Ignite Creation Date:
2024-10-26 @ 3:40 PM
Last Modification Date:
2024-10-26 @ 3:40 PM
Study NCT ID:
NCT06600178
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-09-03
Brief Title:
Study Targeting Myocardial Perfusion and Symptom Relief in Women with SGLT2 Inhibitors STRONG
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Innovative Therapy to Treat Women with Angina with Nonobstructive Coronary Artery Disease ANOCA and Coronary Microvascular Disease
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
STRONG
Brief Summary:
Heart disease is the leading cause of death among men and women In 2017 more than 400000 of the one million deaths among women in the United States were related to cardiovascular disease mostly due to atherosclerotic ischemic heart disease Ischemic heart disease in women is different from that of men Women have a unique phenotype with fewer calcified lesions and more non-obstructive disease lt50 diameter narrowing Among symptomatic women presenting for invasive coronary angiography 40-65 have non-obstructive coronary artery disease They often receive no specific therapy Women suffering from non-obstructive coronary artery disease represent a large population of untreated or poorly treated patients
Women with anginal symptoms associated with non-obstructive coronary disease have an elevated risk for major adverse cardiac events a high symptom burden and reduced quality of life Anginal symptoms associated with non-obstructive coronary disease creates substantial economic impact with frequent time missed from work and productivity limitations Although the underlying mechanisms of disease are incompletely understood coronary endothelial andor microvascular dysfunction has been implicated To date few appropriately designed trials of therapeutic strategies targeting women with anginal symptoms associated with non-obstructive coronary disease and persistent symptoms exist
Sodium-glucose cotransporter 2 inhibitors a new drug class approved for the treatment of diabetes has been shown to significantly reduce atherosclerotic events hospitalization from heart failure cardiovascular and total mortality and progression of chronic kidney disease In preclinical models of myocardial infarction dapagliflozin has demonstrated attenuation of cardiac fibrosis and adverse tissue remodeling and improved cardiac function Furthermore empagliflozin has been shown to improve coronary microvascular function and increase cardiac output in mice These findings suggest that Sodium-glucose cotransporter 2 inhibitors therapy may have beneficial impact in women
The study team hypothesizes that Sodium-glucose cotransporter 2 inhibitors treatment will improve Coronary Microvascular Disease in women with anginal symptoms associated with non-obstructive coronary disease by several pathways including reducing markers of systemic Inflammation and improving coronary blood flow leading to a reduction of the functional impact of this disease process The hypothesis will be addressed through the following three aims
Aim 1 Test the hypothesis that Sodium-glucose cotransporter 2 inhibitors treatment improves coronary microvascular disease in women with no evidence of epicardial obstructive coronary artery disease
Aim 2 Test the hypothesis that Sodium-glucose cotransporter 2 inhibitors treatment improves angina symptoms and other quality of life measurements associated with the improvement of CFR
AIM 3 Identify the effect of Sodium-glucose cotransporter 2 inhibition on inflammation pathways and markers of systemic
Women with anginal symptoms associated with non-obstructive coronary disease have an elevated risk for major adverse cardiac events a high symptom burden and reduced quality of life Anginal symptoms associated with non-obstructive coronary disease creates substantial economic impact with frequent time missed from work and productivity limitations Although the underlying mechanisms of disease are incompletely understood coronary endothelial andor microvascular dysfunction has been implicated To date few appropriately designed trials of therapeutic strategies targeting women with anginal symptoms associated with non-obstructive coronary disease and persistent symptoms exist
Sodium-glucose cotransporter 2 inhibitors a new drug class approved for the treatment of diabetes has been shown to significantly reduce atherosclerotic events hospitalization from heart failure cardiovascular and total mortality and progression of chronic kidney disease In preclinical models of myocardial infarction dapagliflozin has demonstrated attenuation of cardiac fibrosis and adverse tissue remodeling and improved cardiac function Furthermore empagliflozin has been shown to improve coronary microvascular function and increase cardiac output in mice These findings suggest that Sodium-glucose cotransporter 2 inhibitors therapy may have beneficial impact in women
The study team hypothesizes that Sodium-glucose cotransporter 2 inhibitors treatment will improve Coronary Microvascular Disease in women with anginal symptoms associated with non-obstructive coronary disease by several pathways including reducing markers of systemic Inflammation and improving coronary blood flow leading to a reduction of the functional impact of this disease process The hypothesis will be addressed through the following three aims
Aim 1 Test the hypothesis that Sodium-glucose cotransporter 2 inhibitors treatment improves coronary microvascular disease in women with no evidence of epicardial obstructive coronary artery disease
Aim 2 Test the hypothesis that Sodium-glucose cotransporter 2 inhibitors treatment improves angina symptoms and other quality of life measurements associated with the improvement of CFR
AIM 3 Identify the effect of Sodium-glucose cotransporter 2 inhibition on inflammation pathways and markers of systemic
Detailed Description:
Heart disease is the leading cause of death among women and men In the NIH-NHLBI-sponsored Women39s Ischemia Syndrome Evaluation WISE study more than 50 of women with angina were found to have either no or minimal coronary artery disease CAD on invasive coronary angiography Women with persistent chest pain but without obstructive IHD had worse cardiac outcomes than asymptomatic women One year after the index evaluation nearly 40 of symptomatic women displayed persistent or worsening symptoms Angina secondary to myocardial ischemia may occur in nonobstructive coronary artery disease ANOCA patients ANOCA is associated with an increased risk for major adverse cardiac events MACE compared with an asymptomatic reference population As such patients with ANOCA have a high symptom burden and reduced quality of life Coronary microvascular dysfunction CMD and vasospasm of the epicardial arteries are the two most common causes of ANOCA
A meta-analysis of the total prevalence of different phenotypes of ANOCA in 6500 patients reported that CMD alone occurred in 23 of patients coronary spasm epicardial or microvascular alone in 19 and CMD and coronary spasm together occurred in 23 of patients This study also reported that women were 145 times more likely to have CMD than men indicating that ANOCA symptoms present differently due to sex Recognition of sex differences accentuates the need for sex-specific research Unfortunately women remain underrepresented in clinical trials of common diseases like acute coronary syndrome ACS coronary artery disease CAD and heart failure
CMD is defined as epicardial andor microvascular endothelial andor non-endothelial dysfunction that limits myocardial perfusion most often detected as reduced coronary flow reserve CFR CFR which is calculated as the ratio of hyperemic to resting absolute myocardial blood flow indicates the myocardium39s ability to increase flow in response to stress or vasodilation Because the coronary microcirculation is beyond the resolution of invasive or non-invasive coronary angiography direct interrogation of coronary microvascular function is necessary to establish the diagnosis of CMD
Positron Emission Tomography PET studies have shown that even in visually normal PET Myocardial Perfusion Imaging impaired CFR adds essential prognostic value In addition abnormalities in the microcirculation could explain inducible myocardial ischemia beyond the effects of epicardial coronary obstruction and identify individuals with a high risk of MACE In patients with very low CFR gt16 women showed a higher frequency of non-obstructive CAD whereas men showed a higher frequency of severely obstructive CAD P0002 A differential effect on outcomes between women and men is noted in individuals with very low CFR CFR gt16 hazard estimated from the linear interaction of CFR and sex in the final model model P lt 0001 interaction P004 High-resolution CMR stress perfusion imaging can quantify CFR both globally and between the endocardium and epicardium A multicenter study of 1049 patients with suspected and known CAD showed that lower myocardial stress myocardial blood flow MBF and CFR by CMR perfusion mapping were associated with death and MACE independent of other clinical risk factors even in patients who had normal qualitative perfusion and no known obstructive CAD Recently developed in-line automated CMR myocardial perfusion mapping has been shown to be reproducible and comparable with PET and can be easily combined into clinical workflows Normal CFR ranges values in this study are comparable to prior studies by other techniques that have ranged from 2703 to 4210 A prior study has shown an CFR threshold of 219 with excellent specificity for detecting CMD with a sensitivity of 95 95 CI 83 to 99 specificity of 72 95 CI 52 to 87 accuracy of 85 95 CI 75 to 92 positive predictive value of 82 95 CI 72 to 89 and negative predictive value of 91 95 CI 72 to 98
The potential mechanisms of CMD appear to be heterogeneous The novel link between Inflammation and coronary vasomotion abnormalities is further supported by the findings that coronary vasoconstriction in response to acetylcholine ACh in patients with early CAD was greater in coronary artery segments with than without macrophage infiltration and vasa vasorum proliferation in an additive manner indicating an important role of inflammation and vasa vasorum proliferation in the pathogenesis of CAD Moreover significant associations among endothelium-independent CMD many inflammatory biomarkers and cardiac diastolic dysfunction were noted in women with angina but no flow-limiting coronary artery stenosis further supporting the role of systemic Inflammation in both CMD and HFpEF as well as providing insights into potential mechanisms underlying the pathophysiology of HFpEF
Although small trials have suggested benefits from angiotensin-converting enzyme ACE inhibitors aspirin and statins there is a lack of appropriately designed clinical outcome trials to inform evidence based therapeutic based on mechanism strategies Sodium-glucose co-transporter 2 inhibitors SGLT2i a new class of drug approved for the treatment of diabetes have been shown to have a significant impact on cardiovascular events Recent clinical trials have demonstrated that SGLT2i reduces MACE prevents heart failure HF hospitalizations Many of these findings were unanticipated and have stimulated substantial mechanistic research to improve the understanding of this class of drug New recommendations suggest using SGLT2i in symptomatic patients with chronic HF to reduce hospitalization and cardiovascular mortality regardless of type 2 diabetes The exact underlying mechanisms underlying these effects however remain largely unknown
In preclinical models of myocardial infarction Dapagliflozin has demonstrated attenuation of cardiac fibrosis and improved cardiac function and remodeling Furthermore empagliflozin has been shown to improve coronary microvascular function and increase cardiac output in mice as evidenced by increased coronary blood flow and fractional ventricular area change as demonstrated by ultrasound imaging Preclinical data has proposed a variety of mechanisms by which SGLT2is can potentially attenuate microvascular and endothelial dysfunction including nitric oxide production oxidative stress Inflammation mitochondrial function cell viability adverse vasoactive paracrine factors from adipose tissue among others In vivo studies have documented that SGLT2 inhibitors attenuate endothelial dysfunction by suppressing Inflammation Steven et al reported a reduction in the expression of inflammatory molecules such as interferon- γ cyclooxygenase-2 and inducible NO synthase after SGLT2 inhibition In a similar manner Dapagliflozin is also reported to reduce several circulating inflammatory markers Additionally in vitro studies have reported suppression of TNF α Previous studies showed that SGLT2 inhibition reduced circulating levels of C-C motif chemokine 2 CCL2 IL-6 and Tumor Necrosis Factor TNFα in ApoEdeficient mice However the impact of SGLT2 inhibition on systemic markers of Inflammation has not been assessed in humans
SIGNIFICANCE AND IMPACT Women39s ischemic heart disease IHD differs from men39s and women have a unique phenotype of less calcified lesions and more non-obstructive disease A significant number of patients with symptoms do not have obstructive coronary artery stenosis This condition is termed ANOCA Patients with ANOCA have a high symptom burden and reduced quality of life Patients with ANOCA report frequent time missed from work and work limitations suggesting a substantial economic impact as reported by the group at UVA One proposed mechanism contributing to ANOCA is CMD There is an increasing recognition that CMD is more prevalent in women There are no randomized controlled outcome trials testing treatment strategies tailored to different pathways that have not been performed therefore the proposed studies are consistent with an unmet urgent need for new novel therapies to target the microcirculation specifically in women with suspected or confirmed ischemic heart disease especially when young who have less atherosclerosis than men and less prevalence of obstructive CAD Measuring myocardial blood flow quantitatively with stress CMR is a particular expertise of the Cardiovascular Imaging Center at the University of Virginia UVA and our research group
SGLT2i are a class of drugs approved for treating diabetes However they have been shown to benefit cardiovascular events significantly Many of these findings were unanticipated and have stimulated substantial mechanistic research to improve the understanding of this class However recent studies show that possible mechanisms of cardiovascular benefit are unlikely to be related to improved glycemic control These benefits included reduced systemic inflammation Therefore in this proposal the impact of SGLT2i on systemic Inflammation and how it improve coronary microvascular function seen in animal models will be studied
INNOVATION This study will focus on a novel study population and a novel therapy Women under investigation for myocardial ischemia are more likely to have non-obstructive CAD and here CMD is relevant Targeting symptomatic women with ischemia and non obstructive CAD is clearly an urgent need This group of patients with a disabling problem also incurs healthcare costs similar to many with obstructive CAD CMD has historically been under-recognized and under-treated Accordingly in recent years CMD has generated substantial interest in the clinical and basic science research community
Innovative diagnostic method Traditionally the non-invasive diagnosis of CMD has been dominated by PET imaging Quantitative high-resolution CMR to quantify coronary myocardial blood flow and myocardial resistance are being developed to diagnose CMD and add a novel additional component to our project and will allow us to explore a potential clinical indication to monitor possible therapies for CMD
Innovative treatment option At present the management strategy for patients with ANOCA and CMD remains unclear due to the absence of randomized trials comparing therapies to reduce adverse cardiac events and available data are limited to cohort studies There are no therapeutic options specifically to treat CMD Our study will test whether SGLT2i therapy improves coronary blood flow and quality of life in women with ANOCA Results will also contribute to understanding this novel drug class39s mechanistic effect in microvascular disease and other major disease states such as insulin resistance
PRELIMINARY STUDIES High-resolution stress CMR value in the assessment of IHD The study team has shown that high-resolution myocardial perfusion imaging with whole-heart coverage has a good diagnostic performance with a sensitivity of 84 95 confidence interval CI 060-096 specificity of 818 95 CI 059-094 and accuracy of 82 067-092 in identifying obstructive CAD These data were presented at the Society for Cardiovascular Magnetic Resonance 25th Annual Scientific Sessions in 2022 CMR perfusion imaging in subjects with risk factors for CMD with non-obstructive CAD The study team has previously demonstrated that myocardial blood flow measured by fully quantitative CMR perfusion imaging is reduced in subjects with risk factors for CMD with non-obstructive CAD compared to healthy controls In patients with risk factors for CMD both CFR 221 195269 vs 293 276319 p lt 0001 and stress myocardial perfusion 265 062 mlming vs 317 049 mlming p lt 0002 were reduced as compared to controls
The site is conducting a feasibility study where prospective patients with ANOCA NCT05762952 are recruited Preliminary data demonstrates a trend towards improving CFR after therapy reduction of epicardial fat tissue and decreased inflammatory markers Furthermore it has been established that a macrophage generation protocol from PBMCs from the baseline visit of the first three patients Morphologically there are clear differences in size between the MCSF stimulated and unstimulated macrophages Likewise the site has conducted enzyme-linked immunoassays ELISAs on secreted TNF- and IL-1β from these macrophages after additional stimulation with LPS and ATP and demonstrated that stimulated macrophages secrete much greater quantities of TNF-α and IL-1β Figure 3B-C
OVERALL STUDY DESIGN This single-center randomized double-blind placebo-controlled study is designed to evaluate coronary flow reserve and quality of life after therapy with SGLT2i compared to placebo in symptomatic women with non-obstructive CAD ANOCA and CMD Recruited women n150 total will be clinically stable with angina or equivalent symptoms with no evidence of obstructive epicardial CAD stenosis gt 50 by invasive catheterization or coronary computed tomography angiography CCTA or FFRCT-FFR gt 08 within the previous two years and CMD diagnosis defined by CFR amplt2 by CMR They will meet the appropriate inclusion and exclusion criteria detailed in Table 1 The study population will include patients both with and without type 2 diabetes as the benefits of SGLT2i appear to be independent of the glycemic effect Figure 4 Overall study design Study participants will receive background standard of care with 75 receiving SGLT2i and 75 receiving placebo treatment for 12 weeks Participants will undergo two stress CMR studies including baseline 12 weeks post-treatment and three blood draws at baseline at six and 12 weeks post-SGLT2i treatment All 150 participants will undergo questionnaires to measure quality of life using the following questionnaires Risk factors of Cardiovascular Disease in Women EQ-5D-3L Duke Activity Status Inventory Modified Morisky Medicine Scale Seattle Angina Questionnaires Rose dyspnea score GAD 7 and PHQ8 metrics at baseline 6 weeks and at 12 weeks post-treatment
After eligibility screening informed consent and randomization procedures by the study team participants will follow up at 6 and 12 weeks and other testing as described later in the protocol
A meta-analysis of the total prevalence of different phenotypes of ANOCA in 6500 patients reported that CMD alone occurred in 23 of patients coronary spasm epicardial or microvascular alone in 19 and CMD and coronary spasm together occurred in 23 of patients This study also reported that women were 145 times more likely to have CMD than men indicating that ANOCA symptoms present differently due to sex Recognition of sex differences accentuates the need for sex-specific research Unfortunately women remain underrepresented in clinical trials of common diseases like acute coronary syndrome ACS coronary artery disease CAD and heart failure
CMD is defined as epicardial andor microvascular endothelial andor non-endothelial dysfunction that limits myocardial perfusion most often detected as reduced coronary flow reserve CFR CFR which is calculated as the ratio of hyperemic to resting absolute myocardial blood flow indicates the myocardium39s ability to increase flow in response to stress or vasodilation Because the coronary microcirculation is beyond the resolution of invasive or non-invasive coronary angiography direct interrogation of coronary microvascular function is necessary to establish the diagnosis of CMD
Positron Emission Tomography PET studies have shown that even in visually normal PET Myocardial Perfusion Imaging impaired CFR adds essential prognostic value In addition abnormalities in the microcirculation could explain inducible myocardial ischemia beyond the effects of epicardial coronary obstruction and identify individuals with a high risk of MACE In patients with very low CFR gt16 women showed a higher frequency of non-obstructive CAD whereas men showed a higher frequency of severely obstructive CAD P0002 A differential effect on outcomes between women and men is noted in individuals with very low CFR CFR gt16 hazard estimated from the linear interaction of CFR and sex in the final model model P lt 0001 interaction P004 High-resolution CMR stress perfusion imaging can quantify CFR both globally and between the endocardium and epicardium A multicenter study of 1049 patients with suspected and known CAD showed that lower myocardial stress myocardial blood flow MBF and CFR by CMR perfusion mapping were associated with death and MACE independent of other clinical risk factors even in patients who had normal qualitative perfusion and no known obstructive CAD Recently developed in-line automated CMR myocardial perfusion mapping has been shown to be reproducible and comparable with PET and can be easily combined into clinical workflows Normal CFR ranges values in this study are comparable to prior studies by other techniques that have ranged from 2703 to 4210 A prior study has shown an CFR threshold of 219 with excellent specificity for detecting CMD with a sensitivity of 95 95 CI 83 to 99 specificity of 72 95 CI 52 to 87 accuracy of 85 95 CI 75 to 92 positive predictive value of 82 95 CI 72 to 89 and negative predictive value of 91 95 CI 72 to 98
The potential mechanisms of CMD appear to be heterogeneous The novel link between Inflammation and coronary vasomotion abnormalities is further supported by the findings that coronary vasoconstriction in response to acetylcholine ACh in patients with early CAD was greater in coronary artery segments with than without macrophage infiltration and vasa vasorum proliferation in an additive manner indicating an important role of inflammation and vasa vasorum proliferation in the pathogenesis of CAD Moreover significant associations among endothelium-independent CMD many inflammatory biomarkers and cardiac diastolic dysfunction were noted in women with angina but no flow-limiting coronary artery stenosis further supporting the role of systemic Inflammation in both CMD and HFpEF as well as providing insights into potential mechanisms underlying the pathophysiology of HFpEF
Although small trials have suggested benefits from angiotensin-converting enzyme ACE inhibitors aspirin and statins there is a lack of appropriately designed clinical outcome trials to inform evidence based therapeutic based on mechanism strategies Sodium-glucose co-transporter 2 inhibitors SGLT2i a new class of drug approved for the treatment of diabetes have been shown to have a significant impact on cardiovascular events Recent clinical trials have demonstrated that SGLT2i reduces MACE prevents heart failure HF hospitalizations Many of these findings were unanticipated and have stimulated substantial mechanistic research to improve the understanding of this class of drug New recommendations suggest using SGLT2i in symptomatic patients with chronic HF to reduce hospitalization and cardiovascular mortality regardless of type 2 diabetes The exact underlying mechanisms underlying these effects however remain largely unknown
In preclinical models of myocardial infarction Dapagliflozin has demonstrated attenuation of cardiac fibrosis and improved cardiac function and remodeling Furthermore empagliflozin has been shown to improve coronary microvascular function and increase cardiac output in mice as evidenced by increased coronary blood flow and fractional ventricular area change as demonstrated by ultrasound imaging Preclinical data has proposed a variety of mechanisms by which SGLT2is can potentially attenuate microvascular and endothelial dysfunction including nitric oxide production oxidative stress Inflammation mitochondrial function cell viability adverse vasoactive paracrine factors from adipose tissue among others In vivo studies have documented that SGLT2 inhibitors attenuate endothelial dysfunction by suppressing Inflammation Steven et al reported a reduction in the expression of inflammatory molecules such as interferon- γ cyclooxygenase-2 and inducible NO synthase after SGLT2 inhibition In a similar manner Dapagliflozin is also reported to reduce several circulating inflammatory markers Additionally in vitro studies have reported suppression of TNF α Previous studies showed that SGLT2 inhibition reduced circulating levels of C-C motif chemokine 2 CCL2 IL-6 and Tumor Necrosis Factor TNFα in ApoEdeficient mice However the impact of SGLT2 inhibition on systemic markers of Inflammation has not been assessed in humans
SIGNIFICANCE AND IMPACT Women39s ischemic heart disease IHD differs from men39s and women have a unique phenotype of less calcified lesions and more non-obstructive disease A significant number of patients with symptoms do not have obstructive coronary artery stenosis This condition is termed ANOCA Patients with ANOCA have a high symptom burden and reduced quality of life Patients with ANOCA report frequent time missed from work and work limitations suggesting a substantial economic impact as reported by the group at UVA One proposed mechanism contributing to ANOCA is CMD There is an increasing recognition that CMD is more prevalent in women There are no randomized controlled outcome trials testing treatment strategies tailored to different pathways that have not been performed therefore the proposed studies are consistent with an unmet urgent need for new novel therapies to target the microcirculation specifically in women with suspected or confirmed ischemic heart disease especially when young who have less atherosclerosis than men and less prevalence of obstructive CAD Measuring myocardial blood flow quantitatively with stress CMR is a particular expertise of the Cardiovascular Imaging Center at the University of Virginia UVA and our research group
SGLT2i are a class of drugs approved for treating diabetes However they have been shown to benefit cardiovascular events significantly Many of these findings were unanticipated and have stimulated substantial mechanistic research to improve the understanding of this class However recent studies show that possible mechanisms of cardiovascular benefit are unlikely to be related to improved glycemic control These benefits included reduced systemic inflammation Therefore in this proposal the impact of SGLT2i on systemic Inflammation and how it improve coronary microvascular function seen in animal models will be studied
INNOVATION This study will focus on a novel study population and a novel therapy Women under investigation for myocardial ischemia are more likely to have non-obstructive CAD and here CMD is relevant Targeting symptomatic women with ischemia and non obstructive CAD is clearly an urgent need This group of patients with a disabling problem also incurs healthcare costs similar to many with obstructive CAD CMD has historically been under-recognized and under-treated Accordingly in recent years CMD has generated substantial interest in the clinical and basic science research community
Innovative diagnostic method Traditionally the non-invasive diagnosis of CMD has been dominated by PET imaging Quantitative high-resolution CMR to quantify coronary myocardial blood flow and myocardial resistance are being developed to diagnose CMD and add a novel additional component to our project and will allow us to explore a potential clinical indication to monitor possible therapies for CMD
Innovative treatment option At present the management strategy for patients with ANOCA and CMD remains unclear due to the absence of randomized trials comparing therapies to reduce adverse cardiac events and available data are limited to cohort studies There are no therapeutic options specifically to treat CMD Our study will test whether SGLT2i therapy improves coronary blood flow and quality of life in women with ANOCA Results will also contribute to understanding this novel drug class39s mechanistic effect in microvascular disease and other major disease states such as insulin resistance
PRELIMINARY STUDIES High-resolution stress CMR value in the assessment of IHD The study team has shown that high-resolution myocardial perfusion imaging with whole-heart coverage has a good diagnostic performance with a sensitivity of 84 95 confidence interval CI 060-096 specificity of 818 95 CI 059-094 and accuracy of 82 067-092 in identifying obstructive CAD These data were presented at the Society for Cardiovascular Magnetic Resonance 25th Annual Scientific Sessions in 2022 CMR perfusion imaging in subjects with risk factors for CMD with non-obstructive CAD The study team has previously demonstrated that myocardial blood flow measured by fully quantitative CMR perfusion imaging is reduced in subjects with risk factors for CMD with non-obstructive CAD compared to healthy controls In patients with risk factors for CMD both CFR 221 195269 vs 293 276319 p lt 0001 and stress myocardial perfusion 265 062 mlming vs 317 049 mlming p lt 0002 were reduced as compared to controls
The site is conducting a feasibility study where prospective patients with ANOCA NCT05762952 are recruited Preliminary data demonstrates a trend towards improving CFR after therapy reduction of epicardial fat tissue and decreased inflammatory markers Furthermore it has been established that a macrophage generation protocol from PBMCs from the baseline visit of the first three patients Morphologically there are clear differences in size between the MCSF stimulated and unstimulated macrophages Likewise the site has conducted enzyme-linked immunoassays ELISAs on secreted TNF- and IL-1β from these macrophages after additional stimulation with LPS and ATP and demonstrated that stimulated macrophages secrete much greater quantities of TNF-α and IL-1β Figure 3B-C
OVERALL STUDY DESIGN This single-center randomized double-blind placebo-controlled study is designed to evaluate coronary flow reserve and quality of life after therapy with SGLT2i compared to placebo in symptomatic women with non-obstructive CAD ANOCA and CMD Recruited women n150 total will be clinically stable with angina or equivalent symptoms with no evidence of obstructive epicardial CAD stenosis gt 50 by invasive catheterization or coronary computed tomography angiography CCTA or FFRCT-FFR gt 08 within the previous two years and CMD diagnosis defined by CFR amplt2 by CMR They will meet the appropriate inclusion and exclusion criteria detailed in Table 1 The study population will include patients both with and without type 2 diabetes as the benefits of SGLT2i appear to be independent of the glycemic effect Figure 4 Overall study design Study participants will receive background standard of care with 75 receiving SGLT2i and 75 receiving placebo treatment for 12 weeks Participants will undergo two stress CMR studies including baseline 12 weeks post-treatment and three blood draws at baseline at six and 12 weeks post-SGLT2i treatment All 150 participants will undergo questionnaires to measure quality of life using the following questionnaires Risk factors of Cardiovascular Disease in Women EQ-5D-3L Duke Activity Status Inventory Modified Morisky Medicine Scale Seattle Angina Questionnaires Rose dyspnea score GAD 7 and PHQ8 metrics at baseline 6 weeks and at 12 weeks post-treatment
After eligibility screening informed consent and randomization procedures by the study team participants will follow up at 6 and 12 weeks and other testing as described later in the protocol
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None