Clinical Studies and Outcomes

Overview

Syncope Clinical Studies

There is a strong and growing body of clinical evidence highlighting the importance of detecting cardiac abnormalities in patients with syncope or unexplained symptoms.

Studies have demonstrated the clinical and economic value of using an insertable cardiac monitor (ICM), such as Reveal^®, in the diagnosis of unexplained syncope:

Study 1

Incidence and Prognosis of Syncope. New England Journal of Medicine.

Study 2

Cost Effectiveness of Reveal Versus Conventional Testing. Journal of the American College of Cardiologists.

Study 3

ISSUE 1: Interpreting Tilt Test Results in Syncope Diagnosis. Circulation.

Study 4

ISSUE 2: International Study on Syncope of Uncertain Etiology 2. European Heart Journal.

AF Clinical Studies

Current ACC/AHA/ESC Guidelines recommend aggressive treatment in the management of atrial fibrillation (AF) to help reduce stroke risk. Therefore identifying patients with any atrial fibrillation, regardless of frequency, duration, or presence of symptoms, is clinically important.

Recent studies found that continuous EGM monitoring with an implantable device identified significantly more patients with AF episodes than standard intermittent monitoring.

Study 5

Presence and Duration of Atrial Fibrillation Detected by Continuous Monitoring: Crucial Implications for The Risk of Thromboembolic Events. J Cardiovascular Electrophysiology.

Study 6

New Insights Into Long-Term Follow-Up of Atrial Fibrillation Ablation: Full Disclosure by an Implantable Pacemaker Device. J Cardiovascular Electrophysiology.

Study 7

Comparison of Continuous Versus Intermittent Monitoring of Atrial Arrhythmias. Heart Rhythm.

Study 8

Perception of Atrial Fibrillation Before and After Radiofrequency Catheter Ablation. Circulation.

Study 9

Relationship Between Atrial Tachyarrhythmias and Symptoms. Heart Rhythm.

Study 1

Incidence and Prognosis of Syncope¹

Objective

Study the epidemiology and prognosis of syncope in the general population.

Methods

Evaluation of the incidence, specific causes, and prognosis of syncope among women and men participating in the Framingham Heart Study from 1971 to 1998.

Results

• "…cardiac syncope can be a harbinger of sudden death"
• Patients with cardiac syncope have a 6-month mortality rate that exceeds 10%
• Cardiac syncope doubled the risk of death

Overall Survival of Participants With Syncope, According to Cause, and Participants Without Syncope
 

Study 2

Cost Effectiveness of Insertable Cardiac Monitors Versus Conventional Testing: Randomized Assessment of Syncope Trial (RAST)¹

Objective

Assess the cost implications of two investigation strategies in patients with unexplained syncope.

Methods

Sixty patients with unexplained syncope were randomized to conventional testing with an external loop recorder, tilt test and EP study, or prolonged monitoring with an insertable cardiac monitor.

Results

• Combining primary strategy with crossover, the diagnostic yield for an insertable cardiac monitor is 43% versus 20% for conventional testing
• Cost per diagnosis of ICM is 26% less than conventional testing

Cost Effectiveness of Insertable Cardiac Monitors Versus Conventional Testing

Study 3

ISSUE 1: Interpreting Tilt Test Results in Syncope Diagnosis – International Study of Syncope of Uncertain Etiology¹

Objective

Understand the cause of syncope in tilt (+) and tilt (-) patients using an insertable cardiac monitor (ICM) as a reference standard.

Methods

The ICM was implanted in 111 patients with syncope, a normal ECG and no significant structural heart disease. Patients had at least 3 episodes of syncope in the previous 2 years.

Results

• Tilt (+) and tilt (-) patients have similar outcomes, recurrences, clinical characteristics, and etiology for syncope
• Tilt (-) patients have symptomatic arrhythmias as often as tilt (+) patients (18% vs. 21%)
• Bradyarrhythmias are more common during spontaneous symptoms than expected
• Recurrence rates are the same for tilt (+) and tilt (-) patients (34%)

Study 4

International Study on Syncope of Uncertain Etiology 2 (ISSUE 2)¹

Objective

ISSUE 2 evaluated the effectiveness of a new strategy utilizing early application of an Insertable Loop Recorder (ILR) to select therapy and reduce syncope recurrence in patients with suspected neurally mediated syncope.

• Only ECG-documented episodes were used to determine therapy treatment
• Therapy selection was independent of tilt table test results
• Both syncope recurrence and burden were assessed

Results

The ILR mechanism-based diagnostic strategy for neurally mediated syncope patients provided specific and effective therapy – with an 80% relative reduction in the one-year syncope recurrence rate in patients who received ILR-based therapy. The dominate therapy was cardiac pacing as the result of a median asystolic pause of 11.5 seconds.

Study 5

Presence and Duration of Atrial Fibrillation Detected by Continuous Monitoring¹

Objectives

Assess the incidence of thromboembolic events related to thromboembolic risk factors of heart failure, hypertension, age > 75 years, diabetes, and prior stroke or transient ischemic attack (quantified through CHADS₂ score) and the presence and duration of atrial fibrillation (AF). The analysis aims to provide input for clinical decisions on antithrombotic therapy. Compare intermittent versus continuous monitoring strategies.

Methods

Study type: Retrospective analysis
Five hundred sixty-eight pacemaker patients with sinus node disease and a history of AF were continuously monitored during 1 year for rhythm status. Additional monitoring strategies, including 24-hour, 1-week, and 30-day Holter sessions, were simulated. Thromboembolic risk was quantified through CHADS₂ score and patients were classified into three AF groups depending on AF presence, absence and duration:

• AF-free: < 5 minutes on 1 day
• AF-5 min: > 5 minutes on 1 day but < 24 hours
• AF-24 hr: > 24 hours

The CHADS₂ score was then combined with AF presence and duration to determine the different risks of thromboembolic events.

Results

• The incidence of thromboembolic events proved to be significantly dependent on the combination of AF classification and CHADS₂ score
• Two subpopulations emerged with significantly different risks of thromboembolic events: 0.8% versus 5% (P = 0.035)
• Standard methods of AF monitoring had a low sensitivity and a low negative predictive value (NPV) in this study

CHADS₂=Heart failure, hypertension, age ≥75 years, diabetes, and prior stroke or transient ischemic attack
Total population of study=568
Columns=CHADS₂ score
Rows=AF Classification

Conclusion

In dual chamber pacemaker patients with clinically documented AF, the incidence of thromboembolic events was significantly dependent on the combination of CHADS₂ score and AF presence and duration. Combining these data can improve risk stratification by discriminating between low- and high-risk patients within the same population.

The study confirmed that standard methods of AF monitoring have a lower sensitivity and a lower negative predictive value in AF characterization and detection than continuous monitoring by an implanted device. This may impact the clinical management of rhythm control strategies and antithrombotic therapies.

Study 6

New Insights Into Long-Term Follow-Up of Atrial Fibrillation Ablation¹

Objectives

Evaluate the extended monitoring capabilities of an implantable device in assessing the very long-term follow-up after radiofrequency (RF) ablation for atrial fibrillation (AF). Compare the difference in perceived outcome between continuous monitoring and standard monitoring options.

Methods

Study type: Cohort
Fourteen patients with implanted pacemakers were selected for pulmonary vein isolation due to highly symptomatic and drug-refractory AF, despite antibradycardic pacing. Patients were continuously monitored for 18.5 ± 9.3 months before and 41.4 ± 15.1 months after their procedures. 24-hour, 48-hour, and 7-day Holter sessions were simulated every 6 months after RF ablation for comparison to permanent monitoring and symptom-based monitoring.

Key Results

• Continuous EGM monitoring identified significantly more patients with AF episodes than symptom-based follow-up or standard Holter monitoring over 24 hours, 48 hours, or 7 days
• Two of the 14 patients experienced AF recurrences after > 12 months free of tachyarrhythmias
• Atrial tachyarrhythmia burden was significantly reduced from a median of 3.6 to 0.3 hours/day (P < 0.001) from an average of 1.7 ablation procedures per patient
• Only three patients (21%) were free of tachyarrhythmic episodes during long-term follow-up

Discrepancy in Perceived Positive Treatment Effect Versus Actual

Note that standard modes of monitoring significantly overestimated positive treatment effect when compared to continuous ECG monitoring.

Conclusion

Extended monitoring capabilities detect significantly more AF episodes than routine follow-up techniques. Previous studies based on these techniques likely overestimated the degree of positive outcomes after RF ablation.

Because AF reoccurred after more than 12 months free of tachyarrhythmias in 14% of the patients, continuous long-term monitoring is crucial before making therapy decisions regarding anticoagulation or antiarrhythmic medications.

A small, implantable, nontherapeutic device would be of considerable value in providing continuous monitoring for AT/AF.

Study 7

Comparison of Continuous Versus Intermittent Monitoring of Atrial Arrhythmias¹

Objectives

Compare intermittent and symptom-based monitoring to continuous monitoring in order to:

• Identify patients with any atrial tachycardia/atrial fibrillation (AT/AF)
• Identify patients with long-duration AT/AF
• Assess AT/AF burden

Methods

Study type: Retrospective analysis
AT/AF data were recorded daily from 574 pacemaker patients over 1 year. Intermittent monitoring simulating annual, quarterly, and monthly 24-hour Holter sessions, plus 7- and 30-day annual long-term recordings were obtained by analyzing data from randomly selected days within a prescribed monitoring window. Symptom-based monitoring was obtained from patients using an external manual activator when any AT/AF symptoms occurred.

Key Results

• 84% of patients experienced > 1 device-recorded AT/AF episode during the follow-up period
• Sensitivity and negative predictive value of all intermittent and symptom-based monitoring were significantly lower compared to those of continuous monitoring (P < 0.001)
• Intermittent and symptom-based monitoring significantly underestimated the actual AT/AF burden
• Identification of patients with AT/AF episodes improved as the intensity of intermittent monitoring increased

Patients Identified With Any AT/AF by Various Methods of Monitoring During a 12-Month Follow-Up Period

All methods of intermittent monitoring in this analysis identified significantly fewer patients with any AT/AF episodes compared with continuous monitoring.

Conclusion

Relying solely on symptoms or intermittent monitoring is quite inaccurate in identifying patients with any AT/AF or long duration AT/AF and in assessing burden. This could negatively impact anticoagulation decisions and inflate estimates of therapy efficacy. A small, implantable, nontherapeutic device that provides monitoring capabilities for AT/AF could be of value. This would also eliminate many patient compliance and tolerance issues that exist with standard external monitoring systems.

Study 8

Perception of Atrial Fibrillation Before and After RF Catheter Ablation¹

Objectives

Assess the incidence of asymptomatic atrial fibrillation (AF) using an objective, long-term monitoring device in highly symptomatic patients undergoing radiofrequency (RF) catheter ablation.

Methods

Study type: Prospective consecutive trial
Highly symptomatic patients with ECG-documented AF (n = 114) and > 1 ineffective trial with an antiarrhythmic drug underwent RF ablation. A continuous 7-day ECG was recorded in all patients before the ablation procedure, immediately after, and again at 3, 6, and 12 months of follow-up. Patients were instructed to complete a detailed log documenting duration and quality of symptoms occurring during the monitoring sessions. More than 70,000 hours of ECG recordings were analyzed.

Key Results

• Asymptomatic AF frequently occurred in highly symptomatic patients before and after RF catheter ablation
• Symptom-only based follow-up substantially overestimated the success rate of the ablation procedure
• After ablation, the incidence of asymptomatic AF-only significantly increased from 5% at baseline to 36% at 12 months (P = 0.05)
• Neither patient characteristics nor arrhythmia patterns could identify a specific subset as high risk to develop asymptomatic AF

Patients' Perceived and Actual AF Before and After RF Ablation

Note that throughout the course of the study, the percentage of patients with asymptomatic AF only, in all patients with documented AF, increased significantly from 5% at baseline to 36% at the 12-month follow-up (P = 0.05).

Conclusion

Asymptomatic AF frequently occurs in highly symptomatic patients before and after RF catheter ablation. A follow-up based solely on a patient's perceived symptoms substantially overestimates the success rate of the RF ablation. Therefore, an objective, long-term monitoring strategy is necessary to analyze rhythms after an ablation procedure, to ensure appropriate antithrombotic therapies as prescribed.

Study 9

Relationship Between Atrial Tachyarrhythmias and Symptoms¹

Objectives

Correlate patient-reported symptoms of atrial fibrillation (AF) with actual rhythm to help assess the reliability of these symptoms as a marker of AF recurrence.

Methods

Study type: Prospective multicenter randomized trial
Forty-eight DDDRP pacemaker patients with a history of AF logged symptomatic events into their devices' memory via a manual activator. They were followed for 12 ± 2 months. Pacemaker-detected atrial tachyarrhythmia events were classified based on the correlation between patient symptoms and the rhythm:

• Symptomatic atrial tachyarrhythmia
• Asymptomatic atrial tachyarrhythmia
• Symptomatic nonatrial tachyarrhythmia

Key Results

• Approximately 94% of documented atrial tachyarrhythmia episodes were asymptomatic
• Only 17% of the time were patient-reported AF symptoms actually associated with atrial tachyarrhythmias

Example of Monitoring Report Showing AF Burden and Patient-Activated Symptom Tagging

The Cardiac Compass^® report documents the number of hours spent each day in AT/AF and the number of episodes per day. Patient-recorded symptomatic AT episodes are also indicated.

Conclusion

Among patients with symptomatic bradycardia and a history of atrial fibrillation, almost 95% of atrial tachyarrhythmias were clinically silent. Perceived symptoms of AF often were an unreliable index of recurrent atrial tachyarrhythmia. Changes in therapy based solely on patient symptoms may lead to inappropriate alterations in medical management.