Clinical trial NCT05076019: Statin Therapy With Atorvastatin in Surgical Aortic Valve Replacement
Official title: Statin Therapy With Atorvastatin in Surgical Aortic Valve Replacement - a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Postoperative Atrial Fibrillation
Lead sponsor: Odense University Hospital
Sponsor class: OTHER
Collaborators: name: Odense Patient Data Explorative Network
name: GCP-unit at Odense University Hospital
First posted: 2021-10-13
Enrollment: 266
Sex: ALL
Minimum age (years): 60
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Intervention: Atorvastatin, n = 133 Dose: 80 mg/daily P.O. Length of preoperative statin exposure: 7 to 14 days prior to surgery Length of postoperative exposure: 30 days Control group: Placebo, n = 133

Study parameters Incidence, placebo group: 36% Incidence, Atorvastatin group: 20% Alpha: 0.05 Beta: 0.2 Power: 0.8 Enrolment ratio: 1:1

Sample size Placebo: 133 Atorvastatin: 133
Primary purpose: PREVENTION

Brief summary: Statins have rapid and significant actions that have potentially important (but not yet proven) implications for postoperative atrial fibrillation and cardiac protection in patients undergoing cardiac surgery.

The focus of this study is, therefore, on patients having surgical aortic valve replacement (with aortotomy) and the development of postoperative atrial fibrillation (POAF). Our aims are: to examine the ability of a clinically durable Atorvastatin prophylactic regime to prevent the development of POAF and other postoperative complications in these patients.

Patients will be randomized to Atorvastatin 80mg or placebo 7 to 14 days preoperative until 30 days postoperative - a total of 37 to 44 days of treatment.

The medication will be double blinded.

The randomized studie will address the following hypotheses in patients undergoing open heart operation with solitary aortic valve replacement with a bioprosthetic valve that

1) 7 to 14 days preoperative and until 30 days postoperative treatment with Atorvastatin 80 mg daily reduces the incidence of POAF in statin-naïve patients.

Detailed description: Trial Participants:

Enrolment for the study is planned to start February 2022 and continue until 266 patients have been enrolled.

DEFINITION OF POAF:

Postoperative AF (I48) is defined as irregular RR-intervals without a traceable p-wave before each QRS complex during at least 30 seconds or entire 12-lead ECG in symptomatic or asymptomatic patients with no prior history of atrial fibrillation or flutter are considered4. Continuous ECG monitoring (8-lead ward monitor) will recognise AF during the entire hospitalization. Anamnesis, electronic health record (EHR), or confirmatory rhythm strip or 12-lead ECG of AF until 30th postoperative day are also considered.

We will also report the burden of atrial fibrillation, and treatment with a rate controlling drug, antiarrhythmic drug, or electrical cardioversion.

Course of action:

Patients undergoing elective surgical aortic valve replacement with bioprosthesis at the Department of Cardiac Surgery at Odense University Hospital will be offered participation in the study.

Potentially eligible patients will be screened according to inclusion/exclusion criteria at the time after eligibility of surgery. This is assessed at a multidisciplinary team (MDT) conference (with attendance of cardiologist, cardiac surgeons and anaesthesiologist) based on clinical evaluation, echocardiographic ultrasound, coronary angiography and lung function test.

Patients eligible to participate in the study will be presented with the information of the study at the time of their out-patient appointment, according to normal routine at Odense University Hospital. At this appointment the patient receives a physical examination and journal record is obtained by a cardiac surgeon (approximately 7 to 14 days prior to planned surgery).

The study-information will be given by one of the participating doctors, while the patient has been informed of the possibility of bringing an assessor of their choice. The information will be delivered in a quiet room blocked to other appointments in the Department of Cardiothoracic Surgery.

During this meeting the patient will be informed of the purpose of this study and the written patient information will be submitted in detail. Patients will be given as much time as wanted after the oral information has been delivered to decide if they wish to participate in the study. Patients will be offered the possibility to call one of the doctors taking part in this study during this time, in case of additional questions. Subjects can leave the study at any time for any reason if they wish to do so, without any consequences.

Signed informed consent will be provided prior to any research procedures. A subject is registered when signed informed consent has been provided and assigned a subject identification code by the computer-generated code. A subject is randomized when a treatment and a randomisation number has been provided. A subject is considered enrolled in the study once the subject is randomized.

Patient data from EHR will be conducted according to study endpoints after signed informed consent is provided. Signed consent gives sponsor and sponsors representatives

Randomization:

Allocation to a numbered treatment pack (Atorvastatin or placebo - blinded) Randomization scheme will be set-up by OPEN data manager with control for beta-blockers and age, and then randomization per se will be executed with the use of REDCap.

The following will be recorded at the day of randomization:

* Conduct information for baseline characteristics
* Transthoracic Echocardiography measurements

Collect baseline blood sample:

• Troponin, CK-MB, Creatinine, CRP

Commence study medication/treatment

Perioperative interventions and outcomes from the day of surgery to the day of discharge:

* Duration of aortic cross clamp (ACC), extracorporeal circulation (ECC), ventilatory support, intensive care unit stay period, hospital stay period
* Continue study medication
* Blood samples:

  * Preoperative: Troponin, CK-MB, Creatinine, CRP, Plasma-Atorvastatin
  * Serial troponin and CK-MB levels: (6, 24, 48, and 96 hours after surgery).
  * Creatinine levels: 48 and 96 hours after surgery.
  * CRP levels: 48 and 96 hours after surgery
* Monitor ECG by continuous Holter monitoring to commence as soon as possible after surgery and continue up to post-operative day 5 evening
* Transthoracic Echocardiography on post-operative day 3-5
* Record fluid intake and output during the first 48 hours following surgery based on IV fluids administration, blood transfusion (if applicable), oral/nasogastric intake, and urine plus surgical drain output
* Record intraoperative defibrillation, removal of external pacemaker, new PPM/ICD, vasopressors, blood transfusion, surgical re-exploration, renal replacement therapy, beta-blockers, ACEi/ARB, Amiodarone, Digoxin, Diuretics, Calcium channel blockers, Potassium supplements, NSAIDs or steroids, non-study statin, use of nephrotoxic antibiotics, contrast agents or potassium sparing diuretics (Yes/No)

Assessment at/after discharge from hospital:

* Continue study medications for 30 days after the surgery
* Phone call on the 30th postoperative day to evaluate symptoms of discomfort compatible with atrial fibrillation
* At the end of the study, all excess study medication can be returned at the local drugstore for safe disposal
* Patient data from EHR will be conducted according to study endpoints.

Eligibility criteria: Inclusion Criteria:

1. Patients undergoing elective solitary SAVR with bioprosthesis
2. Patients who are in sinus rhythm and not taking any anti-arrhythmic medication, other than beta-adrenergic blocking agents, at the time of surgery
3. No prior use of HMG-CoA reductase inhibitors the last 3 months and at least 7 days prior to the time of surgery
4. Age \>60 years
5. Willingness and provision of informed consent to be randomized

Exclusion Criteria:

1. Prior history of atrial fibrillation
2. Prior history of cardiac surgery
3. Known adverse reaction to HMG-CoA reductase inhibitors
4. Hepatic dysfunction (Alanin-aminotransferase more than twice the upper limit)
5. Creatinine \>200 µmol/L
6. Known intolerance to statins or history of muscle toxicity with statins
7. Known intolerance to any of the excipients in Lipistad
8. Treatment with anti-viral medicine (glecaprevir/pibrentasvir) for hepatitis

Primary outcomes:
measure: Number of Participants with POAF - In-hospital
timeFrame: In-hospital up to 10 days
measure: Number of Participants with POAF - Early
timeFrame: Early (≤30 days) incidence of POAF
measure: Total duration of POAF - In-hospital
timeFrame: In-hospital up to 10 days
Secondary outcomes:
measure: Rate of All-cause mortality - In-hospital
timeFrame: In hospital up to 10 days
measure: Rate of All-cause mortality - Early
timeFrame: Early (≤30 days)
measure: Rate of All-cause mortality - intermediate
timeFrame: intermediate (1 year)
measure: Myocardial injury - Tn
timeFrame: After surgery until discharge up to 10 days.
measure: Myocardial injury - CKMB
timeFrame: After surgery until discharge up to 10 days.
measure: Stroke - Early
timeFrame: Early (≤30 days)
measure: Stroke - Intermediate
timeFrame: Intermediate (1 year)
measure: Trans ischemic attack - Early
timeFrame: Early (≤30 days)
measure: Trans ischemic attack - Intermediate
timeFrame: Intermediate (1 year)
measure: Myocardial infarction - Early
timeFrame: Early (≤30 days)
measure: Myocardial infarction - Intermediate
timeFrame: Intermediate (1 year)
measure: Permanent pacemaker - Early
timeFrame: Early (≤30 days)
measure: Permanent pacemaker - Intermediate
timeFrame: Intermediate (1 year)
measure: ICD implantation - Early
timeFrame: Early (≤30 days)
measure: ICD implantation - Intermediate
timeFrame: Intermediate (1 year)
measure: Acute kidney injury - Early
timeFrame: Early (≤30 days)
measure: Acute kidney injury - Intermediate
timeFrame: Intermediate (1 year)
measure: LVEF
timeFrame: Before surgery compared with prior to discharge (On the 3rd to 5th postoperative day).
measure: Strain
timeFrame: Before surgery compared with prior to discharge (On the 3rd to 5th postoperative day).
measure: Peak gradient
timeFrame: Before surgery compared with prior to discharge (On the 3rd to 5th postoperative day).
measure: Mean gradient
timeFrame: Before surgery compared with prior to discharge (On the 3rd to 5th postoperative day).
measure: TAPSE
timeFrame: Before surgery compared with prior to discharge (On the 3rd to 5th postoperative day).
measure: Length of stay on ICU
timeFrame: Day of surgery to the day of discharge from ICU. Up to 52 weeks.
measure: Length of stay in hospital
timeFrame: Day of surgery to the day of discharge. Up to 52 weeks.
Other outcomes:
Locations:
city: Odense
country: Denmark
facility: Odense University Hospital
Study officials:
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