Stroke: Pharmacological Prevention

00:01 So let's talk about stroke prevention.

00:03 When I think about stroke prevention, I divided into two buckets.

00:07 There is primary stroke prevention, which is treatment of individuals with no history of stroke.

00:12 Those are patients who are at very high risk for an ischemic event, such as patients with atrial fibrillation without a prior stroke.

00:20 And then there is secondary stroke prevention.

00:22 This is treatment of individuals who have already had a stroke or a TIA and are at risk for a future event.

00:29 What type of agents do we use to prevent stroke either for primary or a secondary prevention? Well, aspirin is one of the most important and effective medicines that are used.

00:39 This is an antiplatelet agent that prevents stroke.

00:44 Dipyridamole is another agent that can be used and sometimes it's combined with aspirin into a brand name product called Aggrenox.

00:53 There are a number of oral P2Y12 inhibitors, clopidogrel, prasugrel, or ticagrelor are three agents that work through inhibition of the P2Y12.

01:05 These are also antiplatelet agents.

01:08 And then there are anticoagulants, enoxaparin sodium or Lovenox is a common anticoagulant used in patients with stroke.

01:16 Coumadin or Warfarin is the historical commonly used anticoagulant that is used and requires frequent monitoring with many drug-drug interactions.

01:25 And so often we use or consider other agents nowadays.

01:30 And then there are the direct oral antithrombin inhibitors, which are called DOACs which can be used to prevent stroke.

01:39 What are the mechanisms of action of the antiplatelet agents and how do we consider their use for different types of stroke? When we think about stroke, there are Cardioembolic strokes are those that come from hypercoagulability and that's one group.

01:53 There are thrombotic or lacunar strokes, and that's a second group.

01:57 And then other causes of stroke where we may need to consider different interventions.

02:00 And I think those three categories are helpful to understanding the types of interventions we would consider in these patients.

02:07 For patients with a Cardioembolic stroke or evidence of hypercoagulability.

02:11 For those patients, anticoagulation is indicated and initiated early and continued after the stroke, except in patients with large stroke, where there are a significant hemorrhage risk, where the initiative anticoagulation is delayed until patients are beyond that risk of bleeding.

02:28 For patients with thrombotic strokes or lacunar strokes, antiplatelet therapy is the treatment of choice.

02:34 We consider aspirin or those oral P2Y12 inhibitors like clopidogrel.

02:40 And then there are other causes of stroke that may require different interventions.

02:44 Watershed strokes are strokes that occur in those distributions.

02:48 Those watershed distributions in between vascular territories, such as the MCA/ACA watershed area or MCA/PCA watershed areas.

02:58 Those strokes occur from reduced perfusion to the brain, and IV fluids or reduction of antihypertensives may be needed to manage stroke risk in those patients.

03:09 In all patients presenting with stroke, we need to consider risk factor modification.

03:15 So let's talk about the mechanisms of action of some of the antiplatelet agents that we use for prevention of stroke.

03:23 First, we have the oral P2Y12 inhibitors, clopidogrel, prasugrel and ticagrelor.

03:30 Next we can think about aspirin is a second category with a different mechanism of action and then there's dipyridamole which also has a different mechanism of action.

03:39 The oral P2Y12 inhibitors block ADP receptors and this really contributes to their reduction in platelet activation and aggregation.

03:48 Aspirin on the other hand inhibits cyclooxygenase or COX and thromboxane A2 and that really contributes to its inhibition of platelet activation and aggregation.

04:00 Dipyridamole has a couple of actions.

04:02 It increases plasma adenosine and increases platelet phosphodiesterase both of which contribute to reduction in platelet activation and aggregation.

04:12 So the mechanism is different for each of these antiplatelet agents or classes of agents.

04:17 But the end result is inhibition of platelet activation.

04:20 The platelets become less sticky, and there's less aggregation of platelets to contribute to clotting.

04:25 And both of those things contribute to a reduction in stroke risk.

04:31 When we think about the mechanisms of action and how that works in the setting of an acute stroke, a stroke it results from plaque rupture, and there's activation of platelets and aggregation of platelets contributing to a thrombus or a clot that reduces perfusion to a part of the brain.

04:46 Some of the things that happen after that plaque rupture is increasing thromboxane A2 and that's really what aspirin does.

04:52 It inhibits that TXA2 production.

04:56 ADP is also released and there's an increase in ADP within the blood vessels and the oral P2Y12 inhibitors as well as to some degree that dipyridamole reduce ATP generation and circulation around that area of plaque rupture.

05:12 There's activation of GPIIb/IIIa receptors.

05:16 And there are a number of GPIIb/IIIa freeway antagonists that are also being studied and can be used in selected situations for patient with acute stroke or with myocardial infarction.

05:27 And the end result is platelet aggregation with thrombus formation and the goal of all of these agents is to prevent that process.

05:35 Let's look at a comparison of some of the various antiplatelet agents.

05:39 These are common medicines used in the secondary prevention of stroke.

05:43 And it is helpful to understand their advantages, their disadvantages, and then some unique features of each of those agents.

05:50 Aspirin is an antiplatelet agent that is used very frequently because it's inexpensive and we have a long experience and good safety data on this agent.

06:00 Some disadvantages is in selected patients that can have limited efficacy, not every patient responds to aspirin.

06:06 And we do know that there are aspirin responders and non-responders and in those non-responders, alternative agents may be needed.

06:14 It can irritate the GI tract and cause it gastritis and so patients may present with gastrointestinal symptoms.

06:21 And then we worry about this possibility of resistant.

06:24 But it is often the first choice in stroke prevention both in the primary prevention and secondary prevention of stroke.

06:33 Aspirin and dipyridamole in some studies can be more effective than aspirin alone.

06:38 We can see a number of of similar and different side effects to aspirin alone, including headache and gastrointestinal symptoms, and it requires twice daily dosing which may be difficult in many patients.

06:50 And then we have the oral P2Y12 inhibitors like clopidogrel, prasugrel and ticagrelor.

06:57 They can be more effective than aspirin in a number of studies and effective in combination with aspirin.

07:02 Aspirin and clopidogrel is commonly used for dual antiplatelet therapy, which can be more effective than either monotherapy alone.

07:11 Side effects that we can see with these include rash, they can be more expensive and response also can be variable in selected patients.

07:23 And then we have the category of dual antiplatelet therapy, aspirin plus clopidogrel.

07:28 This is a potent combination of agents that is considered in patients with minor stroke or TIA.

07:34 There is an increased risk of bleeding both CNS and systemic bleeding.

07:38 And so dual antiplatelet therapy is really considered early after the stroke within the first 30 to 90 days that peak period of where patients are at risk for recurrent stroke.

07:48 And then patients are dosed reduced or reduced to typically aspirin monotherapy alone.

07:54 And this is used as you see here in patients with TIA or mild stroke and that's measured by the NIH Stroke Scale, a score of less than or equal to 5 and in mild stroke with significant extracranial vascular disease.

08:08 And then lastly, there is an agent cilostazol.

08:11 This is a phosphodiesterase inhibitor, it's used very rarely but you'll see it sometimes used for patients who have failed all of the other agents we've talked about.

08:19 Patients who have had a stroke on aspirin and clopidogrel or the combination of dual antiplatelet therapy.

08:26 This agent can be more effective than either agent alone, it's an antiplatelet and vasodilator agent.

08:32 We can see headache and gastrointestinal symptoms and it's not FDA approved for stroke.

08:37 But in some cases considered off label for patients who have been failed or refractory to other agents.