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

Exclusion Criteria

• •Pregnancy, planned pregnancy, or breast-feeding
• •Female patients of childbearing potential who are unwilling to use a highly effective contraception method during trial participation according to CTFG. In addition, a negative 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 blockers for 48 hours before invasive coronary reactivity testing (e.g. clinical need for rate control in case of permanent atrial fibrillation, recurrent angina symptoms without any possibility to wihthold ongoing medication)
• •Known hypersensitivity or contraindication to bisoprolol or diltiazem or any of its excipients.
• •Concomitant therapy with systemic drugs that are strong inhibitors of both CYP3A4 and P-gp (azole antimycotics such as ketoconazole and itraconazole or HIV protease inhibitors 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 (alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥2.0 upper limit of normal (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 of randomization and the duration of this trial
• •Patients who are unwilling to consent to saving and propagation of pseudonymized medical 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 or procedures, and/or to comply with all required study procedures to the best of patient's and investigator's knwoledge
• •Active coronavirus disease 2019 (COVID-19) at time of randomization