Clinical trial NCT04342819
Conditions: Platelet Dysfunction Due to Drugs
Sponsor: The University of The West Indies
Start date: 2020-01-01; Completion date: 2021-12-31
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The mechanistic effects of empagliflozin on platelet function profiles have not yet been ascertained.

Detailed description:
Sodium GLucose Transport 2 inhibitors (SGLT2I), including empagliflozin, reduce the likelihood of hospitalization for heart failure and death in persons with type 2 diabetes, of which the mechanism has not been fully elucidated. The mechanistic effects of empagliflozin on platelet function profiles have not yet been ascertained. It remains unclear if this reduction in cardiovascular death is mediated by decreased platelet reactivity.

Arms: arm 1: Empagliflozin 25 mg per oral once daily
Interventions: intervention 1: SGLT2 inhibitor
Intervention descriptions: intervention 1: Sodium-Glucose Like Transporter 2 Inhibitor

Protocol documents:
Prot_SAP_001.pdf: 
 
 
The Effect of Empagliflozin on Platelet Function Profiles in Patients with Stable Coronary 
Artery Disease in Trinidad: The EFFECT Pilot Study 
 
NCT: NCT04342819 
Document Date: 1 January 2020 
 
Thrombosis iN Trinidad (TNT) Investigators: 
Naveen Anand Seecheran, MBBS (MD), MSc, FACP, FACC, FESC, FAHA, FSCAI 
American Board of Internal Medicine certified Interventional Cardiologist 
Honorary Consultant and Clinical Lead of the Cardiac Care Unit, Eric Williams Medical Sciences 
Complex 
Lecturer (Above Bar) in Adult Medicine, University of the West Indies, St Augustine. 
Phone +1 (868) 753-7686 
Email nseecheran@gmail.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Rationale and Background: 
 
Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel represents the standard of care 
for the prevention of recurrent ischemic events in patients undergoing percutaneous coronary 
intervention (PCI). For more than 20 years, dual antiplatelet therapy with aspirin and 
Clopidogrel has remained the cornerstone of treatment for patients with acute coronary 
syndrome (ACS). However, some patients have impaired clopidogrel response and thus persist 
with high on-treatment platelet reactivity (HPR) resulting in an increased risk of 
atherothrombotic events. The boxed warning added to the clopidogrel label underscoring the 
potential risk of adverse cardiovascular outcomes among patients with a “poor metabolizer” 
genotype and advocating the use of other antiplatelet medications or alternative dosing 
strategies for these patients has led to investigations of treatment options associated with 
more optimal platelet inhibition. These include switching to a novel generation P2Y12 inhibitor 
(e.g. prasugrel or ticagrelor).    
 
Sodium-glucose transport 2 inhibitors (SGLT2i) such as empagliflozin have been found to reduce 
the risk of hospitalization for heart failure and death in individuals with type 2 diabetes, 
although the exact mechanism behind this effect is not yet fully understood. It is also uncertain 
whether empagliflozin's impact on platelet function plays a role in its ability to decrease 
cardiovascular mortality. SGLT2i therapies have become increasingly important for T2DM 
patients, as evidenced by major clinical trials like EMPA-REG OUTCOME and DAPA-HF, which 
have shown a significant reduction in major adverse cardiovascular events (MACE). The exact 
mechanisms responsible for these positive cardiovascular outcomes are still being investigated. 
It is currently unknown whether SGLT2 inhibition has an antiplatelet effect. However, a pilot 
study has shown that empagliflozin does have a greater antiplatelet effect than traditional 
treatments for T2DM patients with coronary artery disease (CAD). This study is important for its 
potential to improve both efficacy and safety in the treatment of T2DM. 
 
 
Hypothesis: 
1. Empagliflozin attenuates platelet reactivity in patients with diabetes mellitus. 
2. Empagliflozin decreases platelet reactivity by 10%. 
 
Null Hypothesis: 
There is no difference in response in patients with stable coronary artery disease on DAPT 
concerning PRUs on Empagliflozin. 
 
Study Goals and Objectives: 
1.      To describe platelet function profiles of patients with stable coronary artery disease on 
DAPT on Empagliflozin. 
  
Study Design: 


 
 
 
The study will be a prospective, open-label study that aims to assess the effect of empagliflozin 
25 mg once daily for 10 days. Patients at the Eric Williams Medical Sciences Complex (EWMSC), 
Mt. Hope, Trinidad and Tobago will be screened for potential eligibility.  
 
 
Methodology: 
Inclusion criteria 
Patients will be screened and considered eligible for the study if they are: 
1.      between 18 and 74 years of age, 
2.      have stable coronary artery disease and diabetes mellitus, already on DAPT with aspirin 
and clopidogrel for at least 6 months, 
3.      not on any physician-prescribed medications or complementary/alternative therapies, 
  
Exclusion criteria 
Patients are ineligible to participate if any of the following criteria are met: 
1.      presence of active internal bleeding or history of bleeding diathesis or clinical findings 
associated with an increased risk of bleeding, 
2.      history of ischemic or hemorrhagic stroke, transient ischemic attack, intracranial 
neoplasm, arteriovenous malformation, or aneurysm, 
3.      history of clinical and/or hemodynamic instability, 
4.      within 1 month of placement of a bare metal stent, 
5.      within 30 days of coronary artery bypass graft surgery or PCI without a stent placed, 
6.      planned coronary revascularization, 
7.      treatment with fibrin-specific fibrinolytic therapy <24 h or non-fibrin-specific fibrinolytic 
therapy <48 h, 
8.      use of an oral anticoagulation agent or international normalized ratio >1.5, 
9.      body weight <60 kg, 
10.  age >75 years, 
11.  hemoglobin <10 g/dL, 
12.  platelet count <100×106/μL, 
13.  creatinine >2 mg/dL, 
14.  hepatic enzymes >2.5 times the upper limit of normal, 
15.  pregnancy and/or lactation. 
 
The study will undergo a formal approval process by the Campus Ethics Committee (CEC) of the 
University of the West Indies (UWI) and all patients are to provide written informed consent 
before participating in the study. The trial will be conducted by the Declaration of Helsinki and 
the International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice 
(GCP). Two clinical research associates (CRAs) will secure and assess the quality of the data and 
the university biostatistician will perform the data analysis after data lock. The CRAs will then 
deliver the database and the analysis results to the principal investigator (PI). Data will be 
coded per patient by first letter of first name, first letter of last name followed by numerical 
date of birth in the order of day, month, and year in a password-protected and encrypted 


 
 
database program in the office of Lecturer Dr. Naveen Seecheran at the Department of Clinical 
Medicine office, 2nd Floor, Building 34, Eric Williams Medical Sciences Complex. 
  
Patient Interview and Case Report Form 
If a patient satisfies the selection criteria from the initial screening process, a physician or CRA-
directed interview will then be administered. Demographic and anthropometric data will be 
recorded on a case report form (CRF). This will comprise the patient’s medical and procedural 
history including any active medications. 
 
Each patient will then be allocated via a computerized randomization program. Patients on 
DAPT for at least 6 months will be tested for platelet function testing with the P2Y12 VerifyNow 
assay at baseline. The patient will be administered empagliflozin 25 mg once daily for 10 days, 
followed thereafter by platelet function testing. The study will be randomized via a computer 
randomization program with a permuted block design and concealment allocation. It is also a 
controlled, prospective trial design, as group A serves to act as a baseline comparator group 
and group B has the desired antiplatelet strategy to be investigated over the longitudinal 2-
week period. The study will also be blinded as patients will be unaware of their treatment 
assignments as well as the CRA or physician (Interventional Cardiologist) that performs the 
platelet function testing. 
  
Blood Sampling, Phlebotomy 
Blood samples for platelet function testing will be collected at baseline before the patients are 
administered empagliflozin (baseline sample). Blood will be drawn via an antecubital vein using 
a 21-gauge needle. The initial 5 mL of all blood samples will be discarded as medical waste as 
per the institution's policy (to avoid spontaneous platelet activation). Several laboratory tests 
will be performed including: 
1.      Complete Blood Count 
2.      Renal Function Profile 
3.      Hepatic Function Profile 
4.      VerifyNow P2Y12 PRU test assay - which will also be performed at the 2nd-week time point 
after patients have completed their assigned treatment schedules.  
Overall, there will be 2 separate instances in which blood sampling/phlebotomy will be 
performed. 
  
Aggregation Testing, Platelet Function Testing 
Citrated blood samples are processed by CRAs and study investigators. The platelet function 
assay to be utilized is the VerifyNow P2Y12 (VN-P2Y12) assay (Accriva, San Diego, California). In 
brief, the VN-P2Y12 assay is a rapid whole blood point-of-care device that reports results as 
P2Y12 reaction units (PRU) and percent inhibition of platelet aggregation (%IPA). Assays will be 
performed as per the instructions of the manufacturer previously described. Please see 
attached: 
●  
http://www.accriva.com/uploads/assets/clsi-procedures/14983-revf.docx 
●  
http://www.accriva.com/uploads/assets/clsi-procedures/14982-revk.doc 
 


 
 
Safety Considerations: 
Overall, patient risk would be considered minimal.  
 
The risks of phlebotomy coupled with treatment and management are:  
1. Arteriospasm, Hematoma – sterile compression bandage will be done to achieve 
hemostasis monitoring of vital signs digital pulse oximetry to ensure perfusion of 
tissues, blood transfusions, Vascular Surgeon consultation for brachial artery repair, 
and/or luminal dilatation. 
2. Nerve damage/injury- Orthopaedic management of possible injury to median nerve, 
evaluation, and follow-up in the clinic, and possible anti-inflammatory medications for 
nerve inflammation. 
3. Infection- Debridement, microscopy, culture, and sensitivity as well as initiating 
empirical broad-spectrum antibiotics, and monitoring for signs of sepsis. If febrile or 
septic shock admission to hospital and commencement of intravenous fluids, 
intravenous antibiotics with possible ICU intervention.  
4. Low risk: Phlebotomy: Vascular spasm, hematoma, local infection, Medium Risk  
Phlebotomy: nerve damage/injury (unlikely), Empagliflozin: urinary tract infections, 
fungal infections, (rare-occasional, usually not life-threatening), Serious Risk 
Phlebotomy: hand surgery (exceedingly rare), Empagliflozin: diabetic ketoacidosis, 
Fournier's gangrene, and hypoglycemia (very rare). 
 
The study will be by the summary of risks and risk-reduction strategies outlined in Table 8 in the 
WHO Guidelines on Drawing Blood: Best Practices in Phlebotomy. Any serious adverse events 
(SAEs) will be recorded as per the Bleeding Academic Research Consortium (BARC) group 
definitions and reported to the Ethics Committee of the University of the West Indies within 24 
hours. The patient will receive health care per the participating institution’s guidelines and 
policies i.e. Cardiology Department at EWMSC, Mt. Hope, Trinidad & Tobago. 
  
Follow-up: 
Patients will be informed of their results in person, or if unavailable via telephone. They will 
also be provided with a hard-copy report of their platelet function profiles. They will also be 
informed on a scheduled basis of the management plan for any serious adverse events (SAEs) 
that may have unfortunately occurred as a result of their direct participation in the study. 
 
Data Management and Statistical Analysis: 
The patient information will be initially recorded on CRFs which will be stored in the Adult 
Medicine Unit locking file cabinets, located at the Department of Clinical Medical Sciences, 
University of the West Indies, St. Augustine. Data will be coded per patient by first letter of first 
name, first letter of last name followed by numerical date of birth in the order of day, month, 
and year in a password-protected and encrypted database program in the office of Lecturer Dr. 
Naveen Seecheran at the Department of Clinical Medicine office, 2nd Floor, Building 34, Eric 
Williams Medical Sciences Complex. Each CRF and study database will be reviewed by 2 CRAs to 
minimize error, and clean and reconcile any conflicting data. We will aim for n of least 16 
patient profiles, see sample size calculations. Any missing information will be censored and 


 
 
thus, not imputed. The study biostatistician will perform routine statistical analyses with SPSS v. 
11.0 software (SPSS, Chicago, IL). Continuous variables are expressed as means ± SD. 
Categorical variables are to be expressed as frequencies and percentages. Student’s t-test will 
be used to compare continuous variables. Comparisons between categorical variables will be 
performed using the two-tailed Fisher’s exact test or Pearson’s χ2 test, as appropriate.  A p-
value of < 0.05 will be considered statistically significant. No adjustments for multiple 
comparisons will be made. Results will be reported as least-square mean ± SEM for the detailed 
analyses. 
 
Sample Size Calculation: 
Assuming: 
1.     A 75 mg/d clopidogrel maintenance dose required at least 5 days and a 600 mg loading 
dose of clopidogrel required up to 8 hours to achieve ~50% steady state of inhibition of ADP-
induced platelet aggregation. 
2.      An estimated decrease of 10%, thus achieving a steady state inhibition of ADP-induced 
aggregation of 55% in patients with empagliflozin. 
3.      Type 1 error rate 5% 
4.      Statistical power of 80% 
         n = 20 
(http://hedwig.mgh.harvard.edu/sample_size/js/js_parallel_quant.html) 
  
Quality Assurance: 
The study will be by GCP and the Declaration of Helsinki. In addition, it will only commence 
after official approval from the Ethics Committee of the University of the West Indies. There will 
be no Data Safety and Monitoring Board (DSMB). Patient Informed Consent Forms (ICFs) and 
Case Report Forms (CRFs) will each be quality-controlled by 2 CRAs and recorded in triplicate (1 
for patient records, 2 for the study team). 
  
Expected Outcomes of the Study: 
The information obtained from the study would be integral in developing antiplatelet strategies 
for patients with impaired platelet reactivity. It will advance knowledge in the field i.e. useful 
for baseline information and hypothesis generation for further studies within the scientific 
community. It will also determine if empagliflozin is an adjunct for non-response to the current 
armamentarium of antiplatelet therapies available in Trinidad and Tobago. This information can 
then reliably inform regulatory bodies e.g. Ministry of Health (MOH) to make additions to the 
national Chronic Disease Assistance Medication Program (CDAP) to include this as a possible 
adjunct to facilitate a more potent antiplatelet effect. 
  
Dissemination of Results and Publication Policy: 
The patients will be informed of their results in person, or if unavailable via telephone. They will 
also be provided with a hard-copy report of their platelet function profiles. The results and 
conclusion of the study will be published for the scientific community for further analysis and 
discussion. The aforementioned study team, including collaborators, will be acknowledged in 


 
 
any publications. The principal investigator (PI) will determine the order of author 
contributorship. 
  
Duration of the Project: 
Please see the Project Management and Gantt Table below. The estimated duration for the 
study is approximately 2 years. 
  
 Problems Anticipated: 
1.      Financial: The resources (see outlined budget below) required for the study are relatively 
expensive and thus, would require funding to ensure successful completion. 
  
Project Management: 
  
ICF 
CRF 
Sample 
Collection 
VN POC 
Analysis 
Database 
Entry 
Statistical 
Analysis 
Manuscript 
Preparation 
Timeline/month
s 
20m 20m 
20m 
20m 
2m 
2m 
2m 
CRA 1 
X 
X 
X 
X 
X 
  
  
CRA 2 
X 
X 
X 
X 
X 
  
  
Bio-Statistician 
  
  
  
  
  
X 
  
NS 
  
  
  
  
  
X 
X 
  
 Ethics: 
The final version of the protocol will be submitted to the Ethics Committee of the University of 
the West Indies, located at the University of the West Indies, St. Augustine, Trinidad and 
Tobago. The study team will await official approval before any study-related activities can 
commence. There are no significant ethical concerns about conducting the study. All patient 
samples (blood) that are surplus to requirements will be discarded as per the participating 
institution’s medical waste protocol. The study will be stringently conducted by the Declaration 
of Helsinki. 
  
Informed Consent Forms: 
Please see the attached Ethics Committee of the University of the West Indies file for the final 
version of ICF. ICFs will be physician or CRA-administered and available only in English. They will 
undergo an approval process by the Ethics Committee of the University of the West Indies 
before the study can commence. Each ICF will be done in triplicate (1 for patient records and 2 
for the study team). The ICF will comprise the important aspects that are per the international 
guidelines outlined in the references. 
  
Budget: 


 
 
Item 
Quantity 
Purpose/Justification 
Total/USD 
VerifyNow ASA and 
P2Y12 PRU Test Kits 
2 
Test Kits for collected 
blood samples 
~21,000 TTD 
Maintenance 
N/A 
Analyzer needs to be 
maintained as per 
Company’s policy 
(located in US - 
shipping, handling & 
insurance) 
~0 TTD 
Stationery 
25 
25 Informed Consent 
Forms & Case Report 
Forms (Triplicate) 
~0 TTD 
Total 
  
  
~$2,000 USD 
  
Other support for the Project: 
The study will be financed via grant support from the University of the West Indies, St. 
Augustine. Applications to other sources of funding will be submitted to the respective 
agencies. 
 
Financing and Insurance: 
The study will be financed via grant support from the University of the West Indies, St. 
Augustine. No specific insurance coverage will be provided to the study participants; however, 
they will receive health care per the participating institution’s guidelines and policies i.e. the 
Cardiology Department at the EWMSC, Mt. Hope, Trinidad & Tobago. 
 
Collaboration with other scientists or research institutions: 
 
Dominick J. Angiolillo, MD, PhD 
Professor of Medicine 
Director, Cardiovascular Research 
Program Director, Interventional Cardiology Fellowship 
University of Florida College of Medicine-Jacksonville 
Division of Cardiology-ACC Building 5th floor 
655 West 8th Street 
Jacksonville, FL - 32209 
Tel: +1-904-244-3378 
Fax: +1-904-244-3102 
E-mail: dominick.angiolillo@jax.ufl.edu 
 
David J. Schneider, MD 


 
 
Professor of Medicine 
Director of Cardiovascular Services 
University of Vermont Health Network 
Director of the Cardiovascular Research Institute, VT 
111 Colchester Ave 
Burlington, VT - 05401 
Tel: +1-802-847-2005 
E-mail: david.schneider@uvmhealth.org 
 
Antonio Tello-Montoliu, MD, PhD 
Consultant in Cardiology 
Cardiology Department 
Hospital Clínico Universitario Virgen de la Arrixaca 
Coordinator of the Working Group of Thrombosis 
Spanish Society of Cardiology 
Member of the Working Group of Thrombosis 
European Society of Cardiology 
  
Key Words: 
●     antiplatelet drugs 
●     Clopidogrel 
●     Empagliflozin 
●     high on-treatment platelet reactivity 
●     platelet function 
  
Abbreviations and Acronyms: 
HOT-PR 
High on-treatment Platelet Reactivity 
LTA 
Light Transmission Aggregometry 
MPA 
Maximal Platelet Aggregation 
PD 
Pharmacodynamic 
PRI 
Platelet Reactivity Index 
PRU 
Platelet Reactivity Units 
VN-P2Y12 
VerifyNow P2Y12 
  
 
 
 
 
 


 
 
 
 
 
 
 
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