Spanish Multicentric Study of Hyperkalaemia Prevalence, Incidence and Prognosis in Patients With Heart Failure and Reduced Ejection Fraction
Conditions: Heart Failure With Reduced Ejection Fraction, Hyperkalemia
Sponsor: Spanish Society of Cardiology

 
 
 
 
 
 
 
 
 
 
 
 
SPANIK-HF Study 
 
SPANISH MULTICENTRIC STUDY OF HYPERKALAEMIA PREVALENCE, INCIDENCE AND 
PROGNOSIS IN PATIENTS WITH HEART FAILURE AND REDUCED EJECTION FRACTION 
 
[Tracking code: ESR-17-13244 ] 
 
ClinicalTrials.gov ID: NCT04141800 
 
V2-18.02.2019 
 
 
 
 
 

 
 
 
 
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SUMMARY 
 
 
 
 
 
 
 
 
 
4 
1. BACKGROUND AND RATIONALE  
 
 
 
 
 
7 
 
2. GOALS 
 
 
 
 
 
 
 
 
 
9 
 
2.1. Main goal  
 
 
 
 
 
 
 
9 
 
2.2. Specific goals 
 
 
 
 
 
 
 
9 
 
3. STUDY DESIGN 
 
 
 
 
 
 
 
 
10 
 
3. 1. Definition of the study population and selection criteria 
 
10 
 
3. 2. Considerations about simple size 
 
 
 
 
11 
 
3. 3. Selection of centres 
 
 
 
 
 
 
11 
3. 4. Source of information  
 
 
 
 
 
12 
 
3. 5. Variables and CRF (appendix 1)  
 
 
 
 
12 
 
3. 6. Study development 
 
 
 
 
 
 
13 
3. 7. Limitations 
 
 
 
 
 
 
 
13 
 
4. DEFINITION OF VARIABLES OF INTEREST  
 
 
 
 
14 
 
5. DATA COLLECTION AND MANAGEMENT   
 
 
 
 
16 
 
5. 1. Data collection  
 
 
 
 
 
 
16 
 
5. 2. Data management 
 
 
 
 
 
 
16 
 
5. 3. Quality assurance 
 
 
 
 
 
 
16 
 
6. PLAN FOR DATA ANALYSIS 
 
 
 
 
 
 
 
17 
 
7. ETHICAL AND SECURITY ISSUES 
 
 
 
 
 
 
18 
Interference with the prescription habits of the attending physician 
Control and report of adverse reactions  
A.- Definitions 
B.- Recording of adverse events 
C.- Sponsor responsibility for report of SUSARs 
 

 
 
 
 
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8. PRACTICAL ISSUES 
 
 
 
 
 
 
 
22 
 
8. 1. Working plan and chronogram  
 
 
 
 
22 
 
8. 2. Baseline and final reports  
 
 
 
 
 
22 
 
8. 3. Dissemination of results 
 
 
 
 
 
23 
 
8.4 Organisation of the study 
 
 
 
 
 
23 
 
 
 
 
 

 
 
 
 
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SUMMARY 
1. Promoter 
Sociedad Española de Cardiología  
2. Title of the study 
SPANISH MULTICENTRIC STUDY OF HYPERKALAEMIA PREVALENCE, INCIDENCE AND 
PROGNOSIS IN PATIENTS WITH HEART FAILURE AND REDUCED EJECTION FRACTION 
3. Main Researchers 
Dr. Marisa Crespo Leiro, A Coruña. 
Dr. Juan Delgado, Madrid.  
Dr. Javier Muñiz García, A Coruña 
4. Scientific Committee 
Dr. Luis Almenar, Valencia 
Dr. Manuel P. Anguita, Córdoba 
Dr. Marisa Crespo Leiro, A Coruña. 
Dr. Juan Delgado, Madrid.  
Dr. Beatriz Díaz Molina, Asturias 
Dr. Nicolás Manito, Barcelona 
Dr. Javier Muñiz García. Instituto Universitario de Ciencias de la Salud, Universidade da 
Coruña. A Coruña 
Dr. Eulalia Roig, Barcelona 
Dr. Javier Segovia, Madrid 
Dr. Luis Miguel Rincón Díaz, AISEC, Madrid 
 
5. Participant centres and researchers 
20 National Public Health System hospitals. Cardiology specialist physicians 
 
6. Clinical Research Ethics Committee (CREC)  
Hospital 12 de Octubre, Madrid 
 
 
 

 
 
 
 
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7. Main goal 
To estimate prevalence and, in medium term basis (12 months), incidence of 
hyperkalaemia in heart failure (HF) outpatients with reduced ejection fraction (REF) 
and its relationship with non-optimal HF therapy and clinical outcomes (mortality and 
hospital admission). 
 
8. Specific goals  
a. –Estimating Hyperkalaemia prevalence in these patients. 
b. -Assessing the role of hyperkalaemia with the use of non-optimal therapy doses.  
c. –Estimating 12 months hyperkalaemia incidence on these patients and describing 
the severity of the episodes.  
d. -Estimating incidence of HF hospital admission and/or death in these patients on a 
medium term basis (12 months) and its association with existence of hyperkalaemia 
during follow up. 
e. –Assessing hyperkalaemia risk during follow-up in relation with the existence of 
diabetes and/or renal failure (RF) at baseline visit. 
 
9. Study design 
National multicentric prospective observational study that includes 12 months follow-
up of consecutive cases of HF outpatients with REF. Inclusion baseline visit and follow –
up visits at 12 months will be scheduled for collecting clinical and blood sample data of 
patients. 
 
10. Study population  
The expected number of patients recruited in 20 Spanish research centres is 600. 
 
11. Chronogram 
Preparation of documentation and protocol: October31st 2018 
Identification and selection of coordinators and researchers: October 2018 
Submission to “Agencia Española del Medicamento y Productos Sanitarios” (AEMPS): 
November 2018 

 
 
 
 
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Presentation to Clinical Research Ethics Committees: November 2018 
Contract signature: December 2018 
Design of case report form (CRF) and electronic case report form (eCRF): January-
March 2019 
Dispatch to centres for assessment and approval: January-February 2019 
Inclusion date for first patient: April 2019 
Inclusion period: April 2019 – October 2019 
Intermediate analysis and presentation of results: second semester 2019 
End of 12 months follow up of the last patient: October 2020 
Final analysis and presentation of definitive results: second semester 2020 
 
12. Promoter and Coordinator Centre data 
Promoter: 
Sociedad Española de Cardiología 
Nuestra Sra. de Guadalupe, 5-7 
28028 Madrid 
Tel: 91 724 23 70 
 
Fax: 91 724 23 71 
 
Coordinating Centre: 
ODDS, S.L. 
Wenceslao Fernández Florez, 1-2º 
15005A Coruña 
Tel: 981 216391 
 
Fax: 981 217539 
proyectos@odds.es 
www.oddsconsultores.es 
 
 

 
 
 
 
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1. BACKGROUND AND RATIONALE 
In the last years, multiple reasons have been increasing the disease burden of heart 
failure (HF) in industrialised countries – also Spain -, being a very important health 
problem. It is foreseeable that this burden will continue increasing in our country1. 
In parallel with this evolution, several treatments already included in clinical 
practiceguidelines2, 3, have proved to be effective in selected groups of patients, 
especially those with systolic function impairment. 
These treatments that interfere with the renin-angiotensin-aldosterone system, 
increase hyperkalaemia risk in HF patients as much as three times3, 4.Hyperkalaemia is 
associated with conduction disorders and risk of potentially life-threatening 
arrhythmias; it is not rare at all, as 20 years ago estimations already indicated 1-10% 
prevalence in hospitalised patients 5. More recent data among ACEI new users suggest 
in the first year 5,6% and 1,7% for potassium values >5 and >5,5 respectively.6  HF 
patients are at increased risk of hyperkalaemia, not only due to the drugs they receive 
(ACEIs/ARB-II, mineralocorticoids receptor antagonists (MRAs) and, more recently, 
sacubitril/valsartan), but also because of the frequent presence of comorbidities 
(diabetes or renal failure, among others).7 
These drugs blocking the renin-angiotensin-aldosterone system have an IA indication 
in the clinical practice guidelines for patients with reduced ejection fraction, so their 
use is becoming more frequent and, subsequently, hyperkalaemia is a growing concern 
for treating HF patients. 7 
Despite the above mentioned, there is no evidence of prospective information for the 
estimation of hyperkalaemia problem in HF patients in the daily Spanish clinical 
practice, although some current registries allows an initial estimation of its prevalence.  
In a recent analysis of the patients included in Spain in the Heart Failure Registry of the 
European Society of Cardiology (ESC) 8 26,3% of patients (401/1526) where MRAs are 
indicated (REF), but not prescribed, the underlying reason for not prescription is 
Hyperkalaemia in 8,5% of them (34/401). There are many “not-prescriptions” that are 
not adequately justified, therefore hyperkalaemia has a larger prevalence (30,6%, 
34/111) among cases where a cause for avoiding MRAs does exist. At least as 
important is the fact that the vast majority of patients, up to 3 of 4, do not reach the 

 
 
 
 
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MRA goal doses and hyperkalaemia is registered as a reason in 10% of cases. This 
transversal information suggests that hyperkalaemia is a problem that deserves 
greater attention due to its negative role in HF therapy. In addition, very recent data 
from a single centre in Spain indicate that normalization of altered potassium levels 
improves prognosis.9 
On the basis of the above described, it is proposed to carry out a prospective registry 
that which would help in completing the existing information for achieving the goals 
described later on. 
 
REFERENCES 
1.- Sayago-Silva I, García-López F, Segovia-Cubero J. Epidemiología de la insuficiencia 
cardiaca en España en los últimos 20 años. Rev Esp Cardiol. 2013;66:649-56.  
2.- Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS et al. 2016 ESC 
Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: 
The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 
2012 of the European Society of Cardiology. Developed with the special contribution of 
the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891-975. 
3.- Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr DE, Drazner MH, et al. 2013 
ACCF/AHA guideline for the management of heart failure: a report of the American 
College of Cardiology Foundation/American Heart Association Task Force on practice 
guidelines. Circulation. 2013;128(16):e240–327 
4.- Jain N, Kotla S Little BB, et al. Predictors of hyperkalemia and death in patients with 
cardiac and renal disease. Am J Cardiol 2012;109:1510-3 
5.- Acker CG, Johnson JP, Palevsky PM, et al. Hyperkalemia in hospitalized patients: 
causes, adequacy of treatment, and results of an attempt to improve physician 
compliance with published therapy guidelines. Arch Intern Med 1998;158:917-24. 
6.- Bandak G, Sang Y, Gasparini A, Chang AR, Ballew SH, Evans M et al. Hyperkalemia 
After Initiating Renin-Angiotensin System Blockade: The Stockholm Creatinine 
Measurements 
(SCREAM) 
Project. 
J 
Am 
Heart 
Assoc. 
2017;6:e005428 
DOI: 10.1161/JAHA.116.005428. 

 
 
 
 
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7.- Sarwar CMS, Papadimitriou L, Pitt B, Piña I. Zannad F, Anker SD et al. Hyperkalemia 
in heart failure. J Am Coll Cardiol 2016; 68:1575-1589. 
8.- Crespo-Leiro MG, Segovia-Cubero J, González-Costello J, Bayes-Genis A, López-
Fernández S, Roig E et al. Adecuación en España a las recomendaciones terapéuticas 
de la guía de la ESC sobre insuficiencia cardíaca: ESC HeartFailure Long-termRegistry. 
Rev Esp Cardiol 2015;68:785-793. 
9.- Núñez J, Bayés-Genís A, Zannad F, Rossignol P, Núñez E, Bodí V et al. Long-Term 
Potassium Monitoring and Dynamics in Heart Failureand Risk of Mortality. Circulation 
2017. Ahead of print 10.1161/CIRCULATIONAHA.117.030576 
 
 
2. GOALS 
 
2.1. Main goal  
To estimate prevalence and, in medium term basis (12 months), incidence of 
hyperkalaemia in heart failure (HF) outpatients with reduced ejection fraction (REF) 
and its relationship with non-optimal HF therapy and clinical outcomes (mortality and 
hospital admission). 
 
2.2. Specific goals 
a. - Estimating Hyperkalaemia prevalence in these patients. 
b. - Assessing the role of hyperkalaemia with the use of non-optimal therapy doses.  
c. - Estimating 12 months hyperkalaemia incidence on these patients and describing 
the severity of the episodes.  
d. - Estimating incidence of HF hospital admission and/or death in these patients on a 
medium term basis (12 months) and its association with existence of hyperkalaemia 
during follow up. 
e. - Assessing hyperkalaemia risk during follow-up in relation with the existence of 
diabetes and/or renal failure (RF) at baseline visit. 
 
 

 
 
 
 
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3. STUDY DESIGN 
National multicentric prospective observational study that includes 12 months follow-
up of consecutive cases of HF outpatients with REF. Inclusion baseline visit and follow –
up visit at 12 months will be scheduled for collecting clinical and blood sample data of 
patients indicated later on in this protocol. 
The study will be performed in ordinary conditions of clinical practice; no additional 
procedures or interventions will be performed. Patients will be selected in cardiology 
outpatient clinics of 20 Spanish centres, including the first 30 patients meeting 
inclusion and exclusion criteria. All patients will undergo the common studies 
according to usual clinical practice and at least both, potassium and renal creatinine 
clearance values will be collected. 
To respond to the main objective, prevalence of hyperkalaemia (as defined later in the 
protocol) at baseline will be determined as well as the appearance of new 
hyperkalaemia cases in the follow up of patients that had normal potassium levels at 
baseline visit; their relationship with outcomes of interest will also be determined. 
Variables to be collected at each visit are indicated in appendix 1. 
 
3. 1. Definition of the study population and selection criteria 
The study population is composed of HF outpatients with REF from excellence Spanish 
centres. 
The study will be performed in 20 Spanish centres, either SEC HF- excellence certified, 
integrating official research networks or with excellent performance proven in 
previous similar initiatives (relation of centres and researchers in Appendix 2). 
Every centre will include the first 30 consecutive cardiology outpatients who fulfil the 
inclusion criteria and that do not present any exclusion criteria. All pre-screened 
patients will be indicated, together with the reason of their exemption if occurs. 
 
Inclusion criteria 
1. Patients, women or men, aged 18 or more 
2. Documented HF with REF (<40%) diagnosis 
3. Signed written informed consent 
 

 
 
 
 
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Exclusion criteria 
1. Any type of disorder affecting the capacity to give free and informed 
written consent 
2. Clinical trial enrolment at the moment of the inclusion 
3. Patients suffering stage 5 chronic kidney disease  
4.  Patients with less than a year life span due to diseases different from HF 
5. Not having completed HF drug titration stage at the moment of inclusion 
(this stage is not completed if, on doctor’s judgement, possible maximum doses have not 
been reached in RAA system drugs and any of these drugs has been included or dose-
modified in recruitment visit) 
6. Informed consent refusal 
At any time during follow-up patients can leave the study (and will be censored in the 
analysis) or retire their consent (and will be excluded from the analysis).  
 
3. 2. Considerations about simple size 
Assuming a 10% risk of outcomes (mortality or HF hospital admission) among the 
exposed (hyperkalaemia), 2.5% among the non-exposed and a 7:1 non-
exposed/exposed ratio, 73 exposed and 511 non-exposed patients should be included 
to have a 80% power to detect these differences with a 95% confidence level. The 
recruitment goal is set at 600 patients.  
This sample size allows a precision of ±2,4%, assuming a prevalence of hyperkalaemia 
at baseline of 10% and with a 95% confidence level.  Furthermore, assuming 5% 
hyperkalaemia cumulative incidence through follow-up among hyperkalaemia-free 
patients at baseline, the proposed sample size, allows a precision of±1,8% with a 95% 
confidence level. 
 
3. 3. Selection of centres 
The number of participant centres throughout Spain will be 20 and a cardiologist will 
be the principal investigator at every centre. The centres have been selected either 
among those with excellence-certified HF units, included in CiberCV Consortium or 

 
 
 
 
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with good performance in previous similar registries; this selection is not random, but 
based on interest and high performance criteria in the field of HF. 
 
3. 4.- Source of information 
Data will be obtained directly from the participants at the planned visits and 
completed with the review of their medical records if needed.   
 
3. 5. Variables and CRF (appendix 1) 
The main outcome variables are:  
a.- Hyperkalaemia. Serum Potassium (K+) will be measured in baseline and follow-up 
visits, but also if there is any intermediate hospital admission. All available potassium 
measurements during follow-up will be reviewed and values of hyperkalaemia 
identified. Hyperkalaemia will be considered with (K+) Values > 5,4 mEq/L  
b.- Proportion of patients using drugs with proven efficacy for HF with REF -but also 
linked with hyperkalaemia- (ACEIs/ARB-II/ARNI and MRAs) and proportion of patients 
with use of optimal doses (based on current ESC heart failure guidelines2) of the same 
drugs; reason for not using them (or not receiving optimal doses) will be registered. 
Proportion of patients in the following categories will also be computed: 
- No ACEi/ARB/ARNI or at less than target dose and no MRA 
- ACEi/ARB/ARNI at target dose and no MRA  
- ACEi/ARB/ARNI at target dose and MRA at less than target dose 
- ACEi/ARB/ARNI at target dose and MRA at target dose  
c.- Hospital admissions during follow-up and main cause for them. Outcomes 
considered will include HF admissions caused by hyperkalaemia and related events. 
Outcome Serum (K+) values will be also registered. 
d.- Mortality and cause.  
HF (and hyperkalaemia) hospital admissions and mortality will be independently 
considered as outcomes; joint outcome incidence of both will be also calculated. 
The remaining variables are set out in appendix 1. The most important variables are 
defined in section 4. 
 

 
 
 
 
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3. 6. Study development 
Every participating centre will include from inclusion date (as described in section 3.1) 
the first 30 heart failure outpatients who fulfil the inclusion criteria and none of the 
exclusion ones. The excluded patients will be also registered, pointing out the reason 
of exclusion. The data to be collected during the initial visit will include the variables 
described in Appendix 1: demographic, clinical, blood sample test, and functional. A 
follow-up and final visit will be scheduled after 12 months for collecting all the 
variables the study requires (Appendix 1). Hospitalisation data since inclusion visit will 
be also collected, together with the information of blood sample test performed in 
such period for detecting hyperkalaemia episodes. Mortality data will include date and 
cause, where possible. If follow-up visit cannot be conducted, the reason for it will be 
registered. The collection and management of data is described in section 5. The 
envisaged length of the study is 24 months since approval date.  
 
3. 7. Limitations 
Mild elevations of serum potassium that do not lead to hospital admission between 
planned visits may go unnoticed.  
 
 
 
 

 
 
 
 
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4. DEFINITION OF VARIABLES OF INTEREST 
 
Heart Failure (HF) with reduced ejection fraction (REF): Patients with confirmed 
diagnosis of HF and with ejection fraction<40%.  
 
Hyperkalaemia: K+values> 5,4 mEq/L.  
 
Optimal doses: the maximum doses of renin-angiotensin-aldosterone related drugs 
that, according to the physician's judgement, the patient can receive. If any of these 
drugs (ACIEs, ARB-II, MRAs or sacubitril-valsartan) is de novointroducedat the initial 
visit, optimal doses will be not considered established.  
 
A previous personal history of diseases and/or outcomes will be registered according 
to the usual practice of every centre. Some of the clarifications needed in every case 
are indicated as follows: 
 
 
Coronary artery disease. Documented existence of any of the following:acute 
myocardial infarction (AMI), acute coronary syndrome (ACS), coronary 
revascularisation (Percutaneous Coronary Angioplasty –PCA - or CABG) or 
coronary stenosis > 50% of arterial lumen in imaging test.  
 
Cerebrovascular diseases. History of ischaemic/haemorrhagicstroke or carotid 
stenosis > 50% of arterial lumen in imaging test.  
 
Peripheral artery disease. Aneurysm of thoracic/abdominal aorta or lower limb 
peripheral arterial disease. 
 
Death due to a major cardiovascular event. Due to ACS, HF, arrhythmia (sudden 
death), arterial aneurysm rupture or stoke.  
 
Arterial thromboembolism. Embolism phenomenon affecting arterial territory – 
(except pulmonary territory). 
 
Ischaemic stroke. Focal neurological deficit originated by cerebral ischemia; 
persists more than 24 hours after a sudden onset. 
 

 
 
 
 
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 
Haemorrhagic stroke: Focal neurological deficit with sudden onset and originated 
by intracranial haemorrhage. 
 
Acute coronary syndrome (ACS): Acute coronary event that present typical ECG 
alterations and/or enzyme elevation. 
 NYHA functional class:  
Functional class I 
No limitation. Ordinary physical activity does not cause 
dyspnoea, fatigue or palpitations.  
Functional class II 
Light limitation of physical activity. Everyday activities cause 
dyspnoea, fatigue or palpitations 
Functional 
class 
III 
Moderate limitation of physical activity. Activities considered 
less intense that everyday ones cause dyspnoea, fatigue or 
palpitations. Patient, however, does not present resting 
dyspnoea.    
Functional 
class 
IV 
Inability to perform activities without limitations. Symptoms 
may be present even at rest 
 
 
Anaemia 
Haemoglobin values <12 g/dl in blood sample tests performed during the previous 
3 months are considered as anaemia; this is the lower value of the normal range 
for adult men and postmenopausal women.  
 
Diabetes (and type) 
 
Considered when personal history reflects diabetes diagnosis (and type).  
 
Arterial hypertension  
Personal history reflecting HTA established diagnosis and/or therapy with 
antihypertensive drugs 
A hypertensive patient will considered as controlled when PA<140/85 mmHg. 
 
Dyslipidaemia 
Considered when personal history reflects dyslipidaemia diagnosis.  
 
Body mass index (BMI): 
- Overweight: BMI (Kg/m2) 25-29,9 
- Obesity: IMC (Kg/m2) ≥30 
 
 

 
 
 
 
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 
Renal function.  
It will be assessed according glomerular filtration rate as follows: 
Stage 1 (GFR>90 ml/min/1,73 m2) 
Stage 2 (GFR ≥ 60 y <90 ml/min/1,73 m2) 
Stage 3 (GFR ≥ 30 y <60 ml/min/1,73 m2) 
Stage 4 (GFR ≥ 15 y <30 ml/min/1,73 m2) 
Stage 5 (GFR <15 ml/min/1,73 m2) 
 
When considered as a dichotomous variable, stages 1 and 2 will be considered 
normal and stages 3, 4 and 5 considered as altered renal function. 
 
5. DATA COLLECTION AND MANAGEMENT  
5. 1. Data collection 
Consecutively, every researcher will handle and explain the information sheet to the 
patients that might fulfil de inclusion criteria (and do not present any exclusion 
criteria) and will ask them to sign the informed consent. Researchers must warrant the 
accuracy and completion of the data collected for the study. Data registered at CRF 
(Appendix 1) should be consistent with source documents used for their collection. 
 
5. 2. Data management 
Data will be collected during initial and follow-up visits and they will be integrated into 
a unique data base of the web platform. Researchers are responsible of the 
information included in the database and will access by means of personal login and 
password. The online platform will include ranges and rules to minimize errors in data 
registering.  
 
5. 3. Quality assurance 
To improve uniformity of interpretation of criteria and/or procedures among centers, 
researchers may contact the promoter, Sociedad Española de Cardiología at the 
Agencia de Investigación de la SEC in order to solve any questions or problems that 
arise during the study: 
 

 
 
 
 
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Agencia de Investigación de la SEC. gcespedes@secardiologia.es. Tel: 91 724 23 70. 
Fax: 91 724 23 71 
Or directly with the project office: 
ODDS, S.L.; proyectos@odds.es; Telf.- 981216391; Fax.- 981217539  
While there is no planned monitorization of data quality, the promoter can, if 
convenient, carry out an audit of the participant centres in order to ensure the 
compliance with best practices during the study. 
 
6. PLAN FOR DATA ANALYSIS 
Hyperkalaemia prevalence at basal visit and the rate of patients who do not receive 
and/or reach optimal doses of drugs of interest (ACIEs, ARB-II, MRAs) will be estimated 
and their corresponding 95% confidence intervals computed. The reason for not 
receiving and/or reaching optimal doses of drugs will be described, especially if it is 
due to hyperkalaemia. 
For those patients who do not present hyperkalaemia at baseline, 12 month 
hyperkalaemia cumulative incidence (95% confidence interval) will be estimated; also 
it will be estimated the proportion of patients who have to modify their therapy due to 
hyperkalaemia. 
The number of episodes of hyperkalaemia during follow-up in relation to the number 
of patients will be estimated and their severity and the therapy changes that induced 
described. Also 12 months cumulative incidence of clinical outcomes will be estimated: 
hospitalisation due to HF or to, hyperkalaemia (and related events) and mortality, 
considered as individual and composite outcomes. The association between 
hyperkalaemia and occurrence of outcomes will be analyses and also adjusted using 
potential confounding factors by means of logistic regression models   
 
The quantitative variables will be generally described using either the mean and the 
standard deviation or the median and interquartile range according them following or 
not a normal distribution. When comparing groups, t-student test will be used for 
continuous variables and chi-share test for qualitative ones. 

 
 
 
 
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Both, intermediate and final analysis, are planned to be carried out after baseline-visit 
closure and at the end of follow up (12 months). 
 
 
7. ETHICAL AND SECURITY ISSUES 
The present study will be assessed by the Clinical Research Ethics Committee of the 
Hospital 12 de octubre, Madrid. The involved patients will sign an informed consent 
(Appendix 3). This study will carried out, as any other research with humans, in 
accordance with the ethical principles reflected in the Declaration of Helsinki and its 
subsequent amendments. The study will also comply with all the requirements laid 
down in current Spanish regulations on the subject of personal data protection. 
 
Interference with the prescription habits of the attending physician 
Given the observational nature of the study, participating in it does not interferes with 
the prescription habits of the attending physicians.   
 
Control and report of adverse reactions  
The main exposure of interest in this study is not a drug but in case that this study is 
classified as EPA-SP by AEMPS and according the legislation contained in orden 
“SAS/347072009, de 16 de diciembre para estudios EPA-SP”, the suspected adverse 
reactions that might be detected over the course of the study will be notified by the 
sponsor (Sociedad Española de Cardiología), following the instructions published by 
the AEMPS (Agencia Española del Medicamento y Productos Sanitarios). Additionally, 
any relevant security event detected during the study should have to be reposted to 
AEMPS and to the competent organs of the concerning autonomous communities 
(AACC). 

 
 
 
 
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A.- Definitions 
A.1.- Adverse event 
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (eg, nausea, chest pain), signs (eg, 
tachycardia, enlarged liver) or the abnormal results of an investigation (eg, laboratory 
findings, electrocardiogram). The term AE is used to include both serious and non-
serious AEs. 
A.2.- Serious adverse event 
A serious adverse event (SAE) is an AE occurring during any study phase that fulfils one 
or more of the following criteria: 
 
Results in death. 
 
Is immediately life-threatening. 
 
Requires 
in-patient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization. 
 
Results in persistent or significant disability or incapacity. 
 
Is a congenital abnormality or birth defect. 
 
Is an important medical event that may jeopardize the patient or may 
require medical intervention to prevent one of the outcomes listed above. 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the above criteria. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists 
for several hours may be considered severe nausea, but not a SAE. On the other hand, 
a stroke that results in only a limited degree of disability may be considered a mild 
stroke but would be a SAE. 
 

 
 
 
 
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B.- Recording of adverse events 
Adverse Events will be collected from time of signature of informed consent 
throughout the end of follow-up. All ongoing and any new AEs/SAEs identified during 
the follow-up period must be followed to resolution. If an Investigator learns of any 
SAEs, including death, at any time after a patient has completed 30 post follow-up 
period, and he/she considers there is a reasonable possibility that the event is causally 
related to the study treatment, the investigator should notify the sponsor by reporting 
the SAE. 
 
The following variables will be collected for each AE: 
 
AE (verbatim). 
 
The date when the AE started and stopped. 
 
Whether the AE is serious or not. 
 
Investigator causality rating against the Investigational Product (yes or no). 
 
Action taken with regard to investigational product. 
 
Outcome. 
In addition, the following variables will be collected for SAEs: 
 
Date AE met criteria for serious AE. 
 
Date Investigator became aware of serious AE. 
 
AE is serious due to. 
 
Date of hospitalization. 
 
Date of discharge. 
 
Probable cause of death. 
 
Date of death. 
 
Autopsy performed. 
 
Description of AE. 
 
Causality assessment in relation to Study procedure(s). 
 
Causality assessment in relation to Other medication. 
 

 
 
 
 
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C.- Sponsor Responsibility for Reporting SUSAR´s 
The investigator will report immediately (first 24 h) any SAE by means of filling and 
sending the corresponding form [Appendix 5] to the CRO (ODDS, S.L.) by fax [981 
217539] or e-mail [proyectos@odds.es]. 
The sponsor/CRO must inform the AEMPS of any adverse events (AE) that occur in 
accordance with the reporting obligations. It is the responsibility of the sponsor to 
compile all necessary information and ensure that the AEMPS receives a report 
according to the AEMPS reporting requirement timelines. 
If a non-serious AE becomes serious, this and other relevant follow-up information 
must also be provided to the AEMPS. 
All SAEs will be documented. The sponsor is responsible for informing the Regulatory 
Authority of the AE as per local requirements. 
 
 
Risk/benefit assessment for patients 
Given that the study is observational, the participation does not involve any risk for 
patient. A better knowledge of the pathology after the study could lead to future 
health benefits. The study will be carried out in the context of daily clinical practice 
and does not impose any restrictions to the researcher physician, with no bearing on 
therapy or follow-up. 
 
Patient information and informed consent (Appendix 3) 
The patients will be provided with information of the study by means of the 
information sheet and oral explanation. The physician will solve the doubts that may 
arise. All the included patients will receive an informed consent form that should be 
signed to participate in the study, participation that can be cancelled at anytime. 
 
 
 

 
 
 
 
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Data confidentiality 
Personal data are confidential. The identity of patients cannot be revealed or disclosed 
except in those cases stipulated by law. Patients will be identified by means of a code 
that only their physician could associate with them. All data will be managed according 
to REGULATION (EU) 2016/679 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 27 
April 2016 on the protection of natural persons with regard to the processing of personal data 
and on the free movement of such data.  
 
 
8. PRACTICAL ISSUES 
8. 1. Working plan and chronogram 
Preparation of documentation and protocol: October31st 2018 
Identification and selection of coordinators and researchers: October 2018 
Submission to “Agencia Española del Medicamento y Productos Sanitarios” (AEMPS): 
November 2018 
Presentation to Clinical Research Ethics Committees: November 2018 
Contract signature: December 2018 
Design of case report form (CRF) and electronic case report form (eCRF): January-
March 2019 
Dispatch to centres for assessment and approval: January-February 2019 
Inclusion date for first patient: April 2019 
Inclusion period: April 2019 – October 2019 
Intermediate analysis and presentation of results: second semester 2019 
End of 12 months follow up of the last patient: October 2020 
Final analysis and presentation of definitive results: second semester 2020 
 
8. 2. Baseline and final reports  
The data will be analysed twice: after the closure of baseline visit and at the end of the 
study. 
 
 

 
 
 
 
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8. 3. Dissemination of results 
The principal investigator is committed to dissemination of results through scientific 
journals and/or meetings and guaranteeing confidentiality of personal data. Once the 
statistical analysis done, the Scientific Committee will issue the Final Results Report 
that will be presented to all the participants following format and method previously 
agreed. Partial and global study data could be used in general publications and in 
national as well as international congresses but always referring the study. Authorship 
will be vested in those responsible for the preparation (Scientific Committee and/or 
Technical Coordination or designated researcher); the remaining participants of the 
study will be mentioned into a group of researchers. If publication rules allow, all the 
main researchers will be individually mentioned. The participant researchers could 
publish their individual data; in such case, the researcher/s shall notify the Scientific 
Committee this circumstance by sending the communication/manuscript that is being 
intended to publish at least 30 days prior to the presentation to the congress/meeting 
or journal. 
 
8.4 Organisation of the study 
8.4.1. Responsibility of Agencia de Investigación de la SEC (supported by the project 
office) 
- General coordination of the study 
- Control of logistics and deadline compliance  
- Elaboration of the protocol (together with the main researcher) and case report form  
-Logistic and administrative issues (committee submissions, contracts with 
researchers, economic management, communications, mail, etc.) 
-  Monitoring of the study 
- Preparation of intermediate and final reports 
 
 

 
 
 
 
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8.4.2. Responsibilities of the participant researchers 
- Acceptance and a commitment to follow all the rules and procedures of the study 
- Facilitate data monitoring and quality control  
- Compliance with ethical and legal principles of clinical research  
- Collaborate with the Scientific Committee and with the Agencia de Investigación de la 
SEC when requested in order to facilitate an optimal progress of the study.  
 
8.4.3. Functions of the Scientific Committee  
- Elaboration of the protocol and case report form 
- Review the documentation of the study and data base 
- Assess the results of the study 
- Review data analysis and prepare the conclusions and the publications