Atrioventricular Interval Modulation (AVIM) Therapy for Blood Pressure Control

Published Congress: EuroPCR 2024

Link: https://www.ahajournals.org/doi/10.1161/JAHA.117.006974
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475046/

Dr. Seda Tanyeri Üzel

Introduction
Atrioventricular Interval Modulation (AVIM) therapy is designed to immediately, significantly and permanently lower blood pressure. AVIM therapy is administered with a dual-chamber pacemaker and does not require an additional procedure. This treatment modality is compatible with traditional right ventricular (RV) and conduction system pacing (CSP) lead placement and can be applied to a broad population of hypertensive patients. AVIM therapy has programmable and adjustable features and can be activated or deactivated as needed. Thanks to these features, AVIM therapy offers a flexible and effective solution to control hypertension.
Effect Mechanism:
AVIM therapy uses an innovative mechanism of action to lower blood pressure. Short AV delay pacing reduces preload and immediately lowers blood pressure. However, this method may create a rebound effect due to autonomic nervous system (ANS) activation. Increased pressure during short AV delay pacing is indicative of increased total peripheral resistance (TPR).
BackBeat AVIM pacing prevents unwanted ANS activation by combining short AV intervals with long AV intervals. This method produces a slow increase in blood pressure and a significant effect on ANS activity and TPR. BackBeat AVIM pacing provides an immediate and permanent reduction in blood pressure.
Positive Hemodynamic Effects Provided by AVIM Therapy:
AVIM therapy provides positive hemodynamic effects with left ventricular relaxation. AV sequential pacing offers improvements in several hemodynamic parameters compared to intrinsic conduction. AVIM therapy provides hemodynamic relief by lowering systolic blood pressure (SBP). It reduces left ventricular end-diastolic volume (EDV), end-systolic volume (ESV) and end-systolic pressure (PES). This means an overall decrease in intracardiac volume and pressure. It reduces the load on the systemic circulation by lowering total peripheral resistance (TPR). Finally, AVIM therapy increases the efficiency of the heart's workload, which improves overall cardiac performance.
The MODERATO I, MODERATO II Pilot, and BackBeat Global Pivotal studies evaluated the safety and effectiveness of AVIM therapy.

MODERATO I Study:
The MODERATO I study was a prospective, single-arm study conducted in 27 patients with persistent hypertension (oSBP > 150 mmHg) that was not controlled despite the use of two or more antihypertensive medications. The patients participating in the study also had a pacemaker indication. The study was conducted with three months of AVIM therapy activation followed by a one-month follow-up period to take into account the Hawthorne effect. The study's primary safety and efficacy evaluation was conducted three months after AVIM therapy activation and was followed for two years.
The MODERATO I study showed that AVIM therapy significantly reduced blood pressure. A decrease in 24-hour ambulatory systolic blood pressure (aSBP) was observed by -11.6 mmHg on the first day, -8.3 mmHg in the first month, and -10.1 mmHg in the third month. Office systolic blood pressure (oSBP) decreased by -16.8 mmHg in the first month, -16.1 mmHg in the third month, -11.1 mmHg in the sixth month, -15.6 mmHg in the twelfth month, -14.4 mmHg in the eighteenth month and -13.1 mmHg in the twenty-fourth month.

MODERATO II Pilot Study:
The MODERATO II study showed promising results with AVIM therapy in pacemaker patients with persistent hypertension. This study was a prospective, multicenter, randomized, controlled, double-blind pilot study combining AVIM therapy and medical treatment versus ongoing treatment with AVIM therapy and medical therapy.
The MODERATO II study showed that AVIM therapy provides promising results in pacemaker patients. In the study, an average of 3.3 medications were used in both groups. While isolated systolic hypertension (ISH) was observed in 88.5% of the AVIM group, this rate was 71.4% in the control group. AVIM therapy produced a -11.1 mmHg reduction in 24-hour aSBP and a -12.4 mmHg reduction in oSBP at six months. In the sixth month of the study, the MACE (Major Adverse Cardiac Events) rate was recorded as 0% in the treatment group and 14.3% in the control group. After two years, a -17.5 mmHg reduction in oSBP was observed in the AVIM therapy group. Additionally, 85% of patients in the AVIM therapy group showed a significant reduction in 24-hour aSBP.

BACKBEAT Global Pivotal Study:
The BackBeat Global Pivotal study is evaluating the effectiveness and safety of AVIM therapy in patients with uncontrolled hypertension. The study was conducted on 500 patients in 80 centers around the world. Participants consisted of patients with uncontrolled hypertension despite the use of a dual-chamber pacemaker and antihypertensive treatment.
Study Design and Purpose:
The New Randomized Global Pivotal BackBeat Study was conducted to investigate the effectiveness and safety of AVIM therapy in patients with uncontrolled hypertension with an indication for a dual-chamber pacemaker. This prospective, multicenter, randomized, double-blind, controlled study was conducted in 500 patients at 80 centers worldwide.
Inclusion criteria included patients with oSBP ? 140 mmHg and 24-hour aSBP ? 130 mmHg and on a stable antihypertensive treatment regimen. Exclusion criteria were atrial fibrillation burden > 10%, left ventricular ejection fraction (LVEF) < 50%, NYHA Class II+, and use of more than three antihypertensive medications.
The primary efficacy endpoint of the study was the group difference in changes in 24-hour mean aSBP at 3 months after randomization. The primary safety endpoint is protection from unexpected serious device events 3 months after randomization. Secondary and other endpoints were continued double-blind follow-up for 12 months for additional collection of long-term safety and efficacy results and secondary endpoints.
Study Flow Chart:
The pre-screening phase is performed for 90 days for hypertensive patients with new Medtronic pacemaker implants. After patients sign the informed consent form, they proceed to the run-in phase. In this phase, only standard pacing is applied for 4 weeks and patients' suitability is tested. At the end of the run-in phase, patients are randomized to the treatment group or control group. The double-blind study phase continues for 12 months. In the treatment group, AVIM therapy and medical treatment are applied, while in the control group, only medical treatment is applied. Primary and secondary endpoints are evaluated at 3 months and 12 months. After the study is completed, patients in the treatment group and control group are followed for 2 years in the open-label crossover follow-up phase.
This study design and flowchart aims to evaluate in detail the effectiveness and safety of AVIM therapy in patients with uncontrolled hypertension.

Results:
AVIM therapy showed significant improvements in various hemodynamic parameters. In the study, two different treatment methods, AVIM and RV pacing, were compared. The findings are as follows:

• Systolic Blood Pressure: 12% decrease with AVIM treatment (mean -17.1 ± 10.1 mmHg); A 1% decrease (mean 1.7 ± 5.1 mmHg) was observed with RV pacing therapy.
• End-Systolic Volume: A 22% reduction (mean -11.0 ± 11.4 ml) was achieved in AVIM treatment. A 4% increase (mean 2.1 ± 12.0 ml) was detected in RV pacing treatment.
• End-Diastolic Volume: An 11% decrease (mean -12.6 ± 14.0 ml) was detected in AVIM treatment. A 1% decrease (mean -1.6 ± 16.8 ml) was observed in RV pacing treatment.
• End-Diastolic Pressure: A 16% reduction (mean -2.3 ± 3.9 mmHg) was achieved in AVIM treatment. A 3% increase (mean 0.29 ± 2.4 mmHg) was detected in RV pacing treatment.
• Total Peripheral Resistance: While an 11% decrease (mean -0.2 ± 0.4 ml/mmHg) was achieved in AVIM treatment, a 2% increase (mean 0.04 ± 0.45 ml/mmHg) was observed in RV pacing treatment.
• Stroke Volume: A 2% decrease (mean -1.6 ± 12.7 ml) was detected in AVIM treatment. A 1% decrease (mean -1.7 ± 13.4 ml) was detected in RV pacing treatment.
• Stroke Work: A 20% reduction (mean -1596 ± 1934) was achieved in AVIM treatment. In RV pacing treatment, 0% change (mean -42.1 ± 1691) was observed (p < 0.05).

These results demonstrate that AVIM therapy provides significant improvements in various hemodynamic parameters along with left ventricular relaxation.
AVIM therapy resulted in a significant reduction in the 24-hour circadian aSBP profile over 6 months compared to the pre-activation period. aSBP values, which were in the range of 130-140 mmHg during the pre-activation period, decreased to the range of 115-130 mmHg after AVIM therapy. This decrease was found to be statistically significant at all hours of the day (P < 0.01).
These results demonstrate that AVIM therapy provides significant improvements in various hemodynamic parameters along with left ventricular relaxation.

AVIM therapy resulted in a significant reduction in the 24-hour aSBP profile over 6 months compared to the pre-activation period. aSBP values, which were in the range of 130-140 mmHg during the pre-activation period, decreased to the range of 115-130 mmHg after AVIM therapy. This decrease was found to be statistically significant at all hours of the day (P < 0.01).

AVIM therapy has proven its effectiveness in the treatment of hypertension by providing significant and permanent blood pressure reductions. Findings from the MODERATO II study show that AVIM therapy provides significant reductions in blood pressure in both the short term (6 months) and long term (3.6 years). In the study, significant improvements were observed in both aSBP and oSBP values ??of patients receiving AVIM therapy [aSBP after 6 months: -8.9 mmHg (P < 0.001), aSBP after 3.6 years: -8.9 mmHg ( P < 0.001) ; oSBP after 6 months: -14.2 mmHg (P < 0.001), oSBP after 3.6 years: -12.5 mmHg (P < 0.001)]. These results suggest that AVIM therapy provides persistent and sustainable blood pressure reductions over the long term.

Comment
AVIM therapy has emerged as a groundbreaking method in the treatment of hypertension, with the findings presented at the EuroPCR 2024 congress. MODERATO I and MODERATO II studies demonstrated the effectiveness and safety of AVIM therapy, providing significant reductions in systolic blood pressure in both the short and long term. In particular, improvements in the 24-hour circadian systolic blood pressure profile and two-year follow-up results show that this treatment method is a sustainable solution. The BackBeat Global Pivotal study supports the effectiveness of AVIM therapy in a wide patient population. AVIM therapy has the potential to improve the quality of life of hypertensive patients by providing a flexible and effective option to control blood pressure.