Upstream therapeutic strategies of Valsartan and Fluvastatin on Hypertensive patients with non-permanent Atrial Fibrillation (VF-HT-AF): study protocol for a randomized controlled trial

The VF-HT-AF study is designed as a prospective, randomized, open-label, four-arm
parallel, and multicenter study. The objective of the study is to test the hypothesis
that upstream therapy using valsartan or fluvastatin is more effective in reducing
the recurrence of AF and the progress from non-permanent AF to permanent AF in hypertensive
patients with non-permanent AF, compared with conventional antihypertensive therapy
using dihydropyridine calcium channel blockers (CCBs). This study will be conducted
according to the principles outlined in the Declaration of Helsinki. Written informed
consent will be obtained from all patients prior to the study. The study protocol
has been approved by the ethics committee of the Second Hospital of Tianjin Medical
University (Clinical ethical review, 2012, No. 27) as well as other participating
medical centers, which are secondary or tertiary healthcare providers in China, and
should provide proof of laboratory quality control. The ethical bodies that approved
our study in the various centers are listed in Additional file 1. If there is any amendment to the protocol, approval must again be sought from the
ethics committee. The study is registered with the Chinese Clinical Trial Registry
(ChiCTR-TRC-12002642). The protocol design is based on the Consolidated Standards
of Reporting Trials (CONSORT) and Standard Protocol Items: Recommendations for Interventional
Trials (SPIRIT, see Additional file 2), and study results will be reported according to these guidelines.

Patient population and entry criteria

Patients enrolled in the study need to meet the inclusive recruited criteria: (1)
have hypertension, defined as an average systolic blood pressure ?140 mmHg (1 mm Hg
= 0.133 kPa) or a diastolic blood pressure ?90mmHg (but a systolic blood pressure
180 mmHg and a diastolic blood pressure 110 mmHg) at the first visit, or the requirement
of any anti-hypertension treatment at enrollment; (2) a history of non-permanent AF
within 1 year prior to the enrollment, as confirmed by electrocardiography (ECG),
and converted to sinus rhythm; (3) have not taken ARBs or angiotensin-converting enzyme
inhibitors (ACEIs) as well as statins in the previous 2 weeks, or are taking ARBs,
ACEIs and statins, but can accept a 2-week washout period; (4) aged 25–79 years;
and (5) willing to sign the informed consent form (Additional file 3).

The exclusion criteria are: (1) persistent AF with a duration ?1 year or permanent
AF; (2) serious left main coronary artery disease identified by coronary angiography;
(3) heart failure (New York Heart Association [NYHA] stage III or IV); (4) acute myocardial
infarction in the previous 3 months; (5) surgical or interventional indications of
valvular heart disease; (6) uncontrolled thyroid disease (abnormal free T3, free T4,
or thyroid stimulating hormone, or requiring any anti-thyroid treatment at enrollment);
(7) serious liver or renal dysfunction (ALT 80 U/l, AST 80 U/l, or creatinine
132 ?mol/l); (8) history of unstable angina pectoris; (9) stroke or transient ischemic
attack within the previous 3 months; (10) poor treatment compliance, such as central
nervous system or mental illness, or a possibility of being uncooperative in the follow-up
period; (11) have taken ARBs, ACEIs or statins but cannot accept a 2-week washout
period; (12) obvious hyperlipidemia that must be treated by statins or fibrates; (13)
contraindication of statins or ARBs; (14) pregnancy or the possibility of pregnancy,
or breast feeding; and (15) aged younger than 25 or older than 79 years.

Study design

The VF-HT-AF study is a randomized, multicenter, open-label, and four-arm parallel
study to evaluate the effectiveness of valsartan, fluvastatin or a combination of
both on recurrent AF in hypertensive patients with non-permanent AF in China. After
providing informed consent, patients will be randomly assigned using a computer system
to one of four groups (the valsartan group, the fluvastatin plus dihydropyridine CCBs
group, the valsartan plus fluvastatin group, and the dihydropyridine CCBs group) by
the School of Public Health of Tianjin Medical University, initially in a 1:1:1:1
ratio. Physicians, who should be qualified medical practitioners, screen and follow
up the patients in hospital outpatient or inpatient clinics. All patients’ data will
be collected using a standard case report form and transmitted to the central database
at the data center. All centers will be regularly monitored for source data documentation.
Missing or questionable data will be completed and corrected by queries.

If the candidate patients have not taken ARBs, ACEIs or statins in the past at least
14 days, they will be directly enrolled and randomized. If the candidate patients
have taken ARBs, ACEIs or statins, they will be randomized after a 14-day washout
period. Baseline data will be collected after the washout period.

The initial dose of fluvastatin will be 40 mg/day at night, while valsartan will be
prescribed initially at 80 mg/day. The fluvastatin dose will be no less than 40 mg/day
and that of valsartan will be no less than 80 mg/day during the follow-up period.
Blood pressures in each group must reach the target blood pressure, which is set at
140/90 mm Hg.

Follow-up

Clinical follow-up using standardized questionnaires will be performed every 3 months
during the 2 years follow-up period from the assignment of each patient.

The dosages and types of all other anti-hypertensive, anti-hyperlipidemia, and anti-arrhythmic
drugs used during the follow-up will be recorded for each patient. Ultrasound echocardiography
will be performed before the patients enter the study and at the end of the follow-up
period. 7-day Holter monitoring will be performed at the baseline, 6 month, 12 month
and at the end of the follow-up period. Patients’ diaries, cardiac function (NYHA
classification) and adverse events during the follow-up period will be collected every
3 months.

Throughout the study, patients should record diaries when they feel discomfort. Arrhythmia-related
symptoms are self-evaluated or evaluated by 7-day Holter monitoring, which has five
poles, is weighted 50 g, 2.0 × 2.7 cm, and can record ECG for 7 days. The 7-day Holter
instruments were manufactured by BORSAM Co. in Shenzhen, Guangdong Province, China,
and provided by the study’s sponsor, Tianjin Institute of Cardiology, Tianjin, China.
The attending physicians will also record blood pressure and ECG during each follow-up.
Unless necessary, anti-arrhythmic drug therapy will be discontinued during the study
according to the attending physicians’ advice for each patient. The design of the
study is shown in Fig. 1.

Fig. 1. Flow-process diagram. BP, blood pressure; ECG, electrocardiography

Compliance strategy

To maximize subjects’ compliance, first, we will have a thorough consent process for
all participants. We will explain the schedule, potential side effects of treatment,
and the responsibilities of the subjects in detail. Second, we will try to prevent
dropouts by providing ongoing support to patients. A direct telephone line set up
for this trial will enable the study team to communicate with the patients personally.
An information sheet will be given to each participant providing them or their caregivers
with means of urgent contact. Extra visits and free medical care will be arranged
for any participant who feels harmed by the trial protocol. Certainly those participants
in the control group should not experience any difference in their condition.

Primary outcome measures

The VF-HT-AF study will examine whether fluvastatin or valsartan has anti-arrhythmic
effects on non-permanent AF, apart from their lipid-lowering and antihypertensive
effects, in comparison with dihydropyridine CCBs. Also, it will confirm whether a
combination of valsartan and fluvastatin has better effects on non-permanent AF than
either drug alone.

Therefore, the primary outcome measure is the change in the development of paroxysmal
AF into persistent or permanent AF, the development of persistent AF to permanent
AF, as well as the change in incidence of overall and persistent AF recurrence, which
will be evaluated by 7-day Holter monitoring and patients’ diaries during the 2-year’s
follow-up of the four treatment groups.

Secondary outcome measures

The secondary outcome measures of this study include the occurrence of: (1) myocardial
infarction; (2) heart failure (NYHA III or IV); (3) cardiogenic shock; (4) serious
bleeding necessitating hospitalization; (5) malignant ventricular arrhythmia (including
ventricular tachycardia or fibrillation); (6) revascularization therapy (coronary
artery bypass graft or percutaneous coronary interventions); (7) radiofrequency catheter
ablation of AF; (8) changes of left atrial dimension, as measured by ultrasound echocardiography;
(9) stroke; (10) cardiovascular mortality; and (11) all-cause mortality.

Definitions

The definitions of AF are made according to 2012 HRS/EHRA/ECAS Expert Consensus 16]. Paroxysmal AF is defined as recurrent AF (at least two episodes) that terminates
spontaneously within 7 days. Episodes of AF no more than 48 hours’ duration that are
terminated with electrical or pharmacologic cardioversion should also be classified
as paroxysmal AF episodes. Persistent AF is defined as continuous AF that is sustained
beyond 7 days. Episodes of AF lasting more than 48 hours, but less than 7 days, in
which a decision is made to cardiovert AF electrically or pharmacologically should
also be classified as persistent AF episodes. Permanent AF refers to long-lasting
episodes of AF that could be considered by any evidence as lasting longer than 1 year,
or to a case of AF for which a decision has been made not to restore or maintain sinus
rhythm by any means, including catheter ablation or surgery. Myocardial infarction
is defined as a cardiac troponin rise accompanied by typical symptoms, pathological
Q waves, ST elevation or depression, or coronary intervention. Heart failure (NYHA
III or IV) requires echocardiographic evidence of reduced left ventricular ejection
fraction or a diagnosis of heart failure by a cardiologist. Cardiogenic shock is defined
by sustained hypotension with tissue hypoperfusion despite adequate left ventricular
filling pressure. Signs of tissue hypoperfusion include oliguria (30 ml/hour), cool
extremities, and altered level of consciousness.

Sample size calculation

The primary outcome measure is the change in the development of paroxysmal AF into
persistent or permanent AF, the development of persistent AF to permanent AF, as well
as the change in incidence of overall and persistent AF recurrence. Power calculations
to provide estimates for the necessary sample size were conducted concerning the primary
outcome measure. The sample size was estimated based on findings from the 12-month
results of the J-RHYTHM II study 11], in which the incidence of persistent AF is estimated to be 6.8 % lower in the valsartan
group than in the CCBs group. To ensure 80 % power at the 5 % significance level,
a sample size of at least 1404 needs to be included. Considering a rejection rate
of 20 %, about 1879 patients need to be approached.

Data management

All the data will be entered and stored in a password-protected computer. To ensure
high quality of the data, a double data entry method will be used. A data monitoring
committee, of which at least two members will be independent of the research team,
will monitor the data management process regularly. All the data will be frozen and
then locked to prevent further editing after the validation by the data monitoring
committee. Only the data monitoring committee, the study research assistant and the
principal investigator will have access to the final data set. The protocol and statistical
results will be published in a scientific journal.

Statistical analysis

All analyses will be performed based on the intention-to-treat principle with differences
assumed to be significant at a two-sided P value 0.05.

Baseline characteristics and follow-up information will be collected for each group
through the questionnaire. Absolute values for each question will be used to calculate
the mean value, standard deviation, median value, percentile, number of cases, and
percentages per group. Statistical significance will be evaluated by analysis of variance
or Kruskal–Wallis rank sum test for continuous variables and chi-squared test for
categorical variables, respectively. Kaplan–Meier curves will be used to describe
the time-dependent occurrence of events, and the log-rank test will be performed to
compare survival distributions for the four groups. To adjust for possible baseline
imbalances between groups, a Cox proportional hazards model will be used. A hazard
ratio will be calculated. In addition, subgroup analyses will be performed corresponding
to the nature of the data. All statistical analyses will be performed using SPSS statistical
software (version 17.00, Chicago, IL, USA).

Quality assurance

Steering committee

The intervention of the steering committee includes general practice training and
practice visits, to develop and monitor the implementation of the protocol. Telephone
support is delivered by the intervention team with assistance from the principle investigators.
The quality of the intervention process will be monitored and assured by a steering
committee using multiple strategies, including a standardized selection, training
and performance assessments of the intervention team, evaluation of general practice
training, records of practice visits kept by the intervention team, and ongoing feedback
by practice staff on the intervention during the 24-month period. The steering committee
will be supported by a statistician, who is responsible for ensuring the timely publication
of this study results.

7-day Holter diagnosis committee

This committee will determine the rhythm of the 7-day Holter ECGs without knowing
the patients’ conditions and will be responsible for the diagnosis of the recorded
7-day Holter ECGs before the analysis of the primary and secondary outcome measures.

Safety monitoring board

The safety monitoring board will be responsible for monitoring patient safety and
will recommend premature cessation of the trial should there be an increase in unpredicted
adverse events.