Arrhythmia Prevention in High Risk Cardiovascular Patients Using Targeted Potassium Levels
Phase: PHASE4
Conditions: Ventricular Arrhythmias and Cardiac Arrest, Implantable Defibrillator User, Hypokalemia, Hyperkalemia, Ventricular Tachycardia, Atrial Fibrillation
Sponsor: Rigshospitalet, Denmark

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Arrhythmia prevention in high risk cardiovascular patients using 
targeted potassium levels  
 
  
January 8, 2025 version 9.0 
Protocol approval no. H-18044908  
  
  
  
  
  
  
  
 

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Content  
 
Content .................................................................................................................................................... 2 
1. Title ..................................................................................................................................................... 5 
2. Rationale, hypothesis and objective .................................................................................................... 5 
Study Rationale ....................................................................................................................................... 6 
Potassium in cardiovascular disease ................................................................................................... 6 
Hypokalemia and potassium homeostasis ........................................................................................... 6 
Cardioprotective effects of potassium: Arrhythmia prevention .......................................................... 7 
Increasing potassium blood levels using aldosterone antagonists and potassium supplementation ... 9 
Whole exome sequencing (WES) and omics ...................................................................................... 9 
Echocardiography – myocardial deformation ................................................................................... 10 
Hypothesis ............................................................................................................................................. 11 
Objectives .............................................................................................................................................. 11 
3. Methods ............................................................................................................................................. 12 
Study design ...................................................................................................................................... 12 
Randomization .................................................................................................................................. 12 
Echocardiography ............................................................................................................................. 13 
Intervention and follow-up ................................................................................................................ 13 
Intervention group ......................................................................................................................... 13 
Control group ................................................................................................................................ 15 
Device programming ......................................................................................................................... 16 
ICD tachy-arrhythmia treatment ................................................................................................... 16 
Endpoints ........................................................................................................................................... 17 
Secondary endpoints ..................................................................................................................... 17 
Death ............................................................................................................................................. 17 
Heart failure hospital admission .................................................................................................... 18 

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Ventricular and supraventricular tachy-arrhythmia therapy ......................................................... 18 
Endpoint committee .......................................................................................................................... 18 
Study time plan ................................................................................................................................. 19 
Deviation from standard care ............................................................................................................ 19 
4. Statistical considerations ................................................................................................................... 19 
Population size and accessibility ....................................................................................................... 19 
Power calculation .............................................................................................................................. 20 
Statistical analysis ............................................................................................................................. 22 
5. Patient population ............................................................................................................................. 22 
Inclusion criteria ................................................................................................................................ 22 
Exclusion criteria .............................................................................................................................. 23 
6. Biological and Genetic material ........................................................................................................ 23 
Collection of biological material ....................................................................................................... 23 
Genetic material collection and analysis ........................................................................................... 23 
Biobank ......................................................................................................................................... 23 
Whole exome sequencing (WES) and omics ................................................................................ 23 
7. Use of data from patient files ............................................................................................................ 24 
Data collection and use ..................................................................................................................... 24 
Data storage and safety ..................................................................................................................... 24 
Data safety monitoring ...................................................................................................................... 25 
8. Use of patient data ............................................................................................................................. 25 
Data from medical records ................................................................................................................ 26 
Data from Danish registries .............................................................................................................. 26 
9. Study organization, funding and budget ........................................................................................... 27 
Study initiators .................................................................................................................................. 27 
10.  
Reimbursement .......................................................................................................................... 29 
11.  
Recruitment of study participants .............................................................................................. 29 

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12.  
Publication of data ..................................................................................................................... 30 
13.  
Ethical considerations ................................................................................................................ 30 
Risk and benefits of the clinical investigation .................................................................................. 30 
Anticipated clinical benefits .......................................................................................................... 30 
Anticipated clinical risks ............................................................................................................... 30 
Interventional medical treatment ....................................................................................................... 31 
14.  
Compensation............................................................................................................................. 32 
15.  
References .................................................................................................................................. 32 
 
  
  
 
  
  
 

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1. Title  
 
Arrythmia prevention in high risk cardiovascular patients using targeted potassium levels  
2. Rationale, hypothesis and objective  
 
Hypokalemia (plasma-potassium (p-K) <3.5 mM) is a frequent encounter in the clinical handling of 
patients with cardiac diseases. There is solid evidence that potassium-sparing drugs increase 
survival and ameliorates symptoms in heart failure patients and several post-hoc studies suggest that 
high-normal levels of p-K decreases the risk of malignant arrhythmias in heart failure patients.  
Yet, current guidelines just recommend to keep p-K ≥3.5 mM, a threshold which is below the 
normal levels in western population (laboratory “normal” reference 3.5-4.9 mM, mean 4.1 mM). No 
guidelines or recommendations address the potential benefits of raising blood levels of potassium to 
the upper normal levels, e.g. through dietary potassium supplementation, potassium-sparing 
diuretics etc. Correspondingly, no major trials have addressed this potential.  
We suggest a trial randomizing a broad non-selected cohort of patients at high risk of life-
threatening cardiac arrhythmia to standard therapy or standard therapy plus a regimen to keep high- 
normal p-K levels.   
Treatment with Implantable Cardioverter-Defibrillators (ICDs) are offered to patients with a broad 
range of cardiovascular diseases; ischemic heart disease, heart failure, cardiomyopathies, primary 
arrhythmia disorders (e.g. long QT syndrome, Brugada syndrome), aborted sudden cardiac death 
etc., i.e. patients with a high burden of malignant arrhythmia who often receive repeated shock 
therapies. Thus, ICD treated patients suffer from a considerable unmet medical need and are the 
target for this study.    
Potassium-sparing diuretics and potassium supplements are inexpensive drugs and frequently 
prescribed in cardiovascular patients to compensate for renal potassium loss related to treatment 
with thiazide and loop diuretics. Most internists in Denmark have in-depth experience in treatment 
of the extremes - hypo- and hyperkalemia. This means a positive study outcome can be easily and 
fast implemented and safely managed by internists and cardiologists.  

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Study Rationale  
 
Potassium in cardiovascular disease  
Low p-K levels are associated with increased morbidity and mortality in patients with heart failure1 
as well as in the general population2. High-normal p-K levels have been shown to be associated 
with an improved outcome compared to normal levels1, an effect that seems to be present even in 
mild hyperkalemia3.  
There are several reasons for the improved survival with increasing potassium levels. Most 
important, potassium plays a crucial role in the formation of the cardiac action potential and with 
higher levels of p-K, action potential duration shortens and the electrical inhomogeneity decrease 
causing a marked decrease in the risk of supraventricular and ventricular arrhythmias. Additionally, 
experimental data suggests a decrease in thrombus formation, atherosclerosis and free radicals with 
higher levels of potassium and diastolic heart function worsens in hypokalemia4.   
Hypokalemia and potassium homeostasis  
Humans evolved on a potassium-rich, sodium-poor diet, and the human body mainly developed 
mechanisms to retain sodium and excrete potassium corresponding to a daily intake of 50 to 150 
mEq (mmol)5. Potassium is excreted in the kidneys matching an oral intake from 50 up to 300-400 
mmol/day. However, modern Western diets (except the Mediterranean-like diets) may have a 
potassium content as low as 25 mmol/day. A corresponding increase in sodium intake secondarily 
increases renal potassium excretion. Hence, modern human diets cause sodium overload and 
potassium depletion6 making hypokalemia a common and reversible condition in the Western 
world.  
Virtually all filtered potassium is resorbed in the proximal convoluted tubule and potassium 
excretion is mainly dependent on the secretion in the distal nephron. Aldosterone and vasopressin 
stimulate potassium secretion and sodium resorption by upregulating the sodium-potassium-ATPase 
(a.k.a. the Na,K-pump) and opening luminal sodium and potassium channels. The total body 
potassium is 3,500 mmol of which 98% is intracellular. Less than 1% of the total body potassium 
content is locates in the plasma, where potassium is maintained between 3.5 and 5.3 mM by renal 
excretion and shifts between intracellular and extracellular fluid compartments, by numerous 
Kchannels, transporters and the Na,K-pump in the cell membranes. It has been calculated that the 

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Na,K-pumps in the skeletal muscles have the capacity to clear the potassium from the extracellular 
phase within seconds. At any given level of potassium content in the body there is a tight  
adjustment of levels of p-K, but still the minute to minute levels are influenced by numerous factors 
during the day including physical activity, insulin, catecholamine and other hormone levels, food 
intake, hydration level etc.     
Due to these regulations it takes a while before a new equilibrium between compartments of the 
total body potassium content is reached after potassium intake is increased. Due to the effective 
secretion mechanisms, intake may have to be substantially increased and most likely accompanied 
by inhibition of aldosterone in order to actively change blood levels within the normal range.  
Cardioprotective effects of potassium: Arrhythmia prevention  
The transmembraneous gradient of potassium is maintained by the Na,K-pump, which is mainly 
stimulated by hyperkalemia and aldosterone, but also by exercise, catecholamines and insulin and 
downregulated by heart failure, hypothyroidism, starvation, diabetes and alcoholism7. The gradient 
between intracellular and extracellular potassium concentrations is one of major determinants of the 
resting transmembrane potential.   
During hypokalemia the resting potential is increased which causes a cellular hyperpolarity and 
hastens depolarization. This is relatively more pronounced in non-sinus nodal tissue and therefore 
automaticity and excitability are increased during hypokalemia8,9. Hypokalemia causes inhibition of 
the outward potassium currents in the cardiomyocytes, which prolongs the repolarization phase and 
leads to dispersion (reflecting electrical inhomogeneity). These changes may present in the ECG as 
QT prolongation and changes in the morphology of the T wave and as changes in conduction and 
automaticity resulting in atrial and ventricular ectopy and sustained arrhythmias. Combined, these 
changes induced by hypokalemia increase the likelihood for development of arrhythmia.   
Multiple clinical studies suggest these mechanisms translate to a decrease in spontaneous cardiac 
arrhythmias with increasing p-K:  
In the EMPHASIS-HF study, which included heart failure patients with mild to moderate 
symptoms, the risk of cardiac endpoints decreased up to a to serum K >5.5 mM (note; serum-K is 
0.4-0.5 mM higher than p-K), after which it rose again10. Rossignol et al. showed that while sudden 
death was not significantly reduced in patients treated with eplerenone vs placebo throughout the 
group, the risk of sudden death was 25% lower in patients who increased s-K >0.11 mM11.  

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Furthermore, eplerenone was found to decrease the risk of atrial fibrillation.   
Eplerenone was also used in the EPHESUS study which included sicker heart failure patients.  
Eplerenone administration resulted in a decrease in mortality and cardiovascular hospitalization 
without an increase in the risk for hyperkalemia (p-K >6 mM)12, and a similar safety profile was 
shown for spironolactone in the Randomized Aldactone Evaluation Study13.  
Even though these studies showed a correlation between increasing p-K and reduced morbidity, the 
clearer correlation between p-K and mortality was presented by Hoss et al.1, who studied nearly 
6,946 patients with heart failure. They identified a clear association between serum K and survival, 
with the best survival at serum K levels of 5-5.5 mM. Survival was 90% at serum K of 5-5.5 mM 
and 70% at serum K <3.5 mM as shown in figure 1a.  
Bird et al.14 included patients who underwent stress echocardiography. All patients had blood 
samples drawn including p-K. Lower values of p-K were associated with an increasing incidence of 
supraventricular and ventricular arrhythmias during the study as shown in figure 1b.  
Lumme et al. showed that potassium supplements were given to patients with hypokalemia due to 
diuretics. As p-K increased, ventricular ectopy ceased15.  
  
Thus, hypokalemia increases the risk of ventricular and supraventricular arrhythmia and sudden 
cardiac death and ventricular as well as atrial arrhythmias can be suppressed by raising p-K levels. 
While this effect seems to be most pronounced in patients with heart failure, it even extends to 
populations without manifest heart disease16.  
 
Figure 1a 
Figure 1b 
Figure 1c 
 
  

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Increasing potassium blood levels using aldosterone antagonists and potassium 
supplementation  
Even though there are no trials actively aiming at maintaining p-K at high-normal levels, useful 
insight regarding the effect on p-K of various interventions exists from previous trials.  
In the EMPHASIS-HF trial, eplerenone was given at a dosage of 25 mg daily to patients with 
preserved kidney function. P-K increased 0.1-0.2 mM on average during the first couple of months 
and remained stable for the entire duration of the trial. The risk of hyperkalemia (P-K >5.5 mM) 
was 11.2% in the eplerenone-group vs. 7.4% in the placebo group10 and the risk of p-K >6 mM was 
minimal.  
Similarly, it is striking that also angiotensin converting-enzyme inhibitors, angiotensin II receptor 
blockers, and beta-blockers all increase plasma K. Thus, a part of the documented clinical outcome 
of these drugs in patients with cardiovascular diseases might relate to this effect.  
Despite the relatively convincing evidence, it has never been tested whether actively keeping the 
blood level potassium in the upper-normal range in patients with cardiovascular disease is possible 
and if this decreases the incidence of ventricular and supraventricular arrhythmias.  
Whole exome sequencing (WES) and omics  
The broad range of cardiovascular diseases necessitating ICD implantation, e.g. ischemic heart 
disease, heart failure, cardiomyopathies, primary arrhythmia disorders (e.g. long QT syndrome, 
Brugada syndrome), sustained ventricular tachycardia and aborted sudden cardiac death – in which 
a specific diagnosis is often not established – have a genetic etiology or a genetic component 
influencing the development of the disease17. Additionally, they have the risk of malignant 
arrhythmias in common. This may relate not only to the patient’s disease per se, but also to other 
common denominators, e.g. genetic pre-dispositions to arrhythmia18, triggered by the disease.    
Thus, several gene variants have been shown to alter the duration of the repolarization phase, and 
thereby modulate the likelihood of arrhythmia. Most of these variants are not considered disease-
causing but may be important modifiers or even triggers of arrhythmia in patients suffering from 
other heart diseases. WES is considered useful for identification of variants associated with 
increased likelihood of arrhythmia, and to identify variants most likely to an additional “hit” for 
development of arrhythmia in patients with hypokalemia.   

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In otherwise stable patients with ICDs, the trigger of a new shock therapy most often remains 
unidentified. Subclinical infections, inflammatory processes, developing hypertrophy and increasing 
fibrosis formation19 possibly related to local tropic factors etc. have been suggested as triggers, but 
remain to be confirmed. The purpose of genomic analysis in this study is to identify variants 
associated with   
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Unstable potassium levels and tendency to develop hypokalemia/hyperkalemia.  
- 
Vulnerability towards developing arrhythmias during hypokalemic and hyperkalemic 
episodes  
 
Echocardiography – myocardial deformation  
Prognosis in cardiac disease is closely related to systolic function which is commonly measured as 
left ventricular ejection fraction (LVEF) by echocardiography. Reduced left ventricular ejection 
fraction (LVEF) of 35% or less is a well-established independent marker of increased risk of 
arrhythmias and sudden cardiac death in ischemic patient20. LVEF has therefore become the main 
risk stratification tool for primary prevention ICD implantation. However, only 30 % of patients 
implanted with an ICD receive appropriate therapy and there is a need for further refinement of 
current selection criteria21.  
New markers of myocardial deformation based on echocardiography have been suggested to be 
more sensitive. Measures based on 2D speckle tracking analysis such as Global longitudinal strain 
(GLS) has proven superior to EF as a measure of LV function and as predictor mortality and cardiac 
events22. Similarly, the myocardial dispersion reflecting the inter-segmental variability in 
contraction duration, has been associated with increased risk of ventricular arrhythmias in a variety 
of high risk populations such as cardiomyopathies, ischemic heart disease and LQTS23. It has been 
suggested that myocardial dispersion can reflect the electrical heterogeneity of the myocardium 
which can be seen in diseases such as LQTS or ARVC. If so, the potential electrical stabilization 
caused by higher potassium levels may also be reflected in the myocardial contractile dispersion.  
There is need to explore such mechanisms and to evaluate advanced echocardiographic deformation 
analysis for the prediction of arrhythmias in larger study populations. The current study represents a 
unique opportunity to study the importance of potassium levels for myocardial function and how 
mechanical heterogeneity may be moderated with different levels of potassium.  

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Hypothesis  
 
Plasma K in the high-normal range reduces the burden of arrhythmias in patients with cardiac 
diseases.   
Objectives  
 
The objectives of this study are:  
1) To investigate whether a stable high-normal level of p-K levels are associated with a 
decrease in malignant arrhythmias and mortality in ICD patients.  
2) To investigate to what extent it is possible to increase and maintain plasma K levels to the 
upper normal range (4.3-4.9 mM), with a study target of p-K 4.5-5.0.  
3) To investigate whether an increase in plasma K is associated with a decreased risk of loss of 
biventricular pacing due to atrial fibrillation and ventricular ectopy in patients undergoing 
cardiac resynchronization therapy.  
4) To investigate the relationship between plasma K levels and incidence of subtypes of 
arrhythmias. 
  
In addition, we want to investigate the genetics associated with:  
1) Low-normal and high-normal levels of p-K  
2) Risk of cardiac arrhythmias at low levels of p-K  
  
Based on echocardiography substudies will be performed to describe the importance of myocardial 
deformation for cardiac arrhythmias. The objectives are to:  
1) Characterize the influence of p-K levels for mechanical heterogeneity  
2) Investigate the association between mechanical dispersion and cardiac arrhythmias  

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3) Prediction of outcome in patients with ICD using conventional and echocardiographic 
markers  
3. Methods  
 
Study design  
The study is a prospective, randomized and open-labelled study. The study enrollment, intervention 
and follow-up cascade are shown in figure 2 and 3.   
Randomization  
Patients will be randomized in a 1:1 ratio to either:   
a) Usual standard of care   
b) Targeted potassium level therapy  
Randomization will be controlled by a computer-based algorithm.  
Patients undergoing screening with levels of p-K > 4,3 mM are excluded but will be asked to 
participate in a non-interventional observational study for which endpoints will be obtained from 
the electronic patient file and the device.   
 

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Echocardiography  
Patients included in the study will have an echocardiogram performed within 4 weeks from 
inclusion and. A optional follow-up echocardiogram will be offered to a subset of the patients near 
the study termination. Studies will be analysed for conventional parameters as well as advanced 
markers of myocardial deformation. Patients are informed that the echocardiogram is focused on 
myocardial function and cannot replace a clinically indicated echocardiogram. In case of clinically 
relevant findings on the echocardiogram, the patient will be referred to the local hospital or general 
practitioner for further investigations. 
   
Intervention and follow-up  
Intervention group  
Blood samples  

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Plasma levels of K, Na, Mg, Ca, hemoglobin, aspartate aminotransferase, eGFR and blood pressure 
and ECG will be measured before and every 2 weeks after dosage adjustment until the p-K target 
has been reached or maximum study dosages prescribed. At first visit, the blood sample will include 
genetics and omics.  
The patients will be followed bi-annually including measurement of plasma K+, Na+, Mg+, Ca2+, 
hemoglobin, aspartate aminotransferase, and eGFR and blood pressure and ECG’s.Weight, 
cardiovascular symptoms, medicine status, hospital admissions will be asked and registered by the 
study team. Side effects from study medication will be inquired as well as adherence to study dose 
previously agreed upon will be ensured, and if not inquired about the reason for non-adherence and 
asked to return to the expected dose if not clinically relevant. 
 
Medical treatment  
Written and oral information on potassium rich diets will be provided by the study team. Medical 
treatment will be up-titrated until a plasma K+ of 4.5-5.0 mM is reached preferably starting with 
aldosterone antagonist treatment followed by oral potassium supplements if needed (see flowchart 
Figure 3). The final choice, however, will be up to the treating physician.   
Patients not already treated with an aldosterone antagonist at a dose of 100 mg/day will be 
commenced on spironolactone or eplerenone according to the choice of the treating physician, with 
an initial dose of 25 mg od. If plasma K <4.5 mM, spironolactone or eplerenone dosages are 
doubled every 2 week until a maximal dosage of 100 mg or 50 mg, respectively, under monitoring 
of blood pressure. If p-K remains <4.5 mM on 100 mg spironolactone or 50 mg eplerenone, 
potassium supplements are prescribed commencing at 1500 mg/day up to a maximal dosage of 1500 
mg TID.   
When maximal dosages or maximal tolerated doses of the above mentioned drugs and supplements 
have been reached or the p-K levels have stabilized between 4.5-5.0 mM the patient will be 
followed bi-annually by the study team as described above..  
A p-K up to 5.2 at a single measurement will be accepted during controls without adjustment of 
medication, but repeated levels of p-K > 5.0 will require medication adjustment. A decrease in 
eGFR up to 30% will be accepted. In the case of severe hyperkalemia (p-K > 6.0 mM), the patient 
should be admitted acutely for treatment. 

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The treatment cascade is shown in figure 3 below.  
  
Control group  
Initiation and adherence to guideline recommended medicine for the disease entity the ICD has been 
implanted for will be ensured. No other medical treatment interference will be done according to 
study protocol.   
Similar to patients in the intervention group, patients randomized to the control group will be 
followed bi-annually +/- 3 months including measurements of plasma K, Na, Mg, Ca, hemoglobin, 
aspartate aminotransferase, and eGFR and blood pressure and ECG, as well as height, weight, 
cardiovascular symptoms, medicine status, and hospital admissions.  
At first visit a blood sample for genetics and omics will be taken.  
Figure 3: Treatment cascade if randomized to intervention.  
 
  
 

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Device programming  
ICD tachy-arrhythmia treatment  
Home monitoring  
All patients with an ICD or CRT-D at the study sites are encouraged to accept home monitoring of 
the device. In this case, the device will transmit within 24 hours of giving anti-tachycardia or shock 
therapy. If ventricular tachycardia (VT) or supraventricular tachycardia (SVT) episodes are 
recorded but not treated, it will be sent during  routine transmissions every 6-12 monthsdepending 
on the study site setup. 
Device programming  
ICDs from all 4 manufactures are implanted at the study sites and even though modest differences 
in programming abilities exist between the vendors, devices are programmed relatively identical at 
the study sites.  
A shock, including anti-tachycardia pacing (ATP) during charge is often programmed at heart rates 
>240 bpm (230-250 bpm). This zone cannot be set to higher levels than 250 bpm and must be set to 
ON for any other ICD therapy to be delivered.  
A fast-VT and a VT zone are available and can be programmed with an individual number of ATP 
therapies to be delivered before shock therapy is delivered. The fast-VT zone is generally 
programmed ON with a treatment zone at heart rates 200-240 bpm. Most often 2-4 ATP treatments 
are delivered before a shock is given. The VT zone is most often used in patients with documented 
VT and set accordingly at rates starting at 130-180/min with a varying number of ATPs delivered.  
Shock is only occasionally set ON in this zone.  
Hence, ICD units are programmed according to the patient’s condition and recommendations to 
ICD therapy is not given per protocol.  
Cardiac resynchronization programming  
Cardiac resynchronization therapy (CRT) aims at restoring synchronized contraction in 
dyssynchronous failing hearts. Successful re-synchronization requires >95% of all heart beats to be 
paced. This is frequently hampered by atrial fibrillation or frequent ventricular ectopy, and approx.  
20% of CRT patients experience periods of low CRT pace for these reasons.  

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Endpoints  
Primary endpoint   
A combination of:  
- ECG documented ventricular tachycardia > 125 bpm lasting > 30 seconds  
- Any appropriate ICD therapy as documented by the ICD or ECG 
- Any hospitalizations > 24 hours due to arrhythmias and/or heart failure leading to a change in 
treatment, e.g., administration of new drugs, or change in doses of already prescribed drugs or 
invasive or non-invasive treatment.   
- All-cause mortality  
Secondary endpoints  
- 
Incidence of supraventricular arrhythmias as documented by ECG or the ICD  
- 
Risk of <92 % CRT-pacing for > 2 weeks (only CRT-D patients)  
- 
Hospitalization for heart failure  
- 
Hospitalization for cardiac arrhythmias  
- 
Hospitalization for electrolyte disturbances or kidney failure  
- 
Appropriate ICD therapy  
- 
Inappropriate ICD therapy 
- 
Change in the burden of ventricular arrhythmias.  
- 
Change in burden of supraventricular arrythmias.  
- 
Change in myocardial structure and/or function. 
  
Death  
Death events will be collected automatically from the Danish Death registry and the devices will be 
interrogated post-mortem.   

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Heart failure and arrhythmiashospital admission  
Information on hospitalizations will be collected every 6 months according to study protocol. The 
patient will be asked for hospitalizations.   
Ventricular and supraventricular tachy-arrhythmia therapy  
Information of ventricular tachyarrhythmia therapy will be obtained from home monitoring systems 
or interrogation of the ICD devices during in-clinic visits. All ICD therapy is routinely adjudicated 
as appropriate or in-appropriate by EP physicians at the study sites. All patients receiving an ICD 
shock are called by the EP personal in the pacemaker outpatient clinic and the circumstances and 
causes of the shock are investigated and described. Patients receiving successful ATP therapy but 
not shock are only contacted if is the first time, if a high number of ATP cycles were delivered or if 
the VT was fast enough to be expected to cause symptoms.  
All tachy-arrhythmias causing appropriate ATP or shock or supraventricular tachy-arrhythmias 
causing inappropriate shock are considered endpoints.  
Information of type of therapy delivered, number of therapies, VT/VF duration and cycle length, 
cause of inappropriate shock (atrial fibrillation, SVT, ICD lead problems) and (if available) 
circumstances causing the shock (i.e. electrolyte disturbances, will be recorded.   
Supraventricular and ventricular arrhythmias not resulting in therapy but documented either because 
they were of too short duration, triggered mode switch of the device etc will be considered 
secondary endpoints.  
In descriptive studies computer-assisted analyses of digital ECG recordings of QT duration and T 
wave morphology will be performed to identify markers or patterns associated with risk of future 
arrhythmia events. Associations with p-K levels and other parameters (electrolytes, genetic and 
omics findings) will also be analyzed.     
Endpoint committee  
An endpoint committee blinded to patient ID will review, adjudicate and classify endpoints. Two 
reviewers will review an endpoint, if disagreement exists, the endpoint committee will consist of 
members from the steering committee,who are all specialists in cardiac electrophysiology and 
device interrogation.   

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Study time plan  
The study will begin as soon as all necessary approvals have been obtained, with a planned start 
Augustst, 2018.   
The study is planned to last until a total of 291 endpoints are registered.  
The study is expected to be finalized in 2025.  
Deviation from standard care  
All patients are following the pathway of standard care during the study. As described, patients 
randomized to the intervention arm will be followed with additional testing until potassium levels 
are in the targeted interval. Please see the paragraph regarding ethical considerations.  
4. Statistical considerations  
 
Population size and accessibility  
There are approximately 8,800 patients with an ICD implanted in DK. Approximately 40% of these 
are followed at Rigshospitalet and at Gentofte Hospital, i.e. approximately 4,000 patients. These are 
controlled in-clinic every 1-2 years. Hence, a population of approx. 4,000 patients can be screened 
during the first 2 years. Additionally, 250 new ICDs and 200 new CRT-Ds are implanted at the 
study sites every year. Of these, 60% are primary prophylactic while 40% are secondary 
prophylactic. Hence, during an enrollment period of 3 years, a total of 5,350 patients will be 
available for screening.  
Among 7,000 patients with heart failure on relevant medical treatment, median value of p-K was 4.5 
mM in patients already on heart failure medication and lower for patients without heart failure.  
Hence meaning that around 50% of patients can be expected to present with a p-K <4.3 mM (figure 
1c).  
Severe chronic renal failure is a relative contraindication for implantation of the device because of 
expected lower benefit and higher risk of infections. In a recent investigation of comorbidities in 
Danish ICD patients, only 3% had chronic renal failure as a diagnosis during a previous 

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hospitalization. Even though precise number are not available, eGFR <30 ml is conservatively 
estimated to be found in 5% of the population.   
Hence, it is expected that the total population available for screening over 3 years is 5,350 x 0.45 = 
2,400 patients.  
The genetics and omics studies are descriptive and explorative.   
Power calculation  
Due to the specific constitution of the population, i.e. a pool of patients screened during 2 years with 
an additive smaller population of new implants recruited during year 3, we have chosen to use a 
traditional rather than sequential design of the study.  
The risk of the combined endpoint is expected to be approximately average of 16% per year based 
on our observations on all Danish ICD patients24 as shown in figure 4 below:  
  
 Figure 4: Incidence of appropriate therapy and all-cause mortality among ICD patients in Denmark 
implanted with an ICD for primary or secondary prevention.  

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Increasing p-K to 4.4-4.9 mM is believed to reduce therapy rates by approximately 40% based on 
the observation from Bird et al. Hence, the annual risk of ICD therapy of cardiovascular death is 
assumed to be 16% in the intervention group and 9.6% in the control group per year.   
It is expected that a proportion of patients cannot be brought to a p-K of 4.5. We expect 30% to 
remain below target values for p-K with a resulting higher risk of the endpoint. This means that 
30% remains with unchanged risk and 70% shows an average 40% risk reduction = (30 x 0.16 + 70 
x 0.096%), total risk in the treatment group 11.5%, i.e. risk reduction of 1- (11.5 / 16 ) of 28%, i.e.  
HR = 0.72  
Based on this a total of 291 events are needed. We expect an enrollment phase of 3 years and 1 year 
additional follow-up to ensure at least 1 year follow-up for all patients, but due to the expected high 
initial enrollment of the existing pool of ICD patients, we expect an average follow-up of 3 years.  
Censoring is expected to be low, but is set conservatively at 10%.  

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Based on these assumptions, a total of 990 patients should be enrolled. We plan on enrolling a total 
of 1,000 patients.  
The power calculation has been overseen by a statistician (Theis Lange).  
Due to COVID-19, there was a reduction in the inclusions rate that have influenced the duration of 
the study. This increase in duration has resulted in a longer duration of the intervention for the patients 
included in the first part of the study. For these patients, we foresee a lower compliance. Additionally, 
the study has observed a lower event rate than anticipated. To be able to reach the number of events 
needed for completion of the study within the next approximately 1.5 years, we would include an 
additional 200 patient, making a total of 1,200 patients.    
 
Statistical analysis  
For the purpose of the primary endpoint, a time-to-first-event survival analysis will be performed on 
the primary endpoint. Besides survival statistics, repeated mixed models will be used to understand 
associations between fluctuations in p-K to drug and potassium supplements therapy as well as the 
association or p-K to primary and secondary endpoints.  
Statistical analysis including for GWAS analysis will be assisted and overseen by a statistician 
attached to the research group.  
5. Patient population  
 
Patients will be screened, enrolled, and followed from the Outpatient Pacemaker Clinics at  
Rigshospitalet, Gentofte Hospital and Roskilde Hospital. Patients already implanted with ICDs or 
CRT-Ds are seen in-clinic every 1-2 years and will be screened and enrolled during these follow-
ups. Patients admitted for ICD/CRT-D implantation will be screened and enrolled during implant 
admission or at the 1- or 3-month obligatory follow-up.   
Inclusion criteria  
- 
Implantable cardioverter defibrillator (ICD) or cardiac resynchronization pacemaker with 
ICD (CRT-D).  
- 
Age >18 years   

23 
 
Exclusion criteria  
- 
Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2  
- 
Pregnancy  
- 
Lack of ability to understand and sign informed consent  
6. Biological and Genetic material  
 
Collection of biological material  
Acquisition of biological material includes measurements of plasma level K, Na, Mg, Ca, 
hemoglobin, aspartate transaminase, and eGFR before and every 2 weeks after dosage adjustment 
until the p-K target has been reached or maximum study dosages prescribed. After analysis these 
blood samples (3 mL x 2) are immediately disposed.  
Genetic material collection and analysis  
At inclusion a blood sample (3 mL x 3) for genetic analysis and omics will be drawn after a separate 
specific informed consent for this part of the study.  
Biobank  
The biological material collected will be stored in a research biobank. Analysis of material from this 
biobank will take place until 2 years after the last patient has finalized his/her participation in the 
study, i. Remaining material on this date will be transferred to a biobank on the department for 
unspecific future research. Remaining material in the biobank in June 30th, 2035 will be destroyed.   
Whole exome sequencing (WES) and omics  
WES will be applied to identify variants associated with increased likelihood of arrhythmia, and to 
identify variants most likely to be associated with a positive response to raised p-K levels.   
In order to identify triggers of arrhythmic events a subset of patients with repeated un-explained 
shock therapies will be offered extensive proteomic studies. Stable patients will serve as controls.  

24 
 
7. Use of data from patient files  
 
Data collection and use  
Data on clinical characteristics, hospitalizations, genetic findings, treatment outcome and 
trajectories will be collected. Genetic data will be combined with data from proteomics and 
transcriptomics studies and protein-protein interaction databases and analyzed using a systems 
biology approach to identify novel disease genes.   
Outcome data such as arrhythmia and device therapies will be derived from the device home-
monitoring system.  
Information used prior to inclusion in the study will be confined to:   
- 
Identification of the patient from the patient snapboard, prior to ICD-implantation or prior to 
routine device-check   
- 
K+ -level and eGFR-level based on routine blood-sample  
- 
Clinical information with regards to cardiovascular history, functional level and 
anticongestive medicine.  
Information obtained from the potential study participants prior to consent will be passed on to the 
researchers.  
Consent from the study participants will allow investigators, sponsors, and sponsor reps as well 
researchers with data safety monitoring responsibilities to access any necessary information 
required to complete the study and for control purposes.  
 Informed consent  
All patients will sign informed consent according to the Helsinki declaration.  
Data storage and safety  
An electronic database will be set up for the study in REDCAP on the capital region medical 
research servers (https://redcap.regionh.dk). The database will contain the crude study data for later 
analysis. This database is approved for containing person-specific data and allows access on 

25 
 
multiple user levels, logging of all access to the data as well as downloading a de-identified version 
of the database for analysis after study conclusion. The database is hosted and maintained by Center 
of IT, Medica and Telephony for the Capital Region.  
Data safety monitoring  
A data safety monitoring board (DSMB) will be constituted before the trial is initiated consisting of 
3 independent researchers within the field. The purpose of the DSMB is to monitor:  
• 
Interim and cumulative data for evidence of study-related adverse events   
• 
Data quality, completeness, and timeliness  
• 
Performance of the three centers  
• 
Adequacy of compliance with goals for recruitment and retention  
• 
Adherence to the protocol  
• 
Factors that might affect the study outcome or compromise the confidentiality of the trial 
data (such as protocol violations, unmasking, etc.)  
• 
Factors external to the study such as scientific or therapeutic developments that may impact 
participant safety or the ethics of the study.  
 
8. Use of patient data  
 
The current study will be conducted in accordance with current Danish legislation on processing of 
personal data /the General Data Protection Regulation, GDPR.   
The Data Protection Agency will be applied for approval, including approval for keeping the 
genetic data after the project is finalized. The regulations of management of data on individual 
persons according to the Sundhedsloven og Persondataloven will be followed.   
Personal data will not be transferred to foreign countries. 

26 
 
Data from medical records 
The following data will be collected after informed consent and enrolment and for up to 10 years after 
the study ends:  
- 
Date and cause of hospitalizations in Denmark, including  
o 
Adjudication of the cause using information from the electronic file 
system (sundhedsplatformen) 
o 
Laboratory results including potassium,sodium, infection tests, TSH, liver 
and kidneytests and ECGs recorded during the hospitalization 
o 
Medicinal status for treatment with cardiovascular drugs (ace-inhibitors, 
angiotensin II antagonists, beta blockers, mineralocorticoid antagonists, diuretics, 
potassium supplementation, class I and III anti arrhythmic drugs 
- 
ICD-therapy (ATP and shock) including changes in ICD programming and recorded 
ICD EGMs as well as ICD related complications, lead extrations, generator replacements and 
change of system to CRT-D, DDD-ICD, VVI-ICD or pure pacemaker systems) 
- 
Date and cause of hospitalization 
- 
Date and cause of death. 
Data from medical records can be used for confirmation of register-based data described below. All 
data are given to the investigator regardless of whether they are collected before or after the informed 
consent is given. 
 
Data from Danish registries 
A register-based follow-up after 3, 5 and 10 years will be used to evaluate long-term outcomes. The 
study will use data on hospitalization diagnoses and dates, prescription drug treatment, laboratory 
tests and death dates from the following Danish National Health Register: The National Patient 
Register, The Causes of Death Register, Shared Medication Record, The Clinical Laboratory 
Information Register, The Register of Pharmaceutical Sales, National Hospital Medication Register,  
 
Screened but not randomized patients in the observation arm 
The patients who had too high plasma potassium to be randomized at the screening, we would also 
follow-up in patient records and national registries for up to 10 years after study termination as 

27 
 
described above. These patients have signed informed consent for the study, but since p-K was > 4.3 
they could not be randomized.  
To follow-up, we will look up the patients in the medical records to get information on vital status. If 
the patient is alive, we will retrieve their contact information and send them a letter via E-boks to 
obtain their consent for the 10-year follow-up. We will follow-up on the invitation letter over the 
telephone if we do not receive and answer to the E-boks invitation. The obtained results will 
contribute to compare the risk of primary and secondary endpoints of the intervention group to 
patients where p-K naturally is > 4.3.  
 
9. Study organization, funding and budget  
 
  
Study initiators  
MD, PhD, Christian Jøns, The Heart Centre B 2142, The National University Hospital,  
Rigshospitalet, Copenhagen, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark, Phone + 45 3545 9863  
Professor, senior consultant, dr.med. Henning Bundgaard, The Heart Centre B 2142, The National  
University Hospital, Rigshospitalet, Copenhagen, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark, 
Phone + 45 3545 0512  
MD, PhD, Niels Risum, The Heart Centre B 2142, The National University Hospital,  
Rigshospitalet, Copenhagen, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark, Phone + 45 3545 9863  
Study organization:  
The study will be performed at Rigshospitalet, Gentofte/Herlev Hospitals, and Roskilde Hospital.  
The study group consists of:  
Christian Jøns, MD. PhD, Rigshospitalet (Study leader Rigshospitalet)  
Henning Bundgaard, Professor, DMSc, Rigshospitalet  

28 
 
Niels Risum, MD, PhD, Rigshospitalet  
Charlotte Larroudé, MD, PhD, Gentofte/Herlev University Hospitals (Study leader Gentofte/Herlev 
Hospital)  
Kasper Iversen, MD, DMSc, Gentofte/Herlev University Hospitals  
Niels Eske Bruun, Professor, DMSc, Zealand University Hospital, Roskilde Hospital (Study leader 
Roskilde Hospital)  
Ketil Jørgen Haugan, MD, PhD, Zealand University Hospital, Roskilde HospitalHelle Skovmand 
Bosselmann, MD, PhD, Zealand University Hospital, Roskilde Hospital  
 
Funding will be applied for through external funds.  
Funding is administered through the finance department at The Copenhagen University Hospital, 
Rigshospitalet, Copenhagen.   
None of the investigators have personal financial interests in the study or personal affiliations with 
study sponsors.  
A specialized nurse technician will be hired specifically for the study at each of the study sites. The 
study technicians/nurses will screen up to 5-10 potentially recruitable patients per day. They will 
inform and include patients, take blood samples, take ECG’s and blood pressure and manage the 
biannual follow-up. Additionally, they will manage all needed registrations.  
Not until the majority of patients are recruited (year 3) a PhD student is employed to plan and 
execute the data analysis and publication of the results.  
Fees for the DSMB are included in the budget.  
Salary for a statistical consult is included in the budget.  
The endpoint committee consists of members of the application and are not paid.  
The cost of study medication not covered by the Danish public health care system will be re-
imbursed.  
 

29 
 
 10.  Reimbursement  
 
There is no reimbursement of expenses for transportation, lack of earnings or drawback allowance 
for study participants.  
 11.  Recruitment of study participants  
 
A continuous screening for potential study participants will take place during the study period.   
A list of patients, with a planned visit  at the outpatient device clinic, will be requested from the 
treating electrophysiologist  Seven days prior to the planned outpatient visit in the device clinic, the 
research nurse will send the study information package either via electronic e-post to the patients 
“e-boks” or, if the patient has requested materiel from the device clinic to be sent via ordinary mail, 
as physical mail to the patient. The letter will inform the patient about the study and the possibility 
to receive further information after the normal ICD check-up has been done. The information 
package will contain 1) recruitment letter, 2) Patient study information and informed consent, 3) the 
form “Forsøgspersoners rettigheder”.  
At the device clinic visit the patient will be asked by the pace technician if they have read the study 
information package and will be interested in additional information.  
The oral information will be given in an un-disturbed room by appointed study personal (i.e study 
nurse, technician or physician who have received training for this purpose). The patient is 
encouraged to invite an assessor to participate at the meeting. The patient will be offered at least 24 
hours to consider his/her participation, i.e. from oral and written information is given and until the 
patient signs the consent form. If the patient consents to participate in the study, the bloodwork 
necessary for randomization will be done following the oral information. If the necessary 
bloodwork has been obtained within 7 days during another un-related clinical visit, these test results 
will be used and the bloodwork will not be repeated.  
For each person, his/her/their mental and physical integrity and rights of privacy will be respected.   
  

30 
 
 
12.  Publication of data  
 
The data will be published in peer-reviewed medical journals after which the data will be 
deidentified and uploaded to a public database for sharing with other researchers.  
Results will be published regardless of whether they are positive, negative, or inconclusive. The 
study will be announced at www.clinicaltrials.gov  
 
13.  Ethical considerations  
 
Risk and benefits of the clinical investigation  
Anticipated clinical benefits  
Besides from the assumed positive effects of high-normal K+ levels in the interventional group, 
patients in both groups followed in the study will be monitored more often compared to what is 
usual practice, and a cardiac specialist will monitor optimal medical treatment at the beginning and 
throughout the trial. Many of the patients enrolled in this trial will not have been seen by a 
cardiologist for several years.  
Anticipated clinical risks  
The risk of hyperkalemia is likely to be increased in the intervention group. In a recent meta 
analysis on the risk of hospitalizations for hyperkalemia associated with mineralocorticoids in heart 
failure, the risk of hyperkalemia was doubled25 (eplerenone 5.0 vs 2.6%, spironolactone 17.5 vs 
7.5%). On the other hand, the risk of hospitalization for hypokalemia is decreased with 50%. In 
general, the risk associated with hypokalemia was associated with a higher risk of death (see figure 
2a and 2b, adapted from Núñez et al26). Hence, we consider the lower risk of hypokalemia along 
with a greater risk of hyperkalemia as being an advantage for the patient.  

31 
 
  
  
Figure 2a and 2b: Risk of death associated with having a blood sample collected with hypokalemia 
or hyperkalemia.  
 
In a study investigation on reasons and management of hyperkalemia, mineralocorticoid treatment 
was the most frequent cause27. Among 600 hospitalizations, by far most of them were mild 
hyperkalemia and treated with cessation of medication and fluid therapy whereas a little less than 
8% required hemodialysis. There were no deaths.  
In both groups additional discomfort from blood sampling can be expected.  
  
Interventional medical treatment  
Potassium supplements are available over-the-counter in Denmark. Treatment with potassium 
supplements and diet recommendations are considered safe.  
The aldosterone antagonists, spironolactone and eplerenone, are prescribed with indication of heart 
failure with symptoms corresponding to NYHA II-IV, liver failure and for treatment of 
hypertension. The major side effects are related to hyperkalemia. This risk is low in patients with 
normal to slightly reduced kidney function. P-K levels will be monitored at intervals short enough 
to reduce the risk of hyperkalemia episodes to a minimum. Hence, the risk of developing severe 
hyperkalemia induced arrhythmia is therefore low. If arrhythmias develop, the patients have an ICD 
implanted and the investigators will be notified immediately since all patients will be using home 
monitoring.  
  

32 
 
 
14.  Compensation  
 
This study is covered by Patienterstatningen. Additional insurance is not necessary.  
 
15. References   
 
  
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3. Ahmed, M. I. et al. Mild hyperkalemia and outcomes in chronic heart failure: a propensity 
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