First Prospective Randomized Trial to Examine a Differential Therapeutic Response in Symptomatic Patients With Non-obstructive Coronary Artery Disease After Coronary Physiological Testing
Trial Snapshot
- Phase
- Phase 4
- Enrollment
- 132
- Locations
- 15
- Primary Endpoint
- Change in angina symptom severity as measured by the Seattle Angina Questionnaire (SAQ) summary score from each period specific baseline to the end of this period (week 4)
Study Overview
Brief Summary
EXAMINE-CAD-DZHK22 is a prospective, randomized, double-blind, placebo-controlled, crossover trial investigating the efficacy of beta blocker (bisoprolol) and calcium channel blocker (diltiazem) therapy in symptomatic patients with non-obstructed coronary arteries according to coronary physiological testing results.
Detailed Description
Patients presenting with recurrent angina but non-obstructed coronary arteries are increasingly recognized and have a high morbidity and symptomatic burden. These patients are often misdiagnosed and discharged without further investigation or treatment. Current European Society of Cardiology (ESC) guidelines for the management of patients with chronic coronary syndromes recommend beta blockers or calcium channel blockers, depending on the presence of abnormal vasodilatation or abnormal vasoconstriction. Scientific evidence to support this recommendation, however, is scarce and no randomized clinical trial of this differential therapy has been performed in these patients. The aim of the EXAMINE-CAD-DZHK22 trial is therefore to compare for the first time the efficacy of beta blocker (bisoprolol) and calcium channel blocker (diltiazem) therapy in reducing angina symptoms in symptomatic patients with non-obstructed coronary arteries according to coronary physiology testing results. This study is the first to investigate whether coronary physiology testing can guide therapeutic management of these patients depending on whether abnormalities of vasodilatation or vasoconstriction are present. The EXAMINE-CAD-DZHK22 trial will thus fill an important knowledge and evidence gap in the treatment of these highly symptomatic patients, and has the potential to pave the way for future large-scale clinical trials in symptomatic patients with non-obstructed coronary arteries.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
Subjects will be randomly assigned to 1 of 6 possible treatment sequences. All treatment sequences will include the consecutive treatment with bisoprolol, diltiazem, and placebo.
Eligibility Criteria
- Ages
- 18 Years to 85 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age 18 - 85 years
- •Recurrent angina symptoms provoked by exercise and/or repeated attacks of angina at rest (both at least for 4 weeks)
- •Absence of flow-limiting coronary artery stenosis (as defined by any coronary artery diameter 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 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
- •Persons who may dependent on the Sponsor, the Investigator or the trial sites, are not eligible to enter the trial
- •Active coronavirus disease 2019 (COVID-19) at time of randomization
Arms & Interventions
diltiazem first, bisoprolol second
Crossover Design: diltiazem first, bisoprolol second, placebo third
Intervention: Diltiazem (Drug)
diltiazem first, bisoprolol second
Crossover Design: diltiazem first, bisoprolol second, placebo third
Intervention: Placebo (Drug)
bisoprolol first, diltiazem second
Crossover Design: bisoprolol first, diltiazem second, placebo third
Intervention: Bisoprolol (Drug)
bisoprolol first, diltiazem second
Crossover Design: bisoprolol first, diltiazem second, placebo third
Intervention: Diltiazem (Drug)
bisoprolol first, diltiazem second
Crossover Design: bisoprolol first, diltiazem second, placebo third
Intervention: Placebo (Drug)
bisoprolol first, placebo second
Crossover Design: bisoprolol first, placebo second, diltiazem third
Intervention: Bisoprolol (Drug)
bisoprolol first, placebo second
Crossover Design: bisoprolol first, placebo second, diltiazem third
Intervention: Diltiazem (Drug)
bisoprolol first, placebo second
Crossover Design: bisoprolol first, placebo second, diltiazem third
Intervention: Placebo (Drug)
diltiazem first, bisoprolol second
Crossover Design: diltiazem first, bisoprolol second, placebo third
Intervention: Bisoprolol (Drug)
diltiazem first, placebo second
Crossover Design: diltiazem first, placebo second, bisoprolol third
Intervention: Bisoprolol (Drug)
diltiazem first, placebo second
Crossover Design: diltiazem first, placebo second, bisoprolol third
Intervention: Diltiazem (Drug)
diltiazem first, placebo second
Crossover Design: diltiazem first, placebo second, bisoprolol third
Intervention: Placebo (Drug)
placebo first, bisoprolol second
Crossover Design: placebo first, bisoprolol second, diltiazem third
Intervention: Bisoprolol (Drug)
placebo first, bisoprolol second
Crossover Design: placebo first, bisoprolol second, diltiazem third
Intervention: Diltiazem (Drug)
placebo first, bisoprolol second
Crossover Design: placebo first, bisoprolol second, diltiazem third
Intervention: Placebo (Drug)
placebo first, diltiazem second
Crossover Design: placebo first, diltiazem second, bisoprolol third
Intervention: Bisoprolol (Drug)
placebo first, diltiazem second
Crossover Design: placebo first, diltiazem second, bisoprolol third
Intervention: Diltiazem (Drug)
placebo first, diltiazem second
Crossover Design: placebo first, diltiazem second, bisoprolol third
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Change in angina symptom severity as measured by the Seattle Angina Questionnaire (SAQ) summary score from each period specific baseline to the end of this period (week 4)
Time Frame: from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks
Assessment of angina symptom severity as measured by the SAQ summary score resulting from the SAQ physical limitation scale, SAQ angina frequency scale, and SAQ quality of life scale. The score ranges from 0 to 100, with the lower the score, the higher the symptom severity and limitations.
Secondary Outcomes
- Duke Activity Status Index (DASI)(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
- Angina diary (nitroglycerin use per week))(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
- SAQ treatment satisfaction scale(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
- SAQ quality of life(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
- Psychological symptoms as assessed by Patient Health Questionnaire (PHQ-9)(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
- Psychological symptoms as assessed by the Hospital Anxiety Depression Scale (HADS))(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
- Functional capacity as assessed by bicycle exercise testing(from baseline (visit 1) to the end of each treatment period (4 weeks, 10 weeks, 16 weeks))
- Quality of Life (Short Form 36 health survey questionnaire)(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
- SAQ angina stability scale(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
- SAQ angina frequency scale(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
- SAQ physical limitation scale(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
- Rose dyspnea scale(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
- Angina diary (Angina episodes per week)(from each period specific baseline to the end of this period, i.e. baseline and 4 weeks; 6 weeks and 10 weeks; 12 weeks and 16 weeks)
Investigators
Ulf Landmesser
Prof. Dr.
Charite University, Berlin, Germany