Clinical trial NCT04606459: COSIMA: COronary SInus Reducer for the Treatment of Refractory Microvascular Angina
Official title: A Multicentric Randomized Open Label Controlled Superiority Trial to Evaluate the Effectiveness of a Therapy With a Coronary Sinus Reducer as Compared to Guideline-directed Medical Therapy in Patients With Refractory Microvascular Angina
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Coronary Microvascular Disease
Refractory Angina
Lead sponsor: Johannes Gutenberg University Mainz
Sponsor class: OTHER
Collaborators: name: Shockwave Medical, Inc.
First posted: 2020-10-28
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In the current randomized, controlled, parallel-groups trial, patients will be randomized to guideline-directed optimal medical therapy with coronary sinus Reducer (Neovasc Reducer™ System) implantation or guideline-directed medical therapy alone.
Primary purpose: TREATMENT

Brief summary: Patients with refractory microvascular angina fulfilling the predefined inclusion and exclusion criteria will be enrolled in this randomized trial. The primary objective is to investigate whether the proportion of patients reporting an improvement in Canadian Cardiovascular Society (CCS) angina class (≥2 classes) is different at six months after implantation of a Coronary Sinus Reducer followed by optimal medical therapy (OMT) compared to OMT alone.

Detailed description: Recent data show that 47% of the patients undergoing coronary angiography for angina have no epicardial disease. Of these, 52% have isolated microvascular angina, 17% have isolated vasospastic angina, 20% have both, and 11% have non-cardiac chest pain. These data suggest that microvascular disease is a highly prevalent condition, which might affect as many as 25% of all patients undergoing coronary angiography (without counting patients with acute coronary syndromes and those with mixed epicardial and microvascular disease). Based on an estimate of the Woman´s Ischemia Syndrome Evaluation (WISE) study, 3-4 million patients with symptoms of myocardial ischemia have non-obstructive coronary artery disease in the United States of America. These patients represent a significant burden in terms of mortality and morbidity as well as in terms of healthcare costs due to disability, hospitalization, and repeat testing.

Patients with microvascular angina require frequent hospitalizations, undergo repeat invasive procedures, have an impaired quality of life and a poor prognosis, since patients with a high index of microvascular resistances) have a higher risk of mortality (hazard ratio (HR) 1.6\[0.8-3.4\], P\<0.001)). An analysis of the WISE study identified an impaired coronary flow reserve in the absence of epicardial disease as the strongest predictor of 5-year adverse events (26.7% versus 12.2%, HR 1.2\[1.1.-1.4\], P=0.008).

Although its importance is acknowledged by the most recent guidelines, microvascular angina represents a major clinical challenge. In particular, there is a strong disagreement on its classification, on the several mechanisms behind its pathophysiology, and the therapeutic alternatives available remain unsatisfactory.

Despite these uncertainties, there is a consensus that this condition is highly frequent, as it affects up to two-thirds of patients who suffer from stable angina and either have no coronary stenoses at angiography or have combined epicardial and microvascular disease.

The limits of medical therapy Traditional anti-ischaemic drugs are the first step in medical treatment, but their effectiveness is very limited in the setting of microvascular disease. Short-acting nitrates can be used to treat anginal attacks, but since nitrates are only effective on large arteries, this therapy is only indicated for the therapy of patients whose symptoms are caused by spasm of epicardial coronaries, and not for true microvascular angina. Beta-blockers limit myocardial oxygen consumption but do not affect the mechanisms of microvascular disease. Calcium antagonists, have shown variable results in clinical trials, but the limitation of this approach is that a significant heterogeneity exists in the types of calcium channels in the vasculature.

Evidence on the coronary sinus reducer In recent years, the coronary sinus reducer has been introduced to treat refractory angina in patients with refractory angina due to obstructive coronary artery disease (CAD) and no revascularization options, a situation similar to microvascular disease. This novel therapy is based on the concept that an elevation in backward pressure in the coronary venous system provokes dilatation of the subendocardial arterioles, resulting in a significant reduction of vascular resistance in this area and a redistribution of blood flow to these ischaemic subendocardial layers. Numerous studies confirm the efficacy of the Reducer for patients suffering from angina who are not candidates for revascularization. Preliminary evidence supporting the use of this device in microvascular disease patients also exists, but requires confirmation in a large, randomized trial.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 and ≤85 years
* Chronic coronary syndrome (including patients with anginal equivalents) refractory angina CCS class III-IV despite guideline-directed medical therapy
* Evidence of reversible ischemia on non-invasive testing
* Evidence of microvascular disease as diagnosed invasively by at least one of the following:

  1. index of microvascular resistances (IMR) \>25 and/or
  2. coronary flow reserve (CFR) \<2.0) with fractional flow reserve (FFR)\>0.8.
* Willingness to participate and ability to understand, read and sign the informed consent document before enrollment in the trial.

Exclusion Criteria:

Subjects presenting at least one of the following criteria will not be enrolled in the trial

* Recent (within 3 months) acute coronary syndrome
* Recent (within 6 months) revascularization by percutaneous coronary intervention (PCI, stent) or coronary artery by-pass surgery (CABG)
* Recent (within 30 days) unsuccessful PCI
* Decompensated congestive heart failure (CHF) or hospitalization due to CHF during the last 3 months
* Left ventricular ejection fraction of \<30%
* Mean right atrial pressure \>15mmHg
* Anomalous or abnormal CS anatomy (e.g., tortuosity, aberrant branch, persistent left superior vena cava \[SVC\]) as demonstrated by angiogram
* CS diameter at the site of planned Reducer implantation greater than 13mm or less than 9.5mm as measured by angiogram
* Severe chronic obstructive pulmonary disease (COPD) indicated by a forced expiratory volume in one second that is less than 55 percent of the predicted value
* Severe valvular heart disease
* A pacemaker electrode in the coronary sinus
* Tricuspid valve replacement or repair
* Chronic renal failure (serum creatinine \>2mg/dL), and/or on chronic hemodialysis
* Moribund, or with comorbidities limiting life expectancy to less than one year
* Known severe reaction to required procedural medications
* Known allergy to stainless steel or nickel
* Need for Magnetic Resonance Imaging (MRI) within 8 weeks after reducer implantation
* Contraindication to dual antiplatelet therapy
* Female of childbearing potential (last menstruation within the last 12 months or who did not undergo tubal ligation, ovariectomy or hysterectomy)

Primary outcomes:
measure: Change in Canadian Cardiovascular Society angina class by two or more classes
timeFrame: 6 months
Secondary outcomes:
measure: Change in angina severity according to the Seattle Angina Questionnaire
timeFrame: Six months
measure: Number of participants with technical success
timeFrame: Implantation day
measure: Procedural success
timeFrame: Implantation day
measure: Frequency of use of sublingual nitrates (times per week)
timeFrame: 6 months, 1 year, 5 years
measure: Parameters of angina and quality of life
timeFrame: at 6 months
measure: Incidence of adverse events
timeFrame: 5 years
measure: Number of documented Emergency Department (ED) visits due to angina episodes
timeFrame: 6 and 12 months
measure: Canadian Cardiovascular Society angina class
timeFrame: 6 months, 1 year, 5 years
measure: Number of unplanned hospitalizations for cardiac ischemia, angina or anginal equivalent, heart failure
timeFrame: 6 months, 1 year, 5 years
measure: Change in 5-level EQ-5D version (EQ-5D-5L)
timeFrame: 6 months
measure: Beck depression inventory
timeFrame: 6 months
Other outcomes:
Locations:
city: Mainz
country: Germany
facility: Center of Cardiology, Cardiology I, university hospital Mainz
state: Rheinland-Pfalz
Study officials:
References: