Randomized Trial to Examine a Differential Therapeutic Response in Symptomatic Patients With Non-obstructive Coronary Artery Disease

Inclusion Criteria:

• Age 18 - 85 years
• Recurrent angina symptoms provoked by exercise and/or repeated attacks of angina atrest (both at least for 4 weeks)
• Absence of flow-limiting coronary artery stenosis (as defined by any coronary arterydiameter reduction >50% or fractional flow reserve ≤0.80)
• Left ventricular ejection fraction (LVEF) >50%
• Written informed consent

Exclusion Criteria:

• Pregnancy, planned pregnancy, or breast-feeding
• Female patients of childbearing potential who are unwilling to use a highly effectivecontraception method during trial participation according to CTFG. In addition, anegative serum or urine pregnancy test must be available prior to randomization.
• Expected life expectancy <1 year
• Contraindications to withholding nitrates, calcium channel blockers, and beta blockersfor 48 hours before invasive coronary reactivity testing (e.g. clinical need for ratecontrol in case of permanent atrial fibrillation, recurrent angina symptoms withoutany possibility to wihthold ongoing medication)
• Known hypersensitivity or contraindication to bisoprolol or diltiazem or any of itsexcipients.
• Concomitant therapy with systemic drugs that are strong inhibitors of both CYP3A4 andP-gp (azole antimycotics such as ketoconazole and itraconazole or HIV proteaseinhibitors such as ritonavir)
• Concomitant therapy with drugs that are strong CYP3A4 inducers (e.g. carbamazepine,phenytoin, rifampicin, St. John's wort)
• Bradycardia (<50/min) at time of randomization
• Symptomatic hypotension (<100 mmHg) at time of randomization
• Cardiogenic shock
• Second and third degree atrioventricular block, sick sinus syndrome, sinoatrial block
• Severe valvular heart disease (grade III)
• Any cardiomyopathy including those with preserved left ventricular ejection fraction (LVEF)
• Chronic obstructive pulmonary disease
• Severe bronchial asthma
• Metabolic acidosis at time of randomization
• Renal failure (creatinine >2.0 mg/dL)
• N-terminal pro B-type natriuretic peptide (NT-proBNP) >300 ng/L
• Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis,cirrhosis) which is associated with moderate or severe hepatic impairment (alanineaminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥2.0 upper limit ofnormal (ULN))
• Untreated pheochromocytoma
• Late stage of peripheral arterial disease or Raynaud's syndrome
• Participation in another clinical trial according to AMG or MPG at the time ofrandomization and the duration of this trial
• Patients who are unwilling to consent to saving and propagation of pseudonymizedmedical data for study reasons
• Persons who are legally detained in an official institution
• Persons likely to not be available to complete all protocol-required study visits orprocedures, and/or to comply with all required study procedures to the best ofpatient's and investigator's knwoledge
• Persons who may dependent on the Sponsor, the Investigator or the trial sites, are noteligible to enter the trial
• Active coronavirus disease 2019 (COVID-19) at time of randomization