Atrial Substrate Modification With Aggressive Blood Pressure Lowering to Prevent AF (SMAC AF)

Atrial fibrillation (AF) is a very common arrhythmia causing many symptoms resulting in numerous hospitalizations. Catheter ablation is a technique that has evolved significantly to improve symptomatic recurrences, but does not offer a 100% cure rate. We hypothesize that the use of aggressive BP lowering will reduce the rate of recurrent AF after catheter ablation for AF. We plan a randomized clinical trial of aggressive BP lowering versus standard BP control to investigate this.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Aggressive Blood Pressure control

Detailed Description

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity, necessitating treatment. Radiofrequency ablation for atrial fibrillation/flutter has evolved significantly and is the closest we have come to a 'cure' for these dysrhythmias. Recurrence of atrial fibrillation in those who have undergone radiofrequency ablation as treatment AF is up to 40% at one year and higher in those with persistent AF. Hypertension is a potent risk factor for AF, but recent studies have demonstrated that even modest increases in BP may lead to a higher incidence of AF. There is no clinical trial evidence to date that has investigated aggressive BP control in patients post radiofrequency ablation for AF to prevent recurrent AF.

Objective: We propose to determine if aggressive BP control reduces recurrent AF post ablation.

Hypothesis: Aggressive BP lowering will reduce the incidence of recurrent AF post ablation.

Research Plan:

Study Design. This will be a randomized open label trial in patients who are post catheter ablation for atrial fibrillation. Randomization to either aggressive BP lowering or standard BP control will occur three to six months prior to the procedure.

Study Population. Patients will be included if they have persistent or high burden paroxysmal (refractory to class 1 or 3 antiarrhythmic medication) and intend to have a catheter ablation procedure for AF.

Followup. Patients will be followed at 3 month intervals for the first year, then every 6 months to a maximum of 30 months or the common study end date has been reached (1 year post randomization for the last patient enrolled).

Statistical Analysis. Kaplan-Meier analysis of the primary outcome will be performed. A Cox proportional hazards model will be constructed to assess the effect of variables chosen a priori on the primary outcome.

• Study Type: Interventional
• Enrollment (Actual): 184
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • QE II Health Sciences Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Documented systolic blood pressure greater than or equal to 130 mmHg
• Undergoing planned catheter ablation for persistent AF (lasting > 7 days and < 365 days or requiring electrical or chemical cardioversion) OR High burden paroxysmal AF > 6 months (greater than or equal to 3 symptomatic episdes in past 6 months and refractory or inteolerant to at least 1 class 1 or 3 antiarrhythmic)

Exclusion Criteria:

• Permanent atrial fibrillation
• Contraindication to Accupril or any other ACE-I
• Women of child-bearing potential
• Life expectancy less than 1 year
• Less than 18 years of age
• Unable to give informed consent
• Known moderate to several renal dysfunction (eGFR < 30 ml/min/1.73m2)
• Prior AF catheter ablation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Aggressive Blood Pressure control; The experimental arm will receive open label therapy to achieve a target systolic blood pressure less than or equal to 120 mmHg. If the average BP is found to be > 120 mmHg at the baseline, telephone or clinic followup visits, treatment will be recommended based on the following regimen (For details, please see Appendix 4): Step 1 - Accupril, titrated to maximum tolerated dose, beginning at 20 mg po od followed by 40 mg successively Step 2 - combination of Accupril with Hydrochlorothiazide 12.5 mg po od. Step 3 - Addition of Atenolol 50 mg po od. Step 4 - Addition of Norvasc 2.5-10 mg po od. Step 5 - Addition of Terazosin 1 mg po od.	Drug: Aggressive Blood Pressure control; Aggressive Blood Pressure therapy, alone or combination therapy, to reach a target BP equal to or less than 120/80 mmHg; Other Names: Norvasc; Atenolol; Hydrochlorothiazide; Accupril; Terazosin
No Intervention: Standard Blood Pressure control; Treatment will be carried out as per the CHEP guidelines. These patients may require ACEi or ARBs for their treatment. No changes to their drug regimen will be made as long as BP measurements are congruent with current guidelines. These modifications will be made as per standard practice by the physician who is primarily involved with their care (this may be a family physician or a specialist, depending on the patient). Patients with diabetes in the standard arm will be treated to a target BP of <130/80 as per the CHEP guidelines.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to symptomatic AF/atrial tachycardia (AT)/atrial flutter (AFl) lasting > 30 seconds more than 3 months post ablation.	This has been altered since the inception of the study to include atrial tachycardia and atrial flutter, as there have been changes to how ablation is performed since the study began. Specifically, the STAR AF2 study found that PVI is similar to PVI in addition to either complex fractionated electrogram ablation or PVI in addition to linear ablation. Given this, the occurrence of AT/AFL was thought to be iatrogenic and occur as a consequence of various ablation strategies, rather than to the substrate, hence was excluded from the primary endpoint. Given the change in strategy of ablation, the inclusion of AT/AFl in the primary outcome is now necessary as it may reflect change in substrate, rather than ablation strategy, as previously thought. In addition, from a patient perspective, the occurence of AT/AFl is indistinguishable from a symptoms point of view.	at least 3 months post catheter ablation

Secondary Outcome Measures

Outcome Measure	Time Frame
Any recurrent atrial fibrillation/atrial tachycardia/atrial flutter post randomization	up to 30 months post randomization
Recurrent atrial fibrillation/atrial tachycardia/atrial flutter (symptomatic or asymptomatic) post ablation	up to 30 months post randomization
atrial fibrillation/atrial tachycardia/atrial flutter burden (pre and post ablation)	up to 30 months post randomization
Generic and disease specific quality of life	12 months
Correlation of BNP and CRP and recurrence of atrial fibrillation/atrial tachycardia/atrial flutter	12 months
Recurrent AF ablation therapy	up to 30 months post randomization
Visits to the ER or hospitalization for atrial arrhythmia	up to 30 months post randomization
Thromboembolic events	up to 30 months post randomization

Collaborators and Investigators

• Sponsor: Nova Scotia Health Authority
• Collaborators: Nova Scotia Health Research Foundation
• Investigators: Principal Investigator: Ratika Parkash, MD MSc, Dalhousie University/QEII HSC

Publications and helpful links

General Publications

• Weng W, Choudhury R, Sapp J, Tang A, Healey JS, Nault I, Rivard L, Greiss I, Bernick J, Parkash R. The role of brain natriuretic peptide in atrial fibrillation: a substudy of the Substrate Modification with Aggressive Blood Pressure Control for Atrial Fibrillation (SMAC-AF) trial. BMC Cardiovasc Disord. 2021 Sep 16;21(1):445. doi: 10.1186/s12872-021-02254-5.
• Parkash R, Wells GA, Sapp JL, Healey JS, Tardif JC, Greiss I, Rivard L, Roux JF, Gula L, Nault I, Novak P, Birnie D, Ha A, Wilton SB, Mangat I, Gray C, Gardner M, Tang ASL. Effect of Aggressive Blood Pressure Control on the Recurrence of Atrial Fibrillation After Catheter Ablation: A Randomized, Open-Label Clinical Trial (SMAC-AF [Substrate Modification With Aggressive Blood Pressure Control]). Circulation. 2017 May 9;135(19):1788-1798. doi: 10.1161/CIRCULATIONAHA.116.026230. Epub 2017 Feb 22.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: February 7, 2007
• First Submitted That Met QC Criteria: February 20, 2007
• First Posted (Estimate): February 21, 2007

Study Record Updates

• Last Update Posted (Actual): June 20, 2017
• Last Update Submitted That Met QC Criteria: June 19, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: atrial fibrillation; blood pressure; catheter ablation
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Urological Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Sodium Chloride Symporter Inhibitors; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Hydrochlorothiazide; Atenolol; Terazosin
• Other Study ID Numbers: RP-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO