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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the drug clopidogrel (also known as Plavix) can reduce the occurrence of new silent brain infarctions—tiny strokes that often show no symptoms but can lead to bigger health issues—in people who have had a stroke or a mini-stroke (transient ischemic attack). Participants will receive either clopidogrel or aspirin to determine which is more effective at lowering the risk of these silent strokes. Individuals who have experienced an ischemic stroke or TIA within the last 90 days and are not already on antiplatelet medication may be suitable for this study. As a Phase 4 trial, this research aims to understand how the already FDA-approved and effective treatment benefits more patients.

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 is the safety track record for these treatments?

Research has shown that clopidogrel is generally well-tolerated. One study found it significantly lowered the risk of strokes caused by blood clots without increasing the risk of serious bleeding, suggesting it is a safe option for stroke prevention. The FDA has already approved clopidogrel for preventing recurrent strokes, further supporting its safety.

Regarding aspirin, studies indicate it reduces the risk of major heart and stroke events and is usually considered safe when taken daily in low doses. Both clopidogrel and aspirin have a strong safety record for preventing strokes. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike the standard of care for silent strokes, which often involves aspirin, clopidogrel offers a different approach by targeting platelet aggregation more effectively. Researchers are excited about clopidogrel because it is already FDA-approved for secondary stroke prevention and may offer enhanced protection against future strokes compared to aspirin. This could potentially reduce the risk of recurrent strokes in patients with silent strokes, providing a significant advancement in treatment options.

What evidence suggests that this trial's treatments could be effective for silent stroke?

In this trial, participants will receive either clopidogrel or aspirin. Research has shown that clopidogrel lowers the risk of stroke in individuals who have experienced minor strokes or transient ischemic attacks. Studies have found that clopidogrel, particularly when combined with aspirin, can be more effective than aspirin alone in preventing additional strokes, though it may also increase the risk of bleeding.

Aspirin, however, has significantly reduced the risk of major heart problems like heart attacks. While its specific effect on preventing silent brain damage hasn't been directly studied, aspirin is commonly used to prevent strokes. Both clopidogrel and aspirin are approved for preventing further strokes in individuals who have already had one, demonstrating their effectiveness for this purpose. ^{1 2 3 6 7}

Who Is on the Research Team?

Calin Ioan Prodan, MD

Principal Investigator

Oklahoma City VA Medical Center, Oklahoma City, OK

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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 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]

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 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]

Citations

1. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/abs/10.1155/2018/7532403

Longitudinal Study on Low‐Dose Aspirin versus Placebo ... Results. Thirty-six subjects received ASA while 47 were untreated. Primary endpoint occurred in 9 controls (19.1%) versus 2 (5.6%) in the ASA ...

2. researchgate.net researchgate.net/publication/382272662_Aspirin_Resistance_and_Ischemic_Stroke

(PDF) Aspirin Resistance and Ischemic Stroke Conclusions Aspirin resistance is associated with increased clinical severity and stroke infarct volume in acute stroke patients. Our results support the need ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6192130/

Longitudinal Study on Low-Dose Aspirin versus Placebo ... SBIs increase the risk of stroke up to four times [2–6] in general population. The presence of SBIs increased the risk of stroke recurrence also in patients ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9254866/

Aspirin for Primary Stroke Prevention Aspirin significantly (p = 0.03) reduced the major cardiovascular events by 15%, all myocardial infarction was 36% less frequent in the aspirin group with a ...

5. ahajournals.org ahajournals.org/doi/10.1161/str.0000000000000116

Prevention of Stroke in Patients With Silent ... The effectiveness of aspirin to prevent stroke has not been studied in this setting. ... Comparative-effectiveness research could be used to associate ...

6. ahajournals.org ahajournals.org/doi/10.1161/strokeaha.115.011889

Silent Brain Infarction and Risk of Future Stroke This approximate doubling of the independent risk of incident stroke was seen in both stroke-free patients and patients with previous stroke.

7. cmaj.ca cmaj.ca/content/192/12/e302

acetylsalicylic acid for prevention of vascular events Daily, low-dose ASA reduces the risk of vascular events including myocardial infarction, stroke and vascular death in patients who have had a ...