BP values 
self-measured at home, the number of anginal attacks and the need to use short-acting nitrates. 
 
Table 1 – Plan of visits during the study 
Procedures 
Screening 
period 
(retrospective) 
V0 
Inclusion 
visit  
(month 0) 
V1 
Follow-up 
visit 
(month 1) 
V2 
Final visit 
(month 3) 
Obtaining patient informed consent 
 
× 
 
 
Inclusion/ non-inclusion criteria  
× 
× 
 
 
Demographic data  
 
× 
 
 
Risk factors and lifestyle  
 
× 
 
 
Medical history 
 
× 
 
 
Medical records on Resting HR; SBP and 
DBP; freaquency of angina attacks per week 
for the nearest date before or at the date of 
the initiation of SPC with Bisoprolol/ 
Perindopril 
 
× 
 
 
Physical examination and vital signs (rest 
heart rate and BP) at the office visit 
 
× 
× 
× 
Current symptoms and the use of short-
acting nitrates 
 
× 
× 
× 
Number of angina attacks per week 
 
× 
× 
× 
Current use of antianginal agents 
 
× 
× 
× 
Current use of other cardiovascular drugs 
 
× 
× 
× 
Current use of other drugs 
 
× 
× 
× 
Treatment adherence assessed by the patient 
(Morisky Medication Adherence Scale) 
 
× 
× 
× 
Current use of bisoprolol/perindopril SPC 
and reasons for discontinuation/ disruption 
of the treatment (if applicable)  
 
× 
× 
× 
Bisoprolol/perindopril SPC dose adjustment 
and reasons Bisoprolol/perindopril SPC 
dose adjustment 
 
× 
× 
× 
Adverse events/drug reactions/special 
situations 
 
× 
× 
× 
 
COLLECTION DATA: 
2.7.4.1. Data evaluation during the screening period: 
HCPs participating in the study will conduct a retrospective analysis of patient’s records for the 
purpose of evaluating patient’s eligibility to be enrolled in the study. Patients with HTN and a 

15 
 
history of MI, who had been initiated with bisoprolol/perindopril SPC within first three months 
before the Index Date (see a definition in Study Design and definitions of Section 2) and who meet 
other inclusion / non inclusion criteria will be included in the study if they sign a consest form at 
the inclusion visit. 
2.7.4.1. Data collection at the inclusion visit (V0): 
• 
Obtaining patient informed consent; 
• 
Checking for inclusion/non-inclusion criteria; 
• 
Physical examination and vital signs; 
• 
Current status of taking bisoprolol/perindopril SPC and a dose regimen; 
• 
Number of weekly angina attacks; 
• 
Current symptoms and the use of short-acting nitrates; 
• 
Current use of antianginal agents; 
• 
Current use of other cardiovascular drugs with doses for calcium channel blockers, 
diuretics, nitrates and statins; 
• 
Baseline assessment of adherence to bisoprolol/perindopril SPC done by patient-reported 
8 item Morisky Medication Adherence Scale; 
• 
Adverse events/drug reactions/special situations. 
 
2.7.4.2. Data collection at the follow-up visit (V1): 
• 
Physical examination and vital signs; 
• 
Current status of taking bisoprolol/perindopril SPC and a dose regimen; 
• 
Number of weekly angina attacks; 
• 
Current symptoms and the use of short-acting nitrates; 
• 
Current use of antianginal agents; 
• 
Adherence to bisoprolol/perindopril SPC assessed by patient-reported 8 items Morisky 
Medication Adherence Scale;  
• 
Current use of other cardiovascular drugs with doses for calcium channel blockers, 
diuretics, nitrates and statins; 
• 
Adverse events/drug reactions/special situations; 
2.7.4.3. Data collection at the final visit (V2): 
• 
Physical examination and vital signs; 
• 
Current status of taking bisoprolol+perindopril SPC and a dose regimen; 
• 
Number of weekly angina attacks ; 
• 
Current symptoms and the use of short-acting nitrates; 
• 
Current use of antianginal agents; 
• 
Current use of other cardiovascular drugs with doses for calcium channel blockers, 
diuretics, nitrates and statins; 

16 
 
• 
Adherence to bisoprolol/perindopril SPC assessed by patient-reported 8 items Morisky 
Medication Adherence Scale; 
• 
Adverse events/drug reactions/special situations; 
 
Figure 1. The scheme of the PRIDE study. 
 
2.7.5 Implementation of non-intervention study  
The treating physician will receive a documentation folder and instructions from the field staff of 
Servier. The patient should be informed of his/her participation in this study and the transfer of 
his/ her clinical data from the site to the responsible professional subcontractor for statistical 
analyses. Written informed consent must be obtained from the patient at the inclusion visit. The 
patient will receive a patient information sheet and a signed informed consent form. The second 
informed consent form must be archived by the doctor. Forms of documents should be filled in a 
readable form with a ballpoint pen in blue or black. In case of correction of erroneous data, they 
must be crossed out and replaced with the correct data. Corrections should be verified by the 
initials and date. No data should be deleted or erased. To ensure a high number of cases suitable 
for analysis, document forms should always be completed carefully and completely. In case of 
occurrence of adverse events (AEs), adverse drug reactions (ARDs), or special situations, it is 
necessary to follow the requirements listed in the section Ошибка! Источник ссылки не 
найден. «Responsibilities of the investigator». Please hand over the folder with the complete 
documentation to your Servier local executive. 
Patients will undergo clinical assessment and receive the standard medical care as usual 
determined by the treating doctor based on their clinical judgement and national guidelines. 
Patients will not receive experimental treatment as a consequence of their participation in the 
observational study.  

17 
 
3 Pharmacovigilance 
Definitions 
3.1.1 Pharmacovigilance information  
Pharmacovigilance data include any unintended or adverse event associated with the use of a 
medicinal product in humans, whether or not considered drug related, including the following 
special situations (situations where no adverse event occurred but information needs to be 
collected):  
• 
exposure during pregnancy or breastfeeding;  
• 
overdose, abuse, misuse, off-label uses, medication error, or occupational exposure 
(including professional one); 
• 
lack of treatment effectiveness of a medicinal product; 
• 
any suspected transmission via medicinal product of an infection agent;  
• 
unintended therapeutic benefit.  
 
3.1.2 Adverse Event (AE)  
Adverse event is any untoward medical occurrence in a patient or a clinical-trial subject who 
received the medicinal product, which does not necessarily have a causal relationship with the use 
of this medicinal product. 
An adverse event can therefore be any unfavourable and unintended sign (e.g. an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
3.1.3 Adverse (drug) reaction (ADR)  
Adverse reaction (synonyms: Adverse drug reaction, Suspected adverse (drug) reaction, Adverse 
effect, Undesirable effect) is a response to a medicinal product which is noxious and unintended.  
“Response” in this context means that a causal relationship between a medicinal product and an 
adverse event is at least a reasonable possibility.  
Adverse reactions may arise from use of the product within or outside the terms of the marketing 
authorization or from occupational exposure. Conditions of use outside the marketing 
authorization include off-label use, overdose, misuse, abuse and medication errors. 
3.1.4 Serious adverse (drug) reaction (SADR) 
Serious adverse reaction is an adverse reaction, which results in death, is life-threatening, requires 
in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or 
significant disability or incapacity, or is a congenital anomaly/birth defect. 

18 
 
“Life threatening” in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused death 
if more severe. 
Medical and scientific judgement should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalisation but might jeopardise the patient or might require 
intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or development 
of dependency or abuse. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
Responsibilities  
3.2.1. Events to be reported  
All available information about the following reported events occurring during the study will be 
recorded:  
• All serious adverse drug reactions related to the use of bisoprolol+perindopril SPC; 
• All non-serious adverse drug reactions related to the use of SPC bisoprolol+perindopril); 
• All reports about special situations (see Ошибка! Источник ссылки не найден.); 
• All adverse events 
3.2.2. Responsibilities of the investigator 
At the visits during the study, the doctor clarifies in a patient participating in the study whether 
he/she had noticed any adverse events (serious or not serious according to the criteria of severity). 
The investigator should determine the presence/absence of a causal relationship between the use 
of the study drug and the adverse event, the presence/absence of criteria for severity, and then 
monitor the outcome of the event. In case of detection of any adverse event/adverse drug reaction 
or occurrence of a special situation during the study (serious or not serious according to the criteria 
of severity), the investigator must fill out the «Adverse event/adverse drug reaction/special 
situation reporting form» (Appendix ) without waiting for the clinical outcome or the results of 
additional investigations. 
If the event is serious, the form should be sent immediately (same or next working day at the latest) 
to Servier company in Russia via e-mail to address pvmail.rus@servier.com or by fax to number 
(495) 937-47-66. The anonymized copies of all the available and relevant laboratory findings, 
hospitalisation reports or other investigation results performed in relation to the adverse event 
should be attached to the form. 

19 
 
3.2.3 Responsibilities of the Sponsor/Marketing Authorisation Holder 
Independently of the regulatory obligations of investigator, the sponsor/marketing authorisation 
holder (MAH) must report the pharmacovigilance data to the appropriate authorities in accordance 
with the Good PharmacoVigilance Practice and local regulations. 
Cases of adverse event are considered to be closed when the patient has recovered or his/her 
condition was stabilised, providing that the available data are sufficiently detailed for adequate 
medical analysis of the case. 
4 Data management, quality management, statistics and reporting 
Data management 
Data collection in this study is carried out using documentation forms. Centralized data entry will 
be carried out by a responsible professional subcontractor for statistical analyses after receiving 
documentation forms. Statistical analysis of the data and the creation of the final statistical report 
on the study will also be carried out by the responsible professional subcontractor for statistical 
analyses. The consistency of reported AE data will be ensured by reconciling the project database 
with the Servier drug safety database. Discrepancies will be resolved by mutual agreement 
between both parties (Servier and professional subcontractor for statistical analyses). 
Statistical analysis 
Due to the non-interventional nature of this study, statistical analysis will be carried out in 
descriptive and exploratory forms. All parameters will be analysed using descriptive statistics. For 
each parameter, the following will be specified: number of patients, mean value, standard error, 
minimum and maximum values, or proportion of each category. All composite endpoints will be 
listed and presented in visual form as graphs and in tables of parameters and their frequencies. For 
categorical variables, absolute values and rates in per cents be calculated. The calculations of 
relative rates will include only patients in whom values of the corresponding variables will be 
available.  
All reports of adverse drug reactions (ARDs), adverse events (AEs), serious ADR/AE, and special 
situations will be encoded, and the results will be listed and classified according to the System-
Organ-Classes (SOCs). 
Accepted level of significance 
In all tests, a significance level of 0.05 will be used, and 2-sided statistical tests will be carried out. 
Report preparation 
The preparation of the final report on the study will begin after the completion of the statistical 
analysis. The publication of the main results is planned within 12 months after the end of the study. 

20 
 
5 Ethical considerations 
The study will be carried out in accordance with the principles of the Helsinki Declaration, 
according to the version revised in Brazil in 2013. The protocol must be reviewed and approved 
by an independent ethics committee after it is submitted by the coordinator or sponsor in 
accordance with local regulatory requirements, especially on the matters relating to data 
protection. Patients will be informed about the conditions for participation in the study, and they 
will have to provide written consent to participate in the study. The doctor must confirm in the 
Case report form (CRF) that the informed consent has been obtained, and he/she must keep one 
original of the signed informed consent form in the patient’s file. “Informed consent” also means 
an individual discussion of procedures, that will be conducted as a part of the study, with the 
patient.  
5.1Patient data privacy  
Investigators should maintain confidentiality of information about patients included in this study. 
Confidential data should contain enough information to contact the patient in case of emergency, 
or if further monitoring is required. Patient's right to privacy is of utmost importance. To protect 
the data confidentiality and preserve patient anonymity, patient’s identity will be encoded in the 
study documentation. Patients can be identified using a unique number, age and gender, which 
will be recorded in the CRF. To reveal the patient’s identity, all investigators will keep a 
confidential list for patient identification containing the names and addresses of the patients, as 
well as their assigned numbers. Thus, only investigator will be able to decode the identity of a 
patient. 
 
6 Appendices 
Appendix 1. Cardiovascular risk assessment. Classification of angina severity according to 
the Canadian Cardiovascular Society (15). 
Functional class  
Signs 
I 
«Latent» angina. Angina with only strenuous exertion. 
II 
Angina with ordinary activity: brisk walking or climbing hill or more than one flight 
of ordinary stairs, after meals, or under emotional stresses. 
III 
Angina markedly limits physical activity. Angina with low efforts: walking at a 
normal pace for less than 500 m, climbing 1-2 flights of stairs. Angina sometimes 
occurs at rest.  
IV 
Inability to carry on any, even minimal physical activity without angina. Anginal 
attacks occur at rest. A history of myocardial infarction or heart failure is common. 
 
 

21 
 
Appendix 2. Classification of blood pressure, and definitions of hypertension grade (2). 
BP categories  
SBP, mm Hg 
 
DBP, mm Hg 
Optimal 
<120 
and 
<80 
Normal  
120–129 
and/or 
80–84 
High normal 
130–139 
and/or 
85–89 
Grade 1 
140–159 
and/or 
90–99 
Grade 2 
160–179 
and/or 
100–109 
Grade 3 
≥180 
and/or 
≥110 
Isolated systolic hypertension1 
≥140 
and 
<90 
1 Isolated systolic hypertension (ISH) should be classified into grades 1, 2, and 3 according to the 
SBP level.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

22 
 
Appendix 3. The New York Heart Association (NYHA) functional classification of heart 
failure (15). 
Functional class  
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart 
failure at rest. If any physical activity is undertaken, discomfort increases. 
 
 
 

23 
 
Appendix 4. The (Modified) eight-item Morisky Medication Adherence Scale. 
 
Each “Never” response is rated as 1, except for item 5, in which “Yes” response is rated as 1, and 
other responses are rated as 0. Total scores range from 0 to 8, with scores of 8 reflecting high 
adherence, 7 or 6 reflecting medium adherence, and <6 reflecting low adherence.  
 
 
 
 
 
 
 
 
 
 

24 
 
 
Appendix 5. Adverse event / Adverse drug reaction / Special Situation Reporting Form 
IC4-05150-065-RUSPlease send this form immediately by fax (495) 937-47-66 or by email to 
pvmail.rus@servier.com, or pass to the associate of the company. 
Year of birth or Age Gender 
 Height 
 Weight 
 Patient’s ID: 
 
|__|__|__|__| or |__|__|__| M / F 
 |__|__|__| 
 |__|__|__| 
 |_|_|_|_|_|_|_|_|_|_| 
  
Description of adverse event/reaction/special situation: 
Date of event onset 
 
|_|_| |_|_| |_|_|_|_| 
Date 
of 
event 
termination (in case 
of recovery) 
 
|_|_| |_|_| |_|_|_|_| 
 
 
 
Criteria of seriousness:  NO 
 
  YES (please, specify from stated below)  
 
 Death  
 
 Life threatening 
 
 Hospitalization or prolongation of existing hospitalisation 
 
 Persistent or significant disability or incapacity 
 
 Congenital anomaly/birth defect 
 
  Medically important event 
Outcome: 
 
 Recovered  
 
 Recovered with consequences (persistent  
 structural or functional impairment) 
 
 Not yet recovered  
 
 No recovery 
 
 Death  
 
 Unknown 
General disease(s) / Concomitant disease(s) (please indicate year when first diagnosed). 
Course adverse event/reaction/special situation (please enclose relevant findings, e.g. laboratory, hospital reports, 
histology, etc.): 
 
Causal relationship with intake of studied drug:⁬ 
 
 NO 
  
 YES  
 NOT APPLICABLE 
 
If «Yes», please indicate dates of the use of studied drug in the first line of the table below:  
 
If «No» or «Not applicable», please specify whether the adverse event/special situation is related to the medication 
of Servier company (which is specified in the table below): 
  NO     YES Please indicate the name of the medication of Servier company: ………………………… 
List of current 
medications  
Daily dose / 
route of 
administration
Dates of intake: 
from 
to 
Indication 
 
 
- 
 
 
 
 
 
 
 
- 
 
 
 
- 
 
 
 
 
 
Name (last, first, patronymic) of doctor:  
Speciality:  
Work address: 
Phone number: ________________________________________ 
 (city code) 
Date:  
 
 
Signature: 
*Special situations are cases when adverse event was not observed, but the information should be collected: the impact of the 
drug during pregnancy/breastfeeding, abuse, misuse, medication error, overdose, off-label use, occupational exposure, or lack of 
efficacy, any suspected transmission via medicinal product of an infection agent, unintended therapeutic benefit…  
Stamp 
(whenever possible) 

25 
 
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Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 1 August, 
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