RIMINI-Pilot: Reduction of Ischemic Myocardium With Ranolazine-Treatment in Patients With Acute Myocardial Ischemia

• Sponsor: Universitätsklinikum Hamburg-Eppendorf (Other)
• Overall Status: Completed
• CT.gov ID: NCT01797484
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 22
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The aim of the RIMINI-Trial is to examine the effect of Ranolazine on ischemic myocardium in acute myocardial ischemia.

A pilot-trial by Venkatamaran et al. recently demonstrated, that the area of ischemic myocardium in patients with stable coronary artery disease can be reduced by Ranolazine-treatment2. This effect was shown by significantly reduced areas of atypical or dysfunctional myocardium in SPECT-examinations.

The dimension of myocardial damage (i.e. area of ischemic myocardium) is directly related to the rate of complications (i.e. left-ventricular pump failure, malignant arrhythmia) and the grade of Rehabilitation to daily life (i.e. persistent reduced left-ventricular ejection fraction).

In patients with stable angina pectoris, Ranolazine is used with beneficial results1. Ranolazine improves diastolic blood flow and therefore microcirculation in the myocardium by reducing diastolic tension (via inhibiting late Na+-Influx and consecutive Ca2+-Overload).

Recently published data2 showed that treatment with Ranolazine significantly reduces the ischemic area in chronic damaged myocardium. This is due the effect of improved microcirculation in hibernating myocardium.

Early administration of Ranolazine and improvement of microcirculation in patients with acute damaged myocardium (i.e. directly after acute ischemia) should lead to a recruitment and re-uptake of cardiac activity of hibernating myocardium.

For the RIMINI-Trial patients are given Ranolazine on top of the guideline-based treatment to reduce the area of acute ischemic myocardium.

Patients with unstable angina pectoris and proof of acute cardiac ischemia, proof of myocardial dyskinesia and angina pectoris in the patient history will receive unaltered guideline-based therapy for acute cardiac ischemia5,6. All necessary procedures will be performed to stabilize patients to a hemodynamically compensated state and patients are then transferred to receive cardiac catheterization (angiography and angioplasty if necessary).

After patients are stabilized Ranolazine will be given additionally to guideline based medication.

The measurement of the ischemic myocardial area will be done via three functional echocardiographies with speckle tracking technique10.

A statistical evaluation of ischemic myocardial area before and after treatment with Ranolazine/Placebo will be done after conclusion of the RIMINI-Trial to show the effect of Ranolazine in acute myocardial ischemia.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease; Acute Myocardial Ischemia	Drug: Ranolazine	Phase 2/Phase 3

Detailed Description

The aim of the RIMINI-Trial is to examine the effect of Ranolazine on ischemic myocardium in acute myocardial ischemia.

A pilot-trial by Venkatamaran et al. recently demonstrated, that the area of ischemic myocardium in patients with stable coronary artery disease can be reduced by Ranolazine-treatment2. This effect was shown by significantly reduced areas of atypical or dysfunctional myocardium in SPECT-examinations.

The dimension of myocardial damage (i.e. area of ischemic myocardium) is directly related to:

1. Rate of complications (i.e. left-ventricular pump failure, malignant arrhythmia)

2. Grade of Rehabilitation to daily life (i.e. persistent reduced left-ventricular ejection fraction)

Early angioplasty and coronary medication are key factors for preventing complications and ensuring sufficient rehabilitation. This is done to reduce the ischemic area as best as possible.

In patients with stable angina pectoris, Ranolazine is used with beneficial results1. Ranolazine improves diastolic blood flow and therefore microcirculation in the myocardium by reducing diastolic tension (via inhibiting late Na+-Influx and consecutive Ca2+-Overload).

Recently published data2 showed that treatment with Ranolazine significantly reduces the ischemic area in chronic damaged myocardium. This is due the effect of improved microcirculation in hibernating myocardium.

Early administration of Ranolazine and improvement of microcirculation in patients with acute damaged myocardium (i.e. directly after acute ischemia) should lead to a recruitment and re-uptake of cardiac activity of hibernating myocardium.

For the RIMINI-Trial patients are given Ranolazine on top of the guideline-based treatment to reduce the area of acute ischemic myocardium.

Patients with unstable angina pectoris and proof of acute cardiac ischemia (Serum levels of Troponin-T-hs >14 pg/ml), proof of myocardial dyskinesia and angina pectoris >/=CCS II (Canadian Cardiovascular Society Classification of Angina Pectoris) in the patient history will receive unaltered guideline-based therapy for acute cardiac ischemia5,6. All necessary procedures will be performed to stabilize patients to a hemodynamically compensated state (normalized levels of blood pressure, heart rate, absent malignant arrhythmia, dyspnoea and angina-like symptoms), and patients are then transferred to receive cardiac catheterization (angiography and angioplasty if necessary).

After patients are stabilized (i.e. via angioplasty, medical treatment) Ranolazine will be given additionally to guideline-based medication (Beta-Blocker, ACE-Inhibitor or AT1-Inhibitor, ASS, Clopidogrel, Statins).

The measurement of the ischemic myocardial area will be done via three functional echocardiographies with speckle tracking technique10 (speckle -tracking echocardiography,

SPE):

1. The first speckle tracking for screening and will be done directly with patients presenting in the emergency room.

2. After stabilization and coronary angiography or -plasty and before the first dose of Ranolazine is given, the second speckle tracking will be done for baseline.

3. After 42 days of Ranolazine-treatment the third and final speckle tracking echocardiography will be done.

A statistical evaluation of ischemic myocardial area before and after treatment with Ranolazine/Placebo will be done after conclusion of the RIMINI-Trial to show the effect of Ranolazine in acute myocardial ischemia.

For controlling and comparing the effect, the RIMINI-Trial will be single-blinded and compared to a group of patients not treated with Ranolazine. Participants will be randomized to the treatment-group or the no-treatment-group using a computer based randomization-method.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Reduction of Ischemic Myocardium With Ranolazine-Treatment in Patients With Acute Myocardial Ischemia
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ranolazine Ranolazine 500mg bid orally 7 days Ranolazine 750mg bid orally 35 days	Drug: Ranolazine; Improvement of myocardial microcirculation; Other Names: Ranexa
No Intervention: No additional medication No additional medication - control group

Outcome Measures

Primary Outcome Measures

1. Left Ventricular Global Strain Rate [42 days after first dose of Ranolazine]

   Relativ acceleration or deceleration (1/s) of left ventricular myocardial sections compared to direct opposite section. The more positive the value, the more simultaneously the movements, the more hemodynamically better.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Proof of acute cardiac ischemia by elevated serum Troponin T-hs levels > 14 pg/nl

• Proof of myocardial dyskinesia with functional echocardiography ("speckle tracking")

• Stable angina pectoris >/= CCS II in patient history

• Stabilized (i.e. normalized vital parameters) patients after coronary angioplasty or angiography

• Coronary angioplasty or angiography not older than 24 hours

• Written informed consent

• Established standard therapy for coronary artery disease (i.e. Beta-Blocker, ACE-Inhibitor or AT1-Inhibitor, ASS, Clopidogrel, Statins)

Exclusion Criteria:

• Patients younger than 18 years of age

• Acute cardio-pulmonary decompensation

• Middle and high grade liver insufficiency (Child-Pugh Score B and C)

• High grade renal insufficiency (Creatinine-Clearance < 30 ml/min)

• Concomitant treatment with potent inhibitors of CYP3A4

• Concomitant administration of class Ia (e.g. quinidine) or class III (e.g. dofetilide, sotalol) antiarrhythmics, except for amiodarone

• Concomitant administration of > 20 mg simvastatin/day

• Patients with heart failure classification NYHA III and NYHA IV

• Homeless patients and drug-addicted patients

• Pregnant and/or breast-feeding women

• Treatment with Ranolazine prior to enrolment in RIMINI-Trial

• Allergy against Ranolazine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Heart Center Hamburg Eppendorf	Hamburg		Germany	20246

Sponsors and Collaborators

• Universitätsklinikum Hamburg-Eppendorf

Investigators

• Principal Investigator: Stefan Blankenberg, Prof. Dr., Director of University Heart Center Hamburg Eppendorf

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University Heart Center Hamburg Eppendorf

Publications

• Andersen GØ, Knudsen EC, Aukrust P, Yndestad A, Oie E, Müller C, Seljeflot I, Ueland T. Elevated serum osteoprotegerin levels measured early after acute ST-elevation myocardial infarction predict final infarct size. Heart. 2011 Mar;97(6):460-5. doi: 10.1136/hrt.2010.206714. Epub 2011 Jan 26.
• El-Kadri M, Sharaf-Dabbagh H, Ramsdale D. Role of antiischemic agents in the management of non-ST elevation acute coronary syndrome (NSTE-ACS). Cardiovasc Ther. 2012 Feb;30(1):e16-22. doi: 10.1111/j.1755-5922.2010.00225.x. Epub 2010 Sep 15. Review.
• Geyer H, Caracciolo G, Abe H, Wilansky S, Carerj S, Gentile F, Nesser HJ, Khandheria B, Narula J, Sengupta PP. Assessment of myocardial mechanics using speckle tracking echocardiography: fundamentals and clinical applications. J Am Soc Echocardiogr. 2010 Apr;23(4):351-69; quiz 453-5. doi: 10.1016/j.echo.2010.02.015. Erratum in: J Am Soc Echocardiogr. 2010 Jul;23(7):734.
• Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grøgaard HK, Bjørnerheim R, Brekke M, Müller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006 Sep 21;355(12):1199-209.
• Miller TD, Gibbons RJ. Measuring myocardium at risk in acute myocardial infarction--a continuing challenge. J Nucl Cardiol. 2010 Oct;17(5):778-80. doi: 10.1007/s12350-010-9278-3.
• Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, Wolff AA, Skene A, McCabe CH, Braunwald E; MERLIN-TIMI 36 Trial Investigators. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007 Apr 25;297(16):1775-83.
• Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernández-Avilés F, Fox KA, Hasdai D, Ohman EM, Wallentin L, Wijns W. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J. 2007 Jul;28(13):1598-660. Epub 2007 Jun 14.
• Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, Falk V, Filippatos G, Fox K, Huber K, Kastrati A, Rosengren A, Steg PG, Tubaro M, Verheugt F, Weidinger F, Weis M; ESC Committee for Practice Guidelines (CPG). Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008 Dec;29(23):2909-45. doi: 10.1093/eurheartj/ehn416. Epub 2008 Nov 12.
• Venkataraman R, Belardinelli L, Blackburn B, Heo J, Iskandrian AE. A study of the effects of ranolazine using automated quantitative analysis of serial myocardial perfusion images. JACC Cardiovasc Imaging. 2009 Nov;2(11):1301-9. doi: 10.1016/j.jcmg.2009.09.006.

• Responsible Party: Tjark Frederik Schwemer, Dr. med., Universitätsklinikum Hamburg-Eppendorf
• ClinicalTrials.gov Identifier: NCT01797484
• Other Study ID Numbers: UHZ-KARD-01-2013
• First Posted: Feb 22, 2013
• Last Update Posted: Jan 12, 2018
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Tjark Frederik Schwemer, Dr. med., Universitätsklinikum Hamburg-Eppendorf: ischemia; myocardium; Ranolazine; dyskinesia; speckle tracking echocardiography
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Ischemia; Ranolazine

Study Results

Participant Flow

Recruitment Details	first patient enrolled: 05-Aug-2013 last patient finished: 05-Jun-2015 All patients were enrolled at University Heart Centre Hamburg Eppendorf

Arm/Group Title	Ranolazine	No Additional Medication
Arm/Group Description	Ranolazine 500mg bid orally 7 days Ranolazine 750mg bid orally 35 days Ranolazine: Improvement of myocardial microcirculation	No additional medication - control group
Period Title: Overall Study
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Ranolazine	No Additional Medication	Total
Arm/Group Description	Ranolazine 500mg bid orally 7 days Ranolazine 750mg bid orally 35 days Ranolazine: Improvement of myocardial microcirculation	No additional medication - control group	Total of all reporting groups
Overall Participants	10	10	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68 (9)	72 (7)	70 (8)
Sex: Female, Male (Count of Participants)
Female	4 40%	5 50%	9 45%
Male	6 60%	5 50%	11 55%

Outcome Measures

1. Primary Outcome

Title	Left Ventricular Global Strain Rate
Description	Relativ acceleration or deceleration (1/s) of left ventricular myocardial sections compared to direct opposite section. The more positive the value, the more simultaneously the movements, the more hemodynamically better.
Time Frame	42 days after first dose of Ranolazine

Outcome Measure Data

Analysis Population Description

Secondary Outcome Measure data was not collected. Initially planned secondary outcome (e.g. cardiac events) was found to interfere with monitoring drug safety

Arm/Group Title	Ranolazine	No Additional Medication
Arm/Group Description	Ranolazine 500mg bid orally 7 days Ranolazine 750mg bid orally 35 days Ranolazine: Improvement of myocardial microcirculation	No additional medication - control group
Measure Participants	10	10
Mean (Standard Deviation) [percentage of change]	18 (2)	23 (3)

Adverse Events

Arm/Group Title	Ranolazine		No Additional Medication
Arm/Group Description	Ranolazine 500mg bid orally 7 days Ranolazine 750mg bid orally 35 days Ranolazine: Improvement of myocardial microcirculation		No additional medication - control group
All Cause Mortality
	Ranolazine		No Additional Medication
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ranolazine		No Additional Medication
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Ranolazine		No Additional Medication
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.