Trial Outcomes & Findings for A Prospective Evaluation of Natriuretic Peptide Based Referral of CHF Patients in Primary Care (NCT NCT02807857)

Last Updated: 2021-02-24

Results Overview

Assessment of treatment regimen with respect to ESC guideline adherence at Visit 1 before referral to cardiologist. ESC Criteria for adherence: Drug Types: Treatment with (1) ACEi or (1) ARB in combination with (1) beta-blocker and (1) MRA for patients w/an LVEF ≤ 35% at V1. Treatment w/(1) ACEi or (1) ARB, in combination with (1) beta-blocker+ without treatment with an MRA for patients with an LVEF \> 35% at visit 1. Drug type \& dose: Guideline adherent with respect to drug types and dosage of all respective guideline drugs ≥ 50% of the recommended target dose.

Recruitment status

COMPLETED

Study phase

Target enrollment

1415 participants

Primary outcome timeframe

Baseline (Visit 1)

Results posted on

2021-02-24

Participant Flow

The enrolled set consisted of 1415 patients. 861 patients were referred to a cardiologist within this study and Based on findings from the interim-analysis, Novartis decided to terminate the study prematurely in March 2018.

Participant milestones

Participant milestones
Measure	Enrolled Patients Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe. Patients who were considered clinically stable with NT-proBNP levels \> 600 pg/ml were described and analyzed in the Follow-Up set.
Enrolled Set STARTED	1415
Enrolled Set COMPLETED	864
Enrolled Set NOT COMPLETED	551
Follow-Up Set STARTED	864
Follow-Up Set COMPLETED	680
Follow-Up Set NOT COMPLETED	184

Reasons for withdrawal

Reasons for withdrawal
Measure	Enrolled Patients Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe. Patients who were considered clinically stable with NT-proBNP levels \> 600 pg/ml were described and analyzed in the Follow-Up set.
Enrolled Set Patients not suitable for follow-up.	551
Follow-Up Set Study Terminated By Sponsor	131
Follow-Up Set Withdrawal by Subject	8
Follow-Up Set Lost to Follow-up	7
Follow-Up Set Physician Decision	6
Follow-Up Set Adverse Event	3
Follow-Up Set Death	27
Follow-Up Set Relocation	2

Baseline Characteristics

Enrolled Set

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Enrolled Patients n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe. Patients who were considered clinically stable an with NT-proBNP levels \> 600 pg/ml were referred to a cardiologist for evaluation and were in the follow-up set.
Age, Continuous	69.8 Years STANDARD_DEVIATION 11.6 • n=99 Participants
Age, Customized <65 years	482 Participants n=99 Participants • Enrolled Set
Age, Customized ≥65 years to <75 years	408 Participants n=99 Participants • Enrolled Set
Age, Customized ≥75 years to <85 years	401 Participants n=99 Participants • Enrolled Set
Age, Customized ≥85 years	124 Participants n=99 Participants • Enrolled Set
Sex: Female, Male Female	436 Participants n=99 Participants
Sex: Female, Male Male	979 Participants n=99 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants
Race (NIH/OMB) Asian	5 Participants n=99 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants
Race (NIH/OMB) Black or African American	2 Participants n=99 Participants
Race (NIH/OMB) White	1282 Participants n=99 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants
Race (NIH/OMB) Unknown or Not Reported	126 Participants n=99 Participants

PRIMARY outcome

Timeframe: Baseline (Visit 1)

Population: Enrolled and Follow-up Set included. Due to missing left ventricular ejection fraction (LVEF) values, some patients could not be classified.

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Clinically Stable Patients Whose Therapy Regimen Adheres to ESC Guideline Recommendations for Drug Types (Level 1) and Drug Type and Dose (Level 2) at Visit 1 (Before Referral to a Cardiologist) Level 1: Drug Type : Adherent	110 Participants	59 Participants
Number of Clinically Stable Patients Whose Therapy Regimen Adheres to ESC Guideline Recommendations for Drug Types (Level 1) and Drug Type and Dose (Level 2) at Visit 1 (Before Referral to a Cardiologist) Level 1: Drug type : Not Adherent	802 Participants	523 Participants
Number of Clinically Stable Patients Whose Therapy Regimen Adheres to ESC Guideline Recommendations for Drug Types (Level 1) and Drug Type and Dose (Level 2) at Visit 1 (Before Referral to a Cardiologist) Patients missing LVEF values	503 Participants	279 Participants

PRIMARY outcome

Timeframe: Month 6

Population: Follow-Up set

Assessment of patients' adherence at Visit 2, for patients who were already adherent at Visit 1, and those who were not adherent at Visit 1, for both drug type and drug type and dose. ESC Criteria for adherence: Drug Types: Treatment with (1) ACEi or (1) ARB in combination with (1) beta-blocker and (1) MRA for patients w/an LVEF ≤ 35% at V1. Treatment w/(1) ACEi or (1) ARB, in combination with (1) beta-blocker+ without treatment with an MRA for patients with an LVEF \> 35% at visit 1. Drug type \& dose: Guideline adherent with respect to drug types and dosage of all respective guideline drugs ≥ 50% of the recommended target dose.

Outcome measures

Outcome measures
Measure	Enrolled Set n=861 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Adherence to ESC Guideline at Visit 2 (After Referral to a Cardiologist, Month 6), for Follow-up Set: Drug Type and Drug Type and Dose Adherence at V2, not adherent at V1 for drug type	3.3 Percentage of Patients	—
Adherence to ESC Guideline at Visit 2 (After Referral to a Cardiologist, Month 6), for Follow-up Set: Drug Type and Drug Type and Dose Adherence at V2, not adherent at V1:drug type/dose	0.8 Percentage of Patients	—
Adherence to ESC Guideline at Visit 2 (After Referral to a Cardiologist, Month 6), for Follow-up Set: Drug Type and Drug Type and Dose Adherence at V2 and V1 for drug type	79.2 Percentage of Patients	—
Adherence to ESC Guideline at Visit 2 (After Referral to a Cardiologist, Month 6), for Follow-up Set: Drug Type and Drug Type and Dose Adherence at Visit 1 for drug type & dose	86.7 Percentage of Patients	—

SECONDARY outcome

Timeframe: Baseline (Visit 1)

Population: Enrolled Set and Follow-Up Set

The duration of Heart Failure was collected at Baseline (Visit 1).

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Duration of Heart Failure >3 years	896 Participants	549 Participants
Duration of Heart Failure ≤3 years	517 Participants	312 Participants

SECONDARY outcome

Timeframe: Baseline (Visit 1)

Population: Enrolled Set and Follow-Up Set

Use of concomitant compounds were collected at baseline (Visit 1)

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Patients With Current Use of Concomitant Compound Diuretics - without mineral corticoid antagonists	934 Participants	625 Participants
Number of Patients With Current Use of Concomitant Compound Beta blocking agents	981 Participants	602 Participants
Number of Patients With Current Use of Concomitant Compound Agents acting on the renin-angiotensin system	834 Participants	491 Participants
Number of Patients With Current Use of Concomitant Compound Diuretics - mineral corticoid antagonists	664 Participants	416 Participants
Number of Patients With Current Use of Concomitant Compound Antithrombotic agents	401 Participants	256 Participants
Number of Patients With Current Use of Concomitant Compound Cardiac therapy	365 Participants	238 Participants
Number of Patients With Current Use of Concomitant Compound Lipid modifying agents	163 Participants	96 Participants
Number of Patients With Current Use of Concomitant Compound Mineral supplements	110 Participants	69 Participants
Number of Patients With Current Use of Concomitant Compound Calcium channel blockers	65 Participants	39 Participants

SECONDARY outcome

Timeframe: 6 months (Visit 2)

Population: Follow-Up Set

Use of concomitant compounds were collected at 6 months (Visit 2)

Outcome measures

Outcome measures
Measure	Enrolled Set n=753 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Follow-Up Patients With Current Use of Concomitant Compound at Visit 2 Diuretics - without mineral corticoid antagonists	581 Participants	—
Number of Follow-Up Patients With Current Use of Concomitant Compound at Visit 2 Beta blocking agents	533 Participants	—
Number of Follow-Up Patients With Current Use of Concomitant Compound at Visit 2 Agents acting on the renin-angiotensin system	476 Participants	—
Number of Follow-Up Patients With Current Use of Concomitant Compound at Visit 2 Diuretics - mineral corticoid antagonists	423 Participants	—
Number of Follow-Up Patients With Current Use of Concomitant Compound at Visit 2 Antithrombotic agents	221 Participants	—
Number of Follow-Up Patients With Current Use of Concomitant Compound at Visit 2 Cardiac therapy	238 Participants	—
Number of Follow-Up Patients With Current Use of Concomitant Compound at Visit 2 Lipid modifying agents	92 Participants	—
Number of Follow-Up Patients With Current Use of Concomitant Compound at Visit 2 Mineral supplements	65 Participants	—
Number of Follow-Up Patients With Current Use of Concomitant Compound at Visit 2 Calcium channel blockers	35 Participants	—

SECONDARY outcome

Timeframe: 6 months

Population: Follow-Up Set

For patients who enter the prospective period of the study the post-referral treatment choice of cardiologists and/or primary care physicians was documented; for patients, for whom the cardiologist and/or primary care physician chose to prescribe a novel Heart Failure treatment, the treatment was assessed, if it fulfills the definition of adherence to European Society of Cardiology (ESC) guideline recommendation. The proportion of patients for whom an ESC guideline adherent treatment was de novo prescribed was assessed stratified according to different parameters.

Outcome measures

Outcome measures
Measure	Enrolled Set n=861 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Percentages of Clinically Stable Patients for Whom the Cardiologist and/or Primary Care Physician Optimizes Treatment Post Referral, Stratified According to Key Baseline Characteristics Cardiologist's advice-No change	45.1 Percentage of Patients	—
Percentages of Clinically Stable Patients for Whom the Cardiologist and/or Primary Care Physician Optimizes Treatment Post Referral, Stratified According to Key Baseline Characteristics Cardiologist's advice-Treatment intensification	30.7 Percentage of Patients	—
Percentages of Clinically Stable Patients for Whom the Cardiologist and/or Primary Care Physician Optimizes Treatment Post Referral, Stratified According to Key Baseline Characteristics Cardiologist's advice-Treatment reduction	6.3 Percentage of Patients	—
Percentages of Clinically Stable Patients for Whom the Cardiologist and/or Primary Care Physician Optimizes Treatment Post Referral, Stratified According to Key Baseline Characteristics Cardiologist's advice-Treatment adaption	17.9 Percentage of Patients	—

SECONDARY outcome

Timeframe: One measurement in all consecutive patients at baseline (Visit 1)

Population: Enrolled Set and Follow-Up Set

NT-proBNP levels (pg/ml) was measured at baseline in all consecutive patients who satisfy the inclusion and exclusion criteria. Measurements were performed on-site by means of a handheld device provided for the purposes of the study. NT-proBNP level categories could be 600 -799 pg/ml, 800 - 999 pg/ml, 1000 - 1200 pg/ml, \> 1200 pg/ml).

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Patients With Different NT-proBNP Level Categories <600 pg/ml	495 Participants	0 Participants
Number of Patients With Different NT-proBNP Level Categories ≥ 600 pg/ml to <800 pg/ml	135 Participants	130 Participants
Number of Patients With Different NT-proBNP Level Categories ≥ 800 pg/ml to <1000 pg/ml	97 Participants	93 Participants
Number of Patients With Different NT-proBNP Level Categories ≥ 1000 pg/ml to <1200 pg/ml	80 Participants	75 Participants
Number of Patients With Different NT-proBNP Level Categories ≥ 1200 pg/ml to <1400 pg/ml	48 Participants	46 Participants
Number of Patients With Different NT-proBNP Level Categories ≥ 1400 pg/ml to <1600 pg/ml	32 Participants	24 Participants
Number of Patients With Different NT-proBNP Level Categories ≥ 1600 pg/ml to <1800 pg/ml	33 Participants	33 Participants
Number of Patients With Different NT-proBNP Level Categories ≥ 1800 pg/ml to <2000 pg/ml	30 Participants	29 Participants
Number of Patients With Different NT-proBNP Level Categories ≥ 2000 pg/ml	465 Participants	431 Participants

SECONDARY outcome

Timeframe: Baseline (Visit 1)

Population: Enrolled Set

Clinically stable patients in this study were defined as those patients for whom the primary care physician did not see a necessity (based on signs and symptoms of HF) to change the current pharmacological and/or device treatment of HF and who were on stable pharmacological and/or device treatment for HF for at least 3 months prior to inclusion.

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Percentages of Clinically Stable Patients Patients not suitable for prospective period	36.8 Percentage of Participants	—
Percentages of Clinically Stable Patients Patients clinically stable	96.9 Percentage of Participants	—
Percentages of Clinically Stable Patients Patients not clinically stable	3.1 Percentage of Participants	—
Percentages of Clinically Stable Patients Patients suitable for prospective period of study	63.2 Percentage of Participants	—

SECONDARY outcome

Timeframe: 6 months

Population: Follow-Up Set

The cardiologists' suggestions for pharmacological and/or device therapy for the treatment of clinically stable CHF patients was documented and assessed by means of descriptive statistical measures stratified by country/region 6 months after baseline.

Outcome measures

Outcome measures
Measure	Enrolled Set n=861 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Patients by Cardiologist Prescription Practice Per Country/Region Western EU	198 Number of Participants	—
Number of Patients by Cardiologist Prescription Practice Per Country/Region Eastern EU	525 Number of Participants	—

SECONDARY outcome

Timeframe: 10 months

Population: Follow-Up Set

At 10 months after baseline (end of study) NT-proBNP was assessed in clinically stable CHF patients with baseline NT-proBNP levels ≥ 600 pg/ml. Thus, for those patients two NT-proBNP measurements were available: at baseline and 10 months later. The individual change of NT-proBNP between both time points were assessed in accordance to the patients' treatment history during the study, i.e. baseline Heart Failure treatment and therapeutic decision taken 6 months after baseline.

Outcome measures

Outcome measures
Measure	Enrolled Set n=861 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Change of NT-proBNP Levels in Clinically Stable Chronic Heart Failure Patients With and Without Treatment Optimization 10 Months After Baseline NT-proBNP [pg/ml] at Visit 1 (Baseline)	2753 pg/mL Standard Deviation 2530	—
Change of NT-proBNP Levels in Clinically Stable Chronic Heart Failure Patients With and Without Treatment Optimization 10 Months After Baseline NT-proBNP [pg/ml] at Visit 3 (10 months)	2245 pg/mL Standard Deviation 2303	—
Change of NT-proBNP Levels in Clinically Stable Chronic Heart Failure Patients With and Without Treatment Optimization 10 Months After Baseline Absolute change in NT-proBNP (V3-V1)	-504 pg/mL Standard Deviation 2607	—

SECONDARY outcome

Timeframe: Baseline (Visit 1), 6 months (Visit 2), 10 months (Visit 3)

Population: Enrolled Set for Visit 1 (Baseline) and Follow-Up Set (Visit 2 and 3) for those clinically stable patients who entered the prospective period of the study

Quality of life (QoL) was assessed by EQ-5D including the dimensions mobility, self-care, usual activity, pain/discomfort, anxiety/depression. A utility index based on UK value sets was built to summarize the information of these five dimensions into a single scale. The utility index can range between -0.281 and 1.0 where a higher number indicates a better health status. In addition, a visual analog scale (VAS) was applied with a possible range between 0 (=worst imaginable health state) and 100 (=best imaginable health state). Scores collected for all patients at baseline (Visit 1) and at Visit 2 and Visit 3 (only patients who entered the prospective period of the study, i.e. clinically stable patients with a NT-proBNP level ≥ 600 pg/ml) were asked to fill out the EuroQol 5D (EQ-5D) quality of life (QoL) questionnaire validated for heart failure (HF).

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Change in EuroQol Five Dimensions Questionnaire (EQ-5D) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) EQ-5D Visual Analog Scale (VAS) - Visit 1	60 Scores on a scale Interval 0.0 to 100.0	60 Scores on a scale Interval 0.0 to 100.0
Change in EuroQol Five Dimensions Questionnaire (EQ-5D) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) EQ5D Utility index - Visit 1	0.81 Scores on a scale Interval -0.17 to 1.0	0.79 Scores on a scale Interval -0.17 to 1.0
Change in EuroQol Five Dimensions Questionnaire (EQ-5D) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) EQ5D Utility index - Visit 2	—	0.80 Scores on a scale Interval -0.11 to 1.0
Change in EuroQol Five Dimensions Questionnaire (EQ-5D) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) EQ5D Utility index absolute change (V2-V1)	—	0.00 Scores on a scale Interval -0.47 to 0.83
Change in EuroQol Five Dimensions Questionnaire (EQ-5D) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) EQ5D Utility index - Visit 3	—	0.78 Scores on a scale Interval 0.28 to 1.0
Change in EuroQol Five Dimensions Questionnaire (EQ-5D) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) EQ5D Utility index absolute change (V3-V1)	—	0.00 Scores on a scale Interval -0.82 to 0.8

SECONDARY outcome

Timeframe: Baseline (Visit 1), 6 months (Visit 2), 10 months (Visit 3)

Population: Enrolled Set for Visit 1 (Baseline) and Follow-Up Set (Visit 2 and 3) for those clinically stable patients who entered the prospective period of the study

The KCCQ is a self-administered questionnaire. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and quality of life, each with different Likert scale wording, including limitations, frequency, bother, change in condition, understanding, levels of enjoyment and satisfaction. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. A positive change from baseline indicates improvement. Scores were collected for all patients at baseline and Visit 2 and Visit 3 (only patients who had entered the prospective period of the study (clinically stable patients with a NT-proBNP level ≥ 600 pg/ml) were asked to complete Kansas City Cardiomyopathy Questionnaire (KCCQ) validated for Heart Failure.

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) KCCQ Total Symptom Score - Visit 1	77.1 Utility Index Score Interval 0.0 to 100.0	74.0 Utility Index Score Interval 0.0 to 100.0
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) KCCQ Clinical Summary Score - Visit 1	72.1 Utility Index Score Interval 0.0 to 100.0	68.8 Utility Index Score Interval 0.0 to 100.0
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) KCCQ Overall Summary Score - Visit 1	70.1 Utility Index Score Interval 4.2 to 100.0	66.1 Utility Index Score Interval 4.2 to 100.0
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) KCCQ Overall Summary Score absolute change (V2-V1)	—	0.0 Utility Index Score Interval -48.4 to 70.8
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) KCCQ Overall Summary Score - Visit 3	—	66.7 Utility Index Score Interval 0.0 to 100.0
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) KCCQ Overall Summary Score absolute change (V3-V1)	—	0.5 Utility Index Score Interval -66.1 to 66.8
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) KCCQ Clinical Summary Score - Visit 2	—	68.8 Utility Index Score Interval 1.0 to 100.0
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) KCCQ Clinical Summary Score abs. change (V2-V1)	—	0.00 Utility Index Score Interval -61.5 to 65.6
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) KCCQ Clinical Summary Score - Visit 3	—	68.8 Utility Index Score Interval 0.0 to 100.0
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total and Individual Sub-scores at Visit 1 (Baseline), Visit 2 (6 Months) and Visit 3 (10 Months) KCCQ Summary Score absolute change (V3-V1)	—	0.0 Utility Index Score Interval -53.1 to 69.0

SECONDARY outcome

Timeframe: Baseline (Visit 1)

Population: Enrolled Set and Follow-Up Set

Living conditions were collected at Baseline (Visit 1).

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Patients in Different Living Conditions Living independently in household (alone)	313 Number of Participants	204 Number of Participants
Number of Patients in Different Living Conditions Living with spouse or significant other	817 Number of Participants	481 Number of Participants
Number of Patients in Different Living Conditions Living in residence with other family member	264 Number of Participants	159 Number of Participants
Number of Patients in Different Living Conditions Living in a long term care facility	20 Number of Participants	16 Number of Participants
Number of Patients in Different Living Conditions Transient housing	1 Number of Participants	1 Number of Participants

SECONDARY outcome

Timeframe: Baseline (Visit 1)

Population: Enrolled Set and Follow-Up Set

Employment status was collected at Baseline (Visit 1).

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Patients in Different Employment Status Student	0 Number of Participants	0 Number of Participants
Number of Patients in Different Employment Status Employed (part-time)	49 Number of Participants	28 Number of Participants
Number of Patients in Different Employment Status Employed (full-time)	144 Number of Participants	51 Number of Participants
Number of Patients in Different Employment Status Homemaker	26 Number of Participants	15 Number of Participants
Number of Patients in Different Employment Status Retired	1034 Number of Participants	680 Number of Participants
Number of Patients in Different Employment Status Unemployed	85 Number of Participants	43 Number of Participants
Number of Patients in Different Employment Status Sustained Sick Leave	73 Number of Participants	40 Number of Participants
Number of Patients in Different Employment Status Missing	4 Number of Participants	4 Number of Participants

SECONDARY outcome

Timeframe: Baseline (Visit 1)

Population: Enrolled Set and Follow-Up Set

Smoking status was collected at baseline (visit 1).

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Patients With Smoking Status Never	779 Number of Participants	500 Number of Participants
Number of Patients With Smoking Status Current	205 Number of Participants	113 Number of Participants
Number of Patients With Smoking Status Former	427 Number of Participants	246 Number of Participants
Number of Patients With Smoking Status Missing	4 Number of Participants	2 Number of Participants

SECONDARY outcome

Timeframe: Baseline (visit 1)

Population: Enrolled Set

Geographic regions were collected at Baseline (Visit 1).

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Patients From Different Geographical Regions RUS	226 Number of Participants	173 Number of Participants
Number of Patients From Different Geographical Regions BEL	201 Number of Participants	114 Number of Participants
Number of Patients From Different Geographical Regions HRV	169 Number of Participants	95 Number of Participants
Number of Patients From Different Geographical Regions SVN	122 Number of Participants	72 Number of Participants
Number of Patients From Different Geographical Regions POL	120 Number of Participants	74 Number of Participants
Number of Patients From Different Geographical Regions LTU	103 Number of Participants	65 Number of Participants
Number of Patients From Different Geographical Regions HUN	94 Number of Participants	58 Number of Participants
Number of Patients From Different Geographical Regions FRA	89 Number of Participants	54 Number of Participants
Number of Patients From Different Geographical Regions ESP	76 Number of Participants	30 Number of Participants
Number of Patients From Different Geographical Regions NOR	58 Number of Participants	33 Number of Participants
Number of Patients From Different Geographical Regions CYP	36 Number of Participants	20 Number of Participants
Number of Patients From Different Geographical Regions LVA	34 Number of Participants	22 Number of Participants
Number of Patients From Different Geographical Regions MLT	26 Number of Participants	17 Number of Participants
Number of Patients From Different Geographical Regions EST	18 Number of Participants	16 Number of Participants
Number of Patients From Different Geographical Regions DNK	19 Number of Participants	4 Number of Participants
Number of Patients From Different Geographical Regions PRT	13 Number of Participants	6 Number of Participants

SECONDARY outcome

Timeframe: Baseline (Visit 1)

Population: Enrolled Set and Follow-Up Set

Health insurance status was collected at Baseline (Visit 1).

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Patients With Health Insurance Status Statutory Health Insurance	1168 Number of Participants	712 Number of Participants
Number of Patients With Health Insurance Status Private Health Insurance	29 Number of Participants	22 Number of Participants
Number of Patients With Health Insurance Status Combined statutory and private health insurance	171 Number of Participants	98 Number of Participants
Number of Patients With Health Insurance Status None	47 Number of Participants	29 Number of Participants

SECONDARY outcome

Timeframe: Baseline (Visit 1)

Population: Enrolled Set and Follow-Up Set

Educational level was collected at Baseline (Visit 1).

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Patients at Different Educational Level Primary Education	396 Number of Participants	248 Number of Participants
Number of Patients at Different Educational Level Secondary Education	730 Number of Participants	421 Number of Participants
Number of Patients at Different Educational Level University	257 Number of Participants	173 Number of Participants
Number of Patients at Different Educational Level None	30 Number of Participants	17 Number of Participants
Number of Patients at Different Educational Level Missing	2 Number of Participants	2 Number of Participants

SECONDARY outcome

Timeframe: Baseline (Visit 1)

Population: Enrolled Set and Follow-Up Set

The primary etiology of Heart Failure was collected at Baseline (Visit 1).

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Patients Per Primary Etiology of Heart Failure Primary Etiology- Ischemic	860 Number of Participants	541 Number of Participants
Number of Patients Per Primary Etiology of Heart Failure Primary Etiology-Non-Ischemic	553 Number of Participants	320 Number of Participants

SECONDARY outcome

Timeframe: Baseline (Visit 1), 6 months, 10 months

Population: Enrolled Set and Follow-Up Set

HF-related hospitalizations was collected in the previous 12 months prior to baseline at baseline visit, at 6 and 10 months post-baseline.

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Number of Patients With Heart Failure (HF)-Related Hospitalizations in the Previous 12 Months Prior to Baseline, and During the Study Visit 1- Up to Baseline	383 Number of Participants	262 Number of Participants
Number of Patients With Heart Failure (HF)-Related Hospitalizations in the Previous 12 Months Prior to Baseline, and During the Study Visit 2-6 months	0 Number of Participants	18 Number of Participants
Number of Patients With Heart Failure (HF)-Related Hospitalizations in the Previous 12 Months Prior to Baseline, and During the Study Visit 3-10 months	0 Number of Participants	22 Number of Participants
Number of Patients With Heart Failure (HF)-Related Hospitalizations in the Previous 12 Months Prior to Baseline, and During the Study Missing	0 Number of Participants	6 Number of Participants

SECONDARY outcome

Timeframe: Baseline (Visit 1)

Population: Enrolled Set and Follow-Up Set

Cardiovascular and non-cardiovascular co-morbidities were collected at baseline (Visit 1)

Outcome measures

Outcome measures
Measure	Enrolled Set n=1415 Participants Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 Participants Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Percentage of Patients With Cardiovascular and Non-cardiovascular Co-morbidities Hypertension	74.2 Percentage of Participants	75.8 Percentage of Participants
Percentage of Patients With Cardiovascular and Non-cardiovascular Co-morbidities Dyslipidemia	61.6 Percentage of Participants	58.8 Percentage of Participants
Percentage of Patients With Cardiovascular and Non-cardiovascular Co-morbidities History of myocardial infarction	43.9 Percentage of Participants	44.4 Percentage of Participants
Percentage of Patients With Cardiovascular and Non-cardiovascular Co-morbidities Atrial fibrillation	40.8 Percentage of Participants	52.3 Percentage of Participants
Percentage of Patients With Cardiovascular and Non-cardiovascular Co-morbidities Obesity	36.1 Percentage of Participants	30.8 Percentage of Participants
Percentage of Patients With Cardiovascular and Non-cardiovascular Co-morbidities Stable angina pectoris	31.4 Percentage of Participants	33.8 Percentage of Participants
Percentage of Patients With Cardiovascular and Non-cardiovascular Co-morbidities Diabetes mellitus type 2	29.9 Percentage of Participants	31.5 Percentage of Participants
Percentage of Patients With Cardiovascular and Non-cardiovascular Co-morbidities Other Comorbidities	13.0 Percentage of Participants	14.0 Percentage of Participants

Adverse Events

Enrolled Set

Serious events: 117 serious events

Other events: 187 other events

Deaths: 32 deaths

Follow-Up Set

Serious events: 114 serious events

Other events: 181 other events

Deaths: 30 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Enrolled Set n=1415 participants at risk Adult male and female patients with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who were managed in a primary care setting in sites across Europe.	Follow-Up Set n=861 participants at risk Patients who were considered clinically stable and with NT-proBNP levels \> 600 pg/ml who were referred to a cardiologist at Visit 1 for evaluation were in the follow-up set.
Blood and lymphatic system disorders Anaemia	0.14% 2/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.23% 2/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Acute myocardial infarction	0.21% 3/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.35% 3/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Angina pectoris	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Angina unstable	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Arrhythmia	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Atrial fibrillation	0.64% 9/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	1.0% 9/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Atrioventricular block	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Cardiac arrest	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Cardiac failure	2.0% 29/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	3.1% 27/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Cardiac failure acute	0.14% 2/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.23% 2/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Cardiac failure chronic	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Cardiac failure congestive	0.14% 2/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.23% 2/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Myocardial infarction	0.28% 4/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.46% 4/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Palpitations	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Tachycardia	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Ventricular extrasystoles	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Cardiac disorders Ventricular tachycardia	0.14% 2/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.23% 2/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Gastrointestinal disorders Constipation	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Gastrointestinal disorders Gastric haemorrhage	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Gastrointestinal disorders Gastric ulcer	0.14% 2/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.23% 2/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Gastrointestinal disorders Melaena	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Gastrointestinal disorders Short-bowel syndrome	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
General disorders Chest discomfort	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
General disorders Death	0.21% 3/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.23% 2/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
General disorders Fatigue	0.14% 2/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.23% 2/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
General disorders Oedema peripheral	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
General disorders Soft tissue inflammation	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
General disorders Sudden cardiac death	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
General disorders Sudden death	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
General disorders Ulcer haemorrhage	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Hepatobiliary disorders Cholelithiasis	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Infections and infestations Bacterial infection	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Infections and infestations Epididymitis	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Infections and infestations Erysipelas	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Infections and infestations Gastroenteritis	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Infections and infestations Intestinal gangrene	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Infections and infestations Orchitis	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Infections and infestations Otitis externa	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Infections and infestations Pneumonia	0.64% 9/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	1.0% 9/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Infections and infestations Respiratory tract infection	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Infections and infestations Sepsis	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Infections and infestations Urinary tract infection	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Injury, poisoning and procedural complications Ankle fracture	0.14% 2/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.23% 2/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Injury, poisoning and procedural complications Electric shock	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Injury, poisoning and procedural complications Fall	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Injury, poisoning and procedural complications Fracture	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Injury, poisoning and procedural complications Head injury	0.14% 2/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.23% 2/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Injury, poisoning and procedural complications Humerus fracture	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Injury, poisoning and procedural complications Subarachnoid haemorrhage	0.14% 2/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.23% 2/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Injury, poisoning and procedural complications Wrist fracture	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Investigations International normalised ratio increased	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Metabolism and nutrition disorders Diabetes mellitus	0.21% 3/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.35% 3/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Metabolism and nutrition disorders Fluid overload	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Metabolism and nutrition disorders Hyponatraemia	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Musculoskeletal and connective tissue disorders Arthritis	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Musculoskeletal and connective tissue disorders Back pain	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Brain neoplasm	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neuroendocrine tumour	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Nervous system disorders Cerebrovascular accident	0.28% 4/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.46% 4/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Nervous system disorders Ischaemic stroke	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Nervous system disorders Syncope	0.35% 5/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.58% 5/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Product Issues Device malfunction	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Psychiatric disorders Delirium	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Renal and urinary disorders Acute kidney injury	0.21% 3/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.35% 3/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Renal and urinary disorders Renal failure	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Reproductive system and breast disorders Endometrial hyperplasia	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Reproductive system and breast disorders Uterovaginal prolapse	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.28% 4/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.35% 3/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Respiratory, thoracic and mediastinal disorders Orthopnoea	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Respiratory, thoracic and mediastinal disorders Pulmonary mass	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.21% 3/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.35% 3/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Skin and subcutaneous tissue disorders Ischaemic skin ulcer	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Social circumstances Homicide	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Surgical and medical procedures Aortic valve repair	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Surgical and medical procedures Cardiac ablation	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Surgical and medical procedures Cardiac pacemaker insertion	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Surgical and medical procedures Cardiac resynchronisation therapy	0.14% 2/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.23% 2/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Surgical and medical procedures Cardioversion	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Vascular disorders Circulatory collapse	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Vascular disorders Hypertension	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Vascular disorders Hypotension	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Vascular disorders Peripheral artery thrombosis	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.
Vascular disorders Vasculitis	0.07% 1/1415 • Adverse Events were collected from FPFV to LPLV up to 2 years.	0.12% 1/861 • Adverse Events were collected from FPFV to LPLV up to 2 years.