In This SectionTexas Health Research & Education Institute
Disease or Condition
Effects of Ranolazine on Major Adverse Cardiovascular Events in Subjects with a History of Chronic Angina Who Undergo Percutaneous Coronary Intervention with Incomplete Revascularization (Cardiology)
This is a study to evaluate the efficacy of ranolazine as compared with placebo when used as part of standard medical therapy in subjects who suffer from chronic angina (chest pain) who have undergone a percutanuous coronary intervention (PCI) but have incomplete revascularization (their blood vessel blockages were not completely removed.)
Written informed consent.
Males and females aged 18 years and older.
History of chronic angina defined as at least 2 episodes of anginal pain or discomfort in the chest, jaw, shoulder, back, neck, or arm that is precipitated by exertion or emotional stress, and relieved by rest or sublingual nitroglycerin, which occurred on at least 2 separate days and at least 14 days prior to the PCI (in the case of staged PCI procedures, at least 14 days prior to the first PCI in the series). Subjects may or may not have additional angina episodes within the 14 days prior to their first PCI in the series, as well as anytime prior to Randomization.
PCI for any indication (ACS or non-ACS). For the purposes of stratification at randomization, ACS will be defined as hospitalization for anginal pain or discomfort within the previous 24 hours to their hospitalization with any one (or more) of thefollowing criteria:
i. Elevated troponin or creatinine kinase-MB (CK-MB) consistent with MI, as reported by local laboratory and measured prior to index PCI
ii. Electrocardiographic changes (including transient changes) comprising new or presumably new ST segment depression = 0.1 mV (= 1 mm), or ST segment elevation = 0.1 mV (= 1 mm) in at least 2 contiguous leads, or new or presumably new Left Bundle Branch Block5. Randomization within 14 days of PCI (in case of staged PCI, of last in the series).
Randomization within 14 days post-PCI. In the case of staged PCI procedures, randomization has to occur within 14 days of last PCI in the series. Subjects may be randomized starting on the day of the PCI and anytime during the following 14 days. PCI is defined as an attempt to cross the lesion with a wire with the intention of performing
Post-PCI (post the last PCI for staged procedures) evidence of incomplete revascularization defined as the presence of one or more visually estimated = 50%
stenoses in one or more coronary arteries with reference vessel diameter of at least 2.0 mm, whether in the target vessel or in a non-target vessel regardless of the presence
or absence of coronary collaterals. In the case of a subject post-CABG, incomplete revascularization is defined as the presence of one or more visually estimated = 50%
stenoses in an unbypassed epicardial vessel with a reference diameter = 2.0 mm, or one or more visually estimated = 50% stenoses in a bypass graft supplying an otherwise unrevascularized myocardial territory.
Clinically stable post-PCI. Subjects randomized in-hospital on day of planned discharge or in clinic are considered stable. Subjects randomized in-hospital prior to day of planned discharge are considered stable if they meet all of the following criteria:
i. CK-MB < 3 times the upper limit of normal (ULN) at least 3 hours post-PCI, or if = 3 times the ULN with evidence of decreasing CK-MB (decreased by at least 20% from the prior measure), as reported by local laboratory. If CK-MB is not
available, a subject must have evidence of normal or decreasing troponin levels (decreased by at least 20% from the prior measure) at least 3 hours post-PCI, as
reported by local laboratory.
ii. Systolic blood pressure = 90 mm Hg and not receiving pressors or inotropes iii. No current requirement for an intra-aortic balloon pump (IABP) or any left ventricular assist device iv. No current requirement for intravenous (IV) nitroglycerin.
Ability and willingness to comply with all study procedures during the course of the study.
Females of childbearing potential must have a negative pregnancy test at Screening (unless surgically sterile or post-menopausal) and must agree to use highly effective
contraception methods from Screening throughout the duration of study treatment and for 14 days following the last dose of study drug. See Section 8.7 for a description of
acceptable methods of contraception and definition of post-menopausal.
Any future planned revascularization (including staged procedures) or possible planned revascularization (ie, planned stress test to assess the imminent need for additional revascularization). Future planned stress tests for purposes of monitoring are permitted but strongly discouraged. Subjects may be enrolled after the last PCI in the staged series or once a decision is made not to perform a follow up PCI, as long as Randomization occurs within 14 days from the last PCI. If a subject has had a stress test post-PCI and prior to Randomization and no further intervention is planned, the subject may be enrolled within 14 days from the last PCI.
Unrevascularized left main coronary artery stenosis = 50%. Subjects with history of CABG to the left coronary system will be considered to have a revascularized left main if at least one graft is patent.
Major complication during or after the index PCI (in the case of staged PCI, the last in the series) including
i. Major bleeding (TIMI Bleeding classification [Appendix 5] or any bleeding requiring = 2 units of red blood cells)
ii. Coronary perforation requiring treatment
iii. Procedural complication requiring surgery (including CABG or peripheral vascular surgery).
Stroke within 90 days prior to Randomization, or any history of stroke with permanent major neurologic disability (eg, aphasia or significant motor dysfunction).
Cardiogenic shock within 90 days prior to Randomization (transient increases in blood pressure without clinical sequelae are not considered to be cardiogenic shock).
New York Heart Association (NYHA) Class III or IV heart failure Severe renal insufficiency as assessed by an estimated GFR < 30 mL/min/1.73m2 using the 4 variable modification of diet in renal disease (MDRD) equation (Appendix 8) per local laboratory (based on the last available measurement prior to Randomization, collected within 1 month prior to the index PCI [in the case of staged PCI, the last in the series]).
Use of Class Ia, Ic, or Class III antiarrhythmics, except for amiodarone (as detailed in Appendix 4).
Current treatment with strong inhibitors of CYP3A (as detailed in Appendix 3).
Current treatment with CYP3A4 inducers or P-gp inducers (as detailed in Appendix 3).
Subjects taking > 20 mg simvastatin daily or > 40 mg lovastatin daily who cannot reduce the dose to 20 mg once daily for simvastatin or 40 mg once daily for lovastatin, or who cannot switch to another statin.
Subjects taking greater than a total of 1000 mg daily of metformin who cannot reduce the dose to a maximum total of 1000 mg daily (additional anti-diabetic medications may be added as clinically indicated to allow subjects to decrease their metformin dose and maintain glycemic control).
Previous treatment with ranolazine for > 7 consective days within 30 days prior to Randomization, or known hypersensitivity or intolerance to ranolazine or to any of the excipients.
Participation in another investigational drug or device study within 30 days prior to Randomization (participation in registries is allowed).
Women who are pregnant or breast feeding.
Non-CAD comorbid conditions (eg, advanced malignancy, severe aortic stenosis) which are likely to result in death within 2 years of Randomization.
Any condition that in the opinion of the investigator would preclude compliance with the study protocol.