Clopidogrel for Silent Stroke

(ECISBI Trial)

Overseen By Calin I Prodan, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: VA Office of Research and Development

Must be taking: Antiplatelets

Must not be taking: Anticoagulants, Thrombolytics

Disqualifiers: Dementia, ESRD, Intracranial hemorrhage, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 36

Duration: 24 months

125 Participants Needed

Trial Summary

What is the purpose of this trial?

Silent brain infarctions (SBIs) are a manifestation of covert cerebrovascular disease, without obvious clinical deficit, noted very often in patients presenting with a new stroke or new transient ischemic attack. SBIs are linked to a significant increase in risk for subsequent stroke and cognitive decline. However, no biomarker is currently available that can predict the recurrence of these subclinical lesions. Coated-platelets are a measure of platelet procoagulant potential significantly increased in patients with ischemic stroke or transient ischemic attack compared to unaffected controls. Higher coated-platelet levels are strongly associated with both the presence and number of SBIs. Among medications approved for preventing stroke recurrence, we identified clopidogrel as a pharmacological agent leading to a decrease in coated-platelet levels. In this project, we plan to evaluate if clopidogrel can decrease the rate of occurrence of new silent brain infarctions. The result will enhance the investigators understanding of the relationship between platelets and silent brain infarcts, leading to improved health care delivery and also potential targets for novel preventive pharmacological interventions.

Will I have to stop taking my current medications?

The trial requires that participants are not on antiplatelet therapy at the time of admission. If you are currently taking antiplatelet medications, you may need to stop them to participate in this study.

What data supports the effectiveness of the drug clopidogrel for silent stroke?

Research shows that clopidogrel, when combined with aspirin, can reduce the risk of stroke in patients with minor strokes or transient ischemic attacks more effectively than aspirin alone, as seen in the CHANCE trial. Additionally, clopidogrel has been found to be more effective than aspirin in preventing certain heart-related events, which suggests it may also be beneficial for stroke prevention. ^{1 2 3 4 5}

Is clopidogrel safe for use in humans?

Clopidogrel is generally considered safe for use in humans, but it can increase the risk of bleeding, especially when used with aspirin. Studies suggest that using clopidogrel with aspirin may require additional measures, like taking proton pump inhibitors, to reduce the risk of gastrointestinal bleeding. ^{2 4 6 7 8}

How does the drug combination of Clopidogrel and Aspirin differ from other treatments for silent stroke?

The combination of Clopidogrel and Aspirin is unique because it offers more potent platelet inhibition compared to Aspirin alone, which may provide additional protection against stroke. This combination is being explored for its potential to prevent silent strokes, a condition for which there are no standard treatments. ^{2 4 9 10 11}

Research Team

Calin Ioan Prodan, MD

Principal Investigator

Oklahoma City VA Medical Center, Oklahoma City, OK

Eligibility Criteria

This trial is for individuals who've had a stroke or transient ischemic attack (TIA) within the last month, have initial MRI scans available, and are not on antiplatelet therapy. They must be willing to participate for two years and need secondary prevention with antiplatelet therapy as decided by their doctor. People with dementia, recent anticoagulant use, allergy to clopidogrel, certain bleeding conditions or severe kidney disease cannot join.

Inclusion Criteria

My symptoms started less than 90 days ago.

Baseline coated-platelet levels at 40%

Initial MRI available

Exclusion Criteria

Prior adverse/allergic reactions to clopidogrel

Dementia (based on chart review or self/proxy report)

Inability to tolerate consenting or phlebotomy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either clopidogrel or aspirin daily for secondary stroke prevention

24 months

Regularly scheduled outpatient visits for up to one year, followed by phone contact for an additional 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including repeat brain MRI scans to assess new silent brain infarctions

24 months

Repeat brain MRI scans at 24 months

Treatment Details

Interventions

• Aspirin
• Clopidogrel

Trial Overview The study tests if Clopidogrel can reduce new silent brain infarctions in patients at risk of strokes due to high coated-platelet levels. It compares the effectiveness of Clopidogrel against Aspirin treatment over a period of 24 months.

Participant Groups

Group I: Clopidogrel Experimental Treatment 1 Intervention

After randomization, patients will receive clopidogrel mg daily for the duration of the study. The VA Research Pharmacy will dispense similar looking pills (using a "dummy pill") with Arm 2 to ensure the double-blind nature of the intervention. Clopidogrel is FDA approved for secondary prevention of stroke. Patients will be followed for 24 months with repeat brain MRI scans obtained at 24 months.

Group II: Aspirin Experimental Treatment 1 Intervention

After randomization, patients will receive aspirin daily for the duration of the study. The VA Research Pharmacy will dispense similar looking pills (using a "dummy pill") with Arm 1 to ensure the double-blind nature of the intervention. Aspirin is FDA approved for secondary prevention of stroke. Patients will be followed for 24 months with repeat brain MRI scans obtained at 24 months.

Aspirin is already approved in European Union, United States, Canada, China for the following indications:

Approved in European Union as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in United States as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in Canada as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in China as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Findings from Research

Clopidogrel is significantly more effective than aspirin for preventing atherothrombotic events in patients with established atherosclerotic disease, as shown in the CAPRIE study.

In patients with acute coronary syndromes, clopidogrel provides substantial benefits over placebo, but adding aspirin to clopidogrel does not improve outcomes in patients with cerebrovascular disease, according to the MATCH trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clopidogrel: cardiologists' panacea or neurologists' headache? Bezerra, DC., Bogousslavky, J.[2009]

In a study of 70 patients who had recently experienced an ischemic stroke, combining clopidogrel with aspirin (C+ASA) resulted in significantly greater inhibition of platelet activity compared to aspirin alone (ASA), indicating enhanced antiplatelet protection.

The C+ASA treatment led to notable reductions in various platelet activation markers and microparticle formation, with no serious adverse events reported, suggesting it is a safe and effective option for improving platelet inhibition in stroke patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of clopidogrel and aspirin in combination versus aspirin alone on platelet activation and major receptor expression in patients after recent ischemic stroke: for the Plavix Use for Treatment of Stroke (PLUTO-Stroke) trial. Serebruany, VL., Malinin, AI., Ziai, W., et al.[2018]

In a study involving 5170 patients, the combination of clopidogrel and aspirin significantly reduced the risk of stroke over one year compared to aspirin alone, with a 10.6% stroke rate in the clopidogrel-aspirin group versus 14.0% in the aspirin group.

The combination treatment did not increase the risk of moderate or severe hemorrhage, indicating that it is a safe option for preventing strokes in high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) Trial: One-Year Outcomes. Wang, Y., Pan, Y., Zhao, X., et al.[2022]

Aspirin is an effective and safe option for preventing recurrent strokes, with low doses being as effective as higher doses but with a better safety profile.

The combination of aspirin and extended-release dipyridamole is more effective than low-dose aspirin alone, while clopidogrel may offer better efficacy than high-dose aspirin, but it requires careful monitoring due to potential genetic factors affecting its effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiplatelet therapy for prevention of recurrent stroke. Badruddin, A., Gorelick, PB.[2021]

In patients with peripheral arterial disease (PAD), clopidogrel (75 mg/day) was found to be a more effective inhibitor of ADP-induced platelet activation compared to aspirin (75 mg/day), significantly reducing platelet aggregation.

Combination therapy with clopidogrel and aspirin resulted in a greater reduction in spontaneous platelet aggregation and serotonin-induced aggregation than either drug alone, suggesting that using both medications together may enhance their effectiveness in managing platelet hyperactivity in PAD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease. Jagroop, IA., Matsagas, MI., Geroulakos, G., et al.[2018]

Clopidogrel reduced the combined risk of ischaemic stroke, myocardial infarction, or vascular death by 8.7% compared to aspirin, indicating its efficacy in preventing serious cardiovascular events in patients with symptomatic atherosclerosis.

Clopidogrel had a significantly lower incidence of gastrointestinal adverse events compared to aspirin, making it a safer option for long-term use, despite a slightly higher occurrence of mild side effects like rash and diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. CAPRIE Steering Committee and Investigators. Clopidogrel versus aspirin in patients at risk of ischaemic events. Harker, LA., Boissel, JP., Pilgrim, AJ., et al.[2023]

The study analyzed data from the FDA Adverse Event Reporting System (FAERS) and found that the combination of clopidogrel and aspirin significantly increases the risk of hemorrhagic events, with an adjusted reporting odds ratio (ROR) of 4.40, while the addition of proton pump inhibitors (PPIs) also raised the risk but to a lesser extent (ROR of 3.40).

Importantly, the concurrent use of PPIs with clopidogrel and aspirin was associated with a reduced risk of gastrointestinal (GI) hemorrhagic events, supporting their use as a protective measure, although they had little effect on the risk of embolic/thrombotic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the Interaction between Clopidogrel, Aspirin, and Proton Pump Inhibitors Using the FDA Adverse Event Reporting System Database. Suzuki, Y., Suzuki, H., Umetsu, R., et al.[2022]

Platelet inhibition by clopidogrel and aspirin is significantly lower immediately after percutaneous coronary intervention (PCI) compared to one day later, indicating a temporary decrease in their effectiveness right after the procedure.

The study, involving 30 patients, highlights the importance of timing in platelet function testing, as results can vary significantly based on when the tests are conducted, which may affect the assessment of patients' responsiveness to antiplatelet therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of antiplatelet drugs clopidogrel and aspirin is less immediately after stent implantation. Siller-Matula, JM., Haberl, K., Prillinger, K., et al.[2018]

In a study of 175 patients undergoing cerebral digital subtraction angiography (DSA), the use of acetylsalicylic acid (ASA) as antiplatelet therapy did not significantly reduce the occurrence of silent strokes, as indicated by high signal intensity lesions on diffusion-weighted MRI.

The results suggest that thromboembolisms may not be the primary cause of silent strokes during DSA, pointing towards alternative causes such as air embolism or mobilized embolic material from the catheter.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetylsalicylic acid does not prevent digital subtraction angiography-related high signal intensity lesions in diffusion-weighted imaging in cerebrovascular patients. A retrospective analysis. Brockmann, C., Seker, F., Weiss, C., et al.[2021]

In a meta-analysis of five studies involving 29,357 patients with recent ischemic stroke, clopidogrel was found to significantly reduce the risk of major cardiovascular and cerebrovascular events compared to aspirin, with a risk ratio of 0.72.

Clopidogrel also demonstrated a lower risk of bleeding events compared to aspirin (risk ratio 0.57), while there was no difference in all-cause mortality between the two treatments, suggesting clopidogrel may be a safer and more effective option for secondary prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefits and Risks of Clopidogrel vs. Aspirin Monotherapy after Recent Ischemic Stroke: A Systematic Review and Meta-Analysis. Paciaroni, M., Ince, B., Hu, B., et al.[2022]

In a study of 70 diabetic patients, combining clopidogrel with aspirin (C + ASA) significantly inhibited platelet activity compared to aspirin alone, showing enhanced antiplatelet effects after one month of treatment.

Despite the increased inhibition of platelet activity with the C + ASA regimen, some platelet biomarkers still showed high residual activity, indicating that diabetic patients may not achieve complete platelet inhibition even with dual therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of clopidogrel and aspirin in combination versus aspirin alone on platelet activation and major receptor expression in diabetic patients: the PLavix Use for Treatment Of Diabetes (PLUTO-Diabetes) trial. Serebruany, VL., Malinin, AI., Pokov, A., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Clopidogrel: cardiologists' panacea or neurologists' headache? [2009]

2. United States pubmed.ncbi.nlm.nih.gov

Effects of clopidogrel and aspirin in combination versus aspirin alone on platelet activation and major receptor expression in patients after recent ischemic stroke: for the Plavix Use for Treatment of Stroke (PLUTO-Stroke) trial. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) Trial: One-Year Outcomes. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Antiplatelet therapy for prevention of recurrent stroke. [2021]

5. England pubmed.ncbi.nlm.nih.gov

The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease. [2018]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. CAPRIE Steering Committee and Investigators. Clopidogrel versus aspirin in patients at risk of ischaemic events. [2023]

7. Japan pubmed.ncbi.nlm.nih.gov

Analysis of the Interaction between Clopidogrel, Aspirin, and Proton Pump Inhibitors Using the FDA Adverse Event Reporting System Database. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

The effect of antiplatelet drugs clopidogrel and aspirin is less immediately after stent implantation. [2018]

9. Germany pubmed.ncbi.nlm.nih.gov

Acetylsalicylic acid does not prevent digital subtraction angiography-related high signal intensity lesions in diffusion-weighted imaging in cerebrovascular patients. A retrospective analysis. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Benefits and Risks of Clopidogrel vs. Aspirin Monotherapy after Recent Ischemic Stroke: A Systematic Review and Meta-Analysis. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Effects of clopidogrel and aspirin in combination versus aspirin alone on platelet activation and major receptor expression in diabetic patients: the PLavix Use for Treatment Of Diabetes (PLUTO-Diabetes) trial. [2018]