The primary objective of the CRAVE feasibility trial is to assess the feasibility of conducting a larger CRAVE platform trial by performing a randomized trial of 30 participants with pulmonary hypertension and right ventricular dysfunction, comparing empagliflozin or ranolazine plus standard of care to standard of care alone.

This study is an investigator-initiated, open label, prospective, multi-centre, phase 2, randomized control trial. This CRAVE feasibility trial will seek to establish the feasibility of a larger platform trial for testing multiple interventions in various domains to improve right ventricular function. In this feasibility trial, 30 participants with pulmonary hypertension and right heart failure with be randomized 1:1:1 to empagliflozin 10 mg daily + standard of care, ranolazine twice daily + standard of care, or standard of care alone. Participant outcomes (medical records review) will be followed for 16 weeks after randomization.

Inclusion Criteria:

1. Age ≥ 18 years.

2. Able to provide informed consent.

3. Able to comply with all study procedures.

4. History of RV dysfunction or RHF secondary to any of:

   a. Group 1 PH, pulmonary arterial hypertension b. Group 2 PH, left heart disease with normal left ventricular ejection fraction (LVEF) > 50% and a previous RHC demonstrating combined pre and post-capillary PH, defined as: i. mPAP >20 mmHg ii. PAWP > 15 mmHg iii. PVR> 2 WU c. Group 3 PH d. Group 4 PH, chronic thromboembolic PH that is either persistent after pulmonary endarterectomy or inoperable due to distal disease.

5. Symptomatic with current NYHA Functional Class II-IV

6. Biomarker and 2D echocardiogram evidence of RV dysfunction within 3 months:

   1. NT-proBNP >300 ng/L and qualitative evidence of at least 'mild' RV dysfunction on echocardiography OR NT-proBNP<300 ng/L and qualitative evidence of at least moderate RV dysfunction and/or dilatation on 2D echocardiogram AND
   2. A quantitative 2D echocardiogram with evidence of RV dysfunction defined as having both of the following:

   i. TAPSE ≤18 mm ii. RV dilatation (RV diameter > 42 mm at the base).

7. Receiving loop diuretics or mineralocorticoid receptor antagonists for at least 4 weeks.

8. Access to an iOS or android smart phone or tablet.

Exclusion Criteria:

1. Estimated glomerular filtration rate (eGFR) <30 ml/min.

2. LVEF < 50%

3. Normal RV size and function

4. Severe aortic or mitral valvular disease

5. Moderate or severe hepatic dysfunction (Child-Pugh Class B or C)

6. Participants requiring augmentation of diuretics or otherwise not meeting definition for clinical stability

7. Pregnancy or lactation

8. Unable to provide consent and comply with follow-up visits

9. Listed for lung, heart or heart/lung transplantation

10. Myocardial infarction or acute coronary syndrome within 90 days of screening

11. Enrolled in another interventional trial

12. Planned cardiac or thoracic surgical intervention in the next 6 months.

13. Known hypersensitivity to empagliflozin or ranolazine.

14. Concurrent treatment with:

    • strong inhibitors of Cytochrome P450 3A4 (CYP 3A4), (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, nelfinavir, ritonavir, indinavir, saquinavir and grapefruit juice)
    • class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide) or class III antiarrhythmics (e.g., sotalol, ibutilide, amiodarone, dronedarone)
    • inducers of CYP 3A4 (e.g., rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort)

15. Congenital long QT syndrome or a QTc interval >500 ms

There is no plan to share individual participant data.