Rationale and Design of a Randomized Controlled Trial on Intensive Management of Blood PRESSure and Cholesterol in Elderly Chinese with Hypertension and Atrial FibrillatION (IMPRESSION) : Cardiology Discovery

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Rationale and Design of a Randomized Controlled Trial on Intensive Management of Blood PRESSure and Cholesterol in Elderly Chinese with Hypertension and Atrial FibrillatION (IMPRESSION)

Zhang, Wei; Chen, Yi; Huang, Qifang; Wang, Ji-Guang

Editor(s): Xu, Tianyu; Fu., Xiaoxia

Author Information
Cardiology Discovery 1(3):p 173-178, September 2021. | DOI: 10.1097/CD9.0000000000000026
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Atrial fibrillation is a common cardiac arrhythmia in the elderly and has become more prevalent worldwide with increasing longevity.[1,2] According to recent clinical trials[3,4] and the real-world setting,[5] hypertension is present in over 70% of patients with atrial fibrillation. Patients with atrial fibrillation and hypertension have an even higher risk of stroke than patients with either disease alone,[6,7] mainly because of the increased risk of embolic stroke associated with atrial fibrillation. Anticoagulation is effective in the prevention of stroke in patients with atrial fibrillation, regardless of whether warfarin or non-vitamin K antagonist oral anticoagulants are used. However, in China, anticoagulation is underused as a treatment for atrial fibrillation because of the high cost and the risk of bleeding.[8] Some advanced invasive techniques have proven to be particularly effective in patients with paroxysmal atrial fibrillation. However, the success rate for persistent atrial fibrillation is low.[9]

Antihypertensive therapy significantly reduces the risk of cardiovascular complications in patients with hypertension. In patients with atrial fibrillation, blood pressure reduction is associated with a lower risk of major bleeding, especially in those receiving anticoagulant therapy.[10,11] Recent researches showed that intensive antihypertensive treatment in patients with hypertension at high cardiovascular risk had the potential to reduce the risk of atrial fibrillation.[12–14] However, few studies have investigated intensive antihypertensive treatment in patients with hypertension and atrial fibrillation.

Statins are widely used in hypertensive patients with cardiovascular risk factors to prevent atherosclerotic cardiovascular diseases.[15] In the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) study in hypertensive patients with at least 3 other cardiovascular risk factors but without apparent elevation of serum total cholesterol (<6.5 mmol/L), adding atorvastatin 10 mg daily to the treatment regimen was associated with a 36% reduction in the incidence of non-fatal myocardial infarction and fatal coronary heart disease and a 27% reduction in the incidence of fatal and non-fatal stroke.[16–18] The presence of atrial fibrillation in elderly patients with hypertension was associated with a significantly higher cardiovascular risk after adjusting for serum total cholesterol.[19] A recent meta-analysis of observational studies showed that statin therapy was associated with 41% and 25% lowering of risk of all-cause and cardiovascular mortality, respectively.[20] Thus, patients with both hypertension and atrial fibrillation may not only benefit from statin therapy but also require even higher dosages of statins.

Therefore, we have designed the Intensive Management of Blood PRESSure and Cholesterol in Elderly Chinese Patients with Hypertension and Atrial FibrillatION (IMPRESSION) trial to investigate whether intensive management of blood pressure and cholesterol would further prevent composite adverse outcomes, including non-fatal stroke, non-fatal myocardial infarction, and cardiovascular death.

General study design

The present study is designed as a multi-center, 2 × 2 factorial, randomized, open-label, blinded-endpoint study. Eligible elderly (≥65 years) patients with both hypertension and atrial fibrillation will be randomly assigned into one of the 4 intervention arms: (1) intensive blood pressure and cholesterol management; (2) intensive blood pressure and less intensive blood cholesterol management; (3) less intensive blood pressure and intensive blood cholesterol management; (4) less intensive blood pressure and cholesterol management. Randomized patients are scheduled for a follow-up by the end of the first month and every 3 months thereafter.

Study population

The study participants will be recruited from community dwellers through a screening procedure. Eligible participants are men and women aged ≥65 years who meet all the inclusion and exclusion criteria as follows: Major inclusion criteria include the presence of hypertension and atrial fibrillation. Hypertension is defined as a clinical blood pressure of 140–179/90–109 mmHg in untreated patients and 140–159/90–99 mmHg in patients treated with monotherapy or combination therapy of 2 low-dose antihypertensive drugs. Atrial fibrillation is defined as a newly diagnosed case by 12-lead electrocardiography (ECG) or a previously documented diagnosis of atrial fibrillation with either sinus or atrial fibrillation rhythm. Details of the inclusion and exclusion criteria are shown in Table 1.

Table 1 - Inclusion and exclusion criteria.
Inclusion criteria
(1) Participant is willing and able to give informed consent for participation in the trial;
(2) Men and women;
(3) Age ≥ 65 years;
(4) Diagnosis of atrial fibrillation by 12-lead ECG or previously diagnosed atrial fibrillation;
(5) Hypertensive patients:
- Untreated, with clinic blood pressure level at 140–179/90–109 mmHg;
- Treated with monotherapy or combination therapy of 2 low-dose antihypertensive drugs, with clinic blood pressure level at 140–159/90–99 mmHg;
Exclusion criteria
(1) Participants who are receiving combination therapy of 2 high dose or more antihypertensive drugs;
(2) Untreated hypertensive patients with clinic blood pressure ≥180/110 mmHg, or treated patients with clinic blood pressure ≥160/110 mmHg, or participants with home blood pressure below 130/80 mmHg;
(3) Serum creatinine ≥115 μmol/L for men and ≥107 μmol/L for women, or patients with proteinuria;
(4) Serum potassium ≥5.0 mmol/L, or <3.5 mmol/L;
(5) Atrial fibrillation patients with heart rate over 100 beats/min who must use β-blockers after clinical evaluation;
(6) Serum total triglycerides concentration exceeds 4.5 mmol/L or patients with familial hypercholesterolemia;
(7) Alanine aminotransferase and aspartate aminotransferase exceed normal upper limit;
(8) Treated subjects in whom withdrawal of antihypertensive treatment is deemed unethical by the investigator (eg, because of the existence of compelling indications other than hypertension for continuous use of previously used antihypertensive agent);
(9) Known allergy or contradictions to one of the drugs to be administered in the study;
(10) History of acute coronary syndrome, acute left heart failure, stroke, aortic dissection, cardiomyopathy, diagnosed peripheral artery disease, implantation of specific cardiovascular treatment devices such as pacemaker, defibrillator and so on, within 6 months;
(11) Suspected or confirmed secondary hypertension;
(12) Uncontrolled diabetes mellitus, with a plasma HbA1c level >8%;
(13) Other conditions deemed relevant by the investigator or current use of unauthorized drugs;
(14) Body mass index ≥35 kg/m2;
(15) History of severe obstructive sleep apnea-hypopnea syndrome;
(16) Inability or unwillingness to comply with all trial requirements.
ECG: Electrocardiogram; HbA1c: Glycosylated hemoglobin.

Potentially eligible residents will be invited to undergo an atrial fibrillation screening procedure. During the screening visit, a single-lead (lead I) ECG will be recorded for 30 seconds with a handheld ECG device (Kardia Mobile®, Mountain View, California, USA). Every ECG rhythm will be reviewed by a cardiologist from the research team. In each center, approximately 1200 individuals will be screened for the recruitment of 30 patients with both hypertension and atrial fibrillation. At the screening visit (2 weeks before randomization), an initial assessment of selection criteria will be performed based on clinical history to determine eligibility. Potentially eligible patients will be invited to participate in the study. After informed consent is obtained, the patient will enter a run-in period, during which a 7-day home blood pressure measurement (HBPM) will be performed with an automated oscillometric blood pressure monitor (Omron HEM-9200T, Omron Healthcare, Kyoto, Japan). If the participant is still eligible after a 2-week run-in period, he or she will have the following information collected and measurements performed, including full medical history, physical examinations, blood and urine sampling, office blood pressure measurement (OBPM), and an ECG examination. Blood measurements included routine tests, serum sodium, potassium and chloride, plasma glucose, and serum lipids, liver transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), creatinine, and uric acid. A urine dipstick test will be performed for spot urine sampling. Cognitive function will be assessed using the Montreal Cognitive Assessment and Mini-Mental State Examination, and frailty will be assessed using the frailty index scale.[21,22]

Randomized treatments

At each study site, the investigator will arrange a randomization visit within 1 month of the screening period. After stratification for age (≥75 years vs. <75 years), sex, and center, eligible patients will be randomized into one of the 4 intervention arms: (1) intensive blood pressure and cholesterol management using a combination of amlodipine/atorvastatin 5/20 mg/day and allisartan tablets 240 mg/day; (2) intensive blood pressure and less intensive blood cholesterol management using a combination of amlodipine/atorvastatin 5/10 mg/day and allisartan tablets 240 mg/day; (3) less intensive blood pressure and intensive blood cholesterol management using amlodipine/atorvastatin 5/20 mg/day; and (4) less intensive blood pressure and cholesterol management using amlodipine/atorvastatin 5/10 mg/day [Figure 1].

Figure 1:
Trial flow diagram. AF: Atrial fibrillation; HBPM: Home blood pressure monitoring.

Antihypertensive and lipid-lowering drugs will be provided by the trial at no cost to the participants. Other antihypertensive drugs will not be allowed to be used during the follow-up, unless the participants have an office blood pressure ≥150/90 mmHg at a follow-up visit. In this case, antihypertensive agents other than calcium-channel blockers or angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ie, a thiazide diuretic, a β-blocker, an α-blocker, or spironolactone) will be allowed.


All randomized participants will be asked for a follow-up by the end of the first month after randomization and every 3 months thereafter. A 7-day HBPM will be performed before every clinic visit. For safety reasons, serum liver transaminase (ALT and AST), creatinine, uric acid, sodium, potassium, chloride, and creatine kinase will be measured at the first month visit. Serum lipids will be measured at 1, 3, 6, 12, 24, and 36 months. At each annual clinic visit, all patients will be evaluated for the same measurements at baseline [Table 2].

Table 2 - Time schedule of enrolment, interventions, assessments and visits for participants
Screening and randomization visits Follow-up visits Unscheduled

Screening period (baseline) Randomization FUV1 FUV2 FUV3 FUV4 FUV5 FUV6 FUV7 FUV8 FUV9 FUV10 FUV11 FUV12 FUV13 Premature discontinuation
Assessment Wk -2 to 0 Wk 0 M1 M3 M6 M9 M12 M15 M18 M21 M24 M27 M30 M33 M36
Selection criteria X
Informed consent X
Clinical history X
Physical examination X
 Office BP X X X X X X X X X X X X X X X X
 Home BP X X X X X X X X X X X X X X X
Blood sample for lipids X X X X X X X X
Blood sample for electrolytes, ALT, AST, creatinine, uric acid and creatine kinase X X X X X X
Blood sample for complete blood count and blood glucose X X X X X
Urine sample for dipstick test X X X X X
Cognitive function and frailty scales X X X X X
Ascertain achievement of BP control X X X X X X X X X X X X X X
Adverse events/safety evaluation X X X X X X X X X X X X X X
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BP: Blood pressure; ECG: Electrocardiography; FUV: Follow-up visit; M: Month; Wk: Week.

Primary and other endpoints and safety evaluations

The primary endpoint will be the composite of non-fatal stroke, non-fatal myocardial infarction, and cardiovascular death. Meanwhile, the secondary outcomes will include all-cause mortality, cardiovascular mortality, fatal and non-fatal stroke, fatal and non-fatal myocardial infarction, hospitalization for heart failure, coronary artery revascularization, peripheral artery revascularization, transient ischemic stroke, and end-stage renal disease.

Adverse events (AEs), including events observed by an investigator or reported by the participant, will be recorded on the AE form during follow-up. Serious AEs (SAEs) will be reported to the coordinating center and other authorities within 24 hours of the event. All AEs marked possibly, probably, or definitely related will be considered as related to the intervention. All SAE reports will be assessed by the Data and Safety Monitoring Board (DSMB) chair monthly and at the DSMB meetings every 6 months. The DSMB will be in charge of protecting trial participants and monitoring trial data, including identifying any tendency, such as increases in unexpected events. The DSMB will take proper action where necessary.

Sample size estimation

The sample size was estimated based on the potential benefits the antihypertensive combination therapy brings. According to previously published reports, the event rate per year of ischemic stroke could be up to 5.3% in patients with non-valvular atrial fibrillation with an average age of 70 years. To estimate the sample size, we have assumed a 5% event rate per year of the composite primary outcome in patients with hypertension and atrial fibrillation, including non-fatal stroke, non-fatal myocardial infarction, and cardiovascular death.[23–25] If a 25% effect rate corresponds to a 10 mmHg between-group difference in systolic blood pressure in the intensive antihypertensive therapy group,[26,27] an alpha of 0.05 (2-sided t test), and a power (1-beta) of 80% is assumed, with a dropout rate of 20% during the study period, at least 481 subjects per study group was considered necessary, for a total of 1200 randomized patients. The sample size will offer 80% power for 25% effect rate corresponding to a 0.90 mmol/L between-group difference, or 60% power for 20% effect rate corresponding to a 0.72 mmol/L between-group difference in serum low-density lipoprotein cholesterol concentration in the intensive blood cholesterol-lowering group.[28]

Data collection and data statement

Data collected at the participating center will be documented in an electronic case report form (e-CRF) on the trial website. Files containing data from device-based examinations (HBPM data and ECG recordings) will also be uploaded to the trial website linked to the study e-CRF for further analysis by the coordinating center. Clinical data including demographics, blood and urine laboratory tests (ie, serum creatinine and estimated glomerular filtration rate (eGFR), fasting plasma glucose, serum uric acid, Na+, K+, and lipids, and urinary sediment), and AE forms during follow-up will be uploaded to the e-CRF.

Data management

Clinical data and raw data from device-based examinations acquired by various techniques will be uploaded in the e-CRF and on the study website supervised by the Data Management Coordinating Center, including an audit trail system. The quality of data acquired with these examinations (ie, ECG, OBPM, and HBPM) will be validated by an expert at the coordinating center. Cardiovascular events (ischemic and hemorrhagic stroke, myocardial infarction, other major cardiovascular events, and cardiovascular and all-cause death) and renal outcomes reported by the investigators and supported by clinical documents (ie, diagnostic tests and medical reports) will be adjudicated by a committee of clinical experts, who will be blinded to the assigned treatment groups, blood pressure levels, and organ damage measurements.

Data analysis plan

For descriptive analyses, categorical data will be presented as frequencies and continuous data as means ± standard deviation or median (interquartile range). For inferential analyses, statistics will be at the 5% probability level, unless stated otherwise. Unpaired t-test (or Mann-Whitney U test in case of non-normal distribution) for continuous variables will be applied to evaluate significant between-group differences for primary and secondary outcomes. The incidence of AEs will be classified by the treatment group. All these analyses will be performed by treatment group, and for the study population as a whole.

The risk ratio model will be used to compare the incidence of composite primary outcomes between intensive and less intensive antihypertensive and lipid-lowering groups. Target organ damage will also be compared between intensive and less intensive antihypertensive and lipid-lowering groups using 2-way analysis of variance for continuous variables and the Chi-square test for categorical variables. Subgroup analyses can be performed for the primary endpoint according to age, sex, or other major baseline characteristics.

Ethical considerations

The IMPRESSION study protocol has initially obtained approval from the Ethics Committee of Ruijin Hospital, Shanghai Jiaotong University School of Medicine. All study centers in this study will apply for approval from the Ethics Review Committees and/or Institution Review Board in their hospitals. The procedures set out in this protocol, including the conduct, evaluation, and documentation, are designed to ensure that the sponsor and investigator abide by the Good Clinical Practice guidelines and follow the guiding principles detailed in the Declaration of Helsinki.

Current progress

The trial commenced screening and recruitment on 15 December 2019 in 43 participating hospitals. As of January 2021, 3907 patients have been enrolled in the screening. The prevalence of atrial fibrillation was 4.6% (95% CI: 3.9%–5.3%, n = 181), including 4.5% (95% CI: 3.9%–5.2%) with known atrial fibrillation either in atrial fibrillation rhythm (2.6%, 95% CI: 2.1%–3.1%, n = 103) or sinus rhythm (1.9%, 95% CI: 1.5%–2.3%, n = 75) and 0.1% (95% CI: 0.01%–0.2%) with newly detected and ECG-confirmed atrial fibrillation (n = 3). Of these 181 patients with atrial fibrillation, 15 patients were randomized into the trial because they had hypertension and met all inclusion and exclusion criteria of the trial. Screening and recruitment are estimated to continue until 2022. After completion of the enrolment, the IMPRESSION team will focus on the follow-up of the participants, ensuring treatment adherence and high-quality data collection, monitoring safety, and collecting and adjudicating trial endpoints.


The IMPRESSION trial targets a group of high-risk patients with both hypertension and atrial fibrillation and aims to determine whether intensive management of blood pressure and cholesterol provides more cardiovascular protection. The findings of this trial will support better patient-centered management plans for the prevention of cardiovascular disease in individuals and provide significant clinical evidence for statins in the treatment of atrial fibrillation.


The authors gratefully acknowledge the investigators from all participating centers.


This research is financially supported by a grant from the Clinical Research Program, Ruijin Hospital, Shanghai Jiaotong University School of Medicine. The study investigators were also financially supported by grants from the National Natural Science Foundation of China (grants 91639203 and 82070435), Ministry of Science and Technology (grants 2015AA020105-06 and 2018YFC1704902), and Ministry of Health (grant 2016YFC0900902), Beijing, China, from the Shanghai Commissions of Science and Technology (grant 19DZ2340200), and Health (a special grant for “leading academics”), Shanghai, China.

Author Contributions

Wei Zhang participated in the writing and review of this article and approved the final draft of the protocol.

Yi Chen participated in the research design and review of this article and approved the final draft of the protocol.

Qifang Huang participated in the research design and review of this article and approved the final draft of the protocol.

Ji-Guang Wang participated in the research design, writing, and review of this article and approved the final draft of the protocol.

Conflicts of Interest

Ji-Guang Wang reports receiving lectures and consultation fees from Novartis, Omron, and Takeda. The other authors declare no conflict of interest.

Editor note: Ji-Guang Wang is an Associate Editor of Cardiology Discovery. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and his research groups.


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Atrial fibrillation; Blood pressure; Hypertension

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