After 14 days of aspirin (acetylsalicylic acid) 300mg for stroke, is a loading dose of clopidogrel required?

From the Guidelines

After 14 days of aspirin 300mg for stroke, a loading dose of clopidogrel is generally not necessary when transitioning to or adding clopidogrel therapy. The standard approach would be to start clopidogrel at its maintenance dose of 75mg daily without a loading dose, as indicated by the most recent guidelines 1. This differs from acute settings where loading doses (typically 300-600mg) are used to achieve rapid platelet inhibition. By day 14 post-stroke, the acute phase has passed, and the immediate need for rapid platelet inhibition is less critical. The maintenance dose of clopidogrel 75mg daily will achieve steady-state antiplatelet effects within 5-7 days, which is acceptable in this subacute setting.

Some key points to consider when making this decision include:

• The risk of recurrent stroke and the potential benefits of dual antiplatelet therapy, as seen in the CHANCE and POINT trials 1
• The increased risk of major hemorrhage associated with dual antiplatelet therapy, as noted in the POINT trial 1
• The importance of monitoring for bleeding complications when combining antiplatelet agents, especially in patients with risk factors such as older age, history of bleeding, or concomitant anticoagulant use

If the clinical situation suggests a need for more immediate dual antiplatelet effect (such as high recurrent stroke risk or planned stenting), it is recommended to discuss with a specialist whether a loading dose might be beneficial in the specific case. However, based on the most recent and highest quality evidence 1, the general recommendation is to start clopidogrel at its maintenance dose without a loading dose.

From the FDA Drug Label

DOSAGE AND ADMINISTRATION Acute coronary syndrome ( 2.1) – Initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. – Initiating clopidogrel tablets without a loading dose will delay establishment of an antiplatelet effect by several days. Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily orally without a loading dose. ( 2.2)

The patient has been on aspirin 300 for stroke for 14 days. To initiate clopidogrel, a loading dose of 300 mg is recommended for acute coronary syndrome, but for recent stroke, the recommended dose is 75 mg once daily orally without a loading dose 2, 3, 4. Since the patient has been on aspirin for stroke, the most relevant indication is recent stroke. Therefore, no loading dose of clopidogrel is needed. The recommended dose is 75 mg once daily orally.

From the Research

Aspirin and Clopidogrel Therapy for Stroke Prevention

• The use of aspirin plus clopidogrel for stroke prevention has been studied in several randomized controlled trials 5, 6, 7, 8, 9.
• These studies have shown that dual antiplatelet therapy (DAPT) with aspirin and clopidogrel can reduce the risk of recurrent stroke and major adverse cardiovascular events compared to aspirin monotherapy 5, 6, 7, 8.
• However, DAPT is also associated with an increased risk of bleeding, including moderate or severe bleeding and major bleeding events 5, 6, 7, 8.

Loading with Clopidogrel after 14 Days of Aspirin

• There is no clear evidence to suggest that loading with clopidogrel is necessary after 14 days of aspirin therapy for stroke prevention.
• The studies mentioned above have primarily focused on the comparison of DAPT with aspirin monotherapy, rather than the specific timing of clopidogrel loading 5, 6, 7, 8, 9.
• However, one study suggests that short-term DAPT (≤ 1 month) started during the early acute ischemic phase may be associated with less bleeding and greater reduction of recurrent strokes compared to longer DAPT or DAPT started later after the index event 6.

Key Findings

• DAPT with aspirin and clopidogrel reduces stroke recurrence and major adverse cardiovascular events, but increases the risk of bleeding 5, 6, 7, 8.
• Short-term DAPT (≤ 1 month) may be more effective and safer than longer DAPT or DAPT started later after the index event 6.
• The use of DAPT with aspirin and clopidogrel appears to be effective only for patients with minor stroke or TIA when started within 24 hours of the ischemic event and continued for a maximum of 21 days 9.