Stroke - Pharmacotherapy
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This document provides an overview of stroke, including its definition, types, risk factors, pathophysiology, clinical presentation, diagnosis, treatment both initially and long-term, and management considerations. The two main types of stroke are ischemic (87%) and hemorrhagic (13%). Risk factors include modifiable factors like hypertension and non-modifiable factors like age. Treatment involves stabilizing the patient, diagnosing with imaging, treating the cause, preventing complications, and long-term prevention with medications like aspirin, statins, and anticoagulants depending on the cause of stroke.
Stroke - Pharmacotherapy
- 2. Definition: • Rapidly developing nurological dysfunction due to acute vascular pathology not related to trauma. • There are two types of stroke: • Ischemic. 87% • Hemorrhagic. 13% -subarachnoid hemorrhage. -intracerebral hemorhage
- 3. Ischemic stroke: • Ischemic strokes occur when blood flow is reduced to a part of the brain or all of the brain, resulting in tissue damage. The reduction in blood flow can be due to decreased systemic perfusion, severe stenosis or blood vessel occlusion. • They are classified to: large artery atherosclerosis, cardioembolsim, small vessel occlusion or other unusual etiology.
- 4. Hemorrhagic stroke Hemorrhagic strokes are characterized by too much blood in the closed cranial cavity. Hemorrhagic strokes are often associated with uncontrolled hypertension and antithrombotic/thrombolytic therapy. They are less common than ischemic strokes but more lethal.
- 5. Risk factors: Non-modifiable: Age. Race. Sex. Low birth weight. Genetic factors. Modifiable: Hypertension. Cigarette smoking. Diabetes. Atrial fibrillation. Dyslipidemia. Asymptomatic carotid stenosis. Sickle cell disease. Poor diet. Obesity. Physical inactivity. Other cardiac diseases (coronary heart disease, heart failure, PAD).
- 6. Pathophysiology (ischemic stroke)
- 7. Hemorrhagic stroke • The presence of blood in the brain parenchyma causes mechanical compression of vulnerable tissue and subsequent activation of inflammation and neurotoxins.
- 8. Clinical presentation: Symptoms: – Weakness on one side of the body. – Inability to speak. – Loss of vision. – Vertigo, falling. – Headache (can be very severe with hemorrhagic stroke).
- 9. Signs: – Hemiparesis, monoparesis, hemisensory deficits. – Vertigo and double vision (posterior circulation involvement). – Aphasia (anterior circulation stroke). – Dysarthia. – Visual field deficits. – Altered level of consciousness.
- 10. INITIAL ASSESSMENT • The history, physical examination, serum glucose, oxygen saturation, and a noncontrast CT scan are sufficient in most cases to guide acute therapy.
- 11. Approach to treatment: 1. Airway, breathing and circulation 2. History and physical examination 3. Neurologic evaluation (NIHSS) 4. Immediate laboratory studies 5. Neuroimaging 6. Cardiac studies
- 12. STROKE MANAGEMENT ISSUES 1. Fluids: a. isotonic saline without dextrose is the agent of choice b. avoid excess free water as in ½ isotonic saline a. avoid fluids containing glucose a. fluid management must be individualized on the basis of cardiovascular status, electrolyte disturbances.
- 13. 2. Hypoglycemia. 3. Hyperglycemia (stress hyperglycemia): 1. Defined as a blood glucose level >126 mg/dL. 2. Can present regardless of diabetes. 3. It is associated with reduced benefit from recanalization with thrombolytic. 4. Treat if glucose >180 mg/dL. 5. Goal is serum glucose concentrations in the range of 140 to 180 mg/dL.
- 14. 4. Swallowing assessment: Dysphagia is common after stroke and is a major risk factor for developing aspiration pneumonia. 5. Head and body position – keep the head of bed in the position that is most comfortable for the patient. – Elevate the head of the bed to 30 degrees if the at risk for: • Elevated intracranial pressure (ie, intracerebral hemorrhage, cerebral edema >24 hours from stroke onset) • Aspiration (eg, those with dysphagia and/or diminished consciousness) • Cardiopulmonary decompensation or oxygen desaturation (eg, those with chronic cardiac and pulmonary disease).
- 15. Mobilization • Mobilization of stable patients after 24 hours may lessen the likelihood of major complications such as pneumonia, deep vein thrombosis, pulmonary embolism, and pressure sores after stroke. • Exceptions; those who exhibit neurologic deterioration upon assuming more upright postures. • very early mobilization, within 24 hours of symptom onset, may be harmful.
- 16. Fever – Increase mortality rates, greater disability, more dependence, worse functional outcome, greater severity, and longer ICU and hospital stays. – R/O primary CNS infection such as meningitis. – maintain normothermia for at least the first several days after an acute stroke.
- 17. Permissive hypertension • Treat if BP > 220/120 mmHg • BP goals in the first 24-48h post stroke: – No IV tPA : <220/120 mmHg – IV tPA : <185/110 mmHg • first-line: labetalol, nicardipine and clevidipine • second-line: nitroprusside (if DBP >120 mmHg)
- 18. • In ICH patients with blood pressure between 150 and 220 mm Hg systolic, early treatment designed to achieve a pressure of less than 140 mm Hg systolic has been shown to be safe and improve functional outcome.
- 19. Fibrinolytics
- 20. • Endovascular thrombectomy with a stent retriever is indicated after tPA but within 6 hours, for patients with proximal vessel occlusion and a small core injury on imaging.
- 21. Alteplase: • No proven mortality benefits. • Reduce disability 3 months post-stroke • Indicated within 4.5h of stroke onset. • tPA: 0.9mg/kg ( max 90mg), 10% as IV bolus, remainder over 1h.
- 22. ANTIPLATELET AGENTS • Aspirin: – Reduce stroke recurrence, death and disability. – Start within 24-48h of stroke onset. • Aspirin vs. ticagrelor: ticagrelor not superior to aspirin. • Antiplatelet agents is not an alternative to intravenous thrombolysis .
- 23. • symptomatic atherosclerotic intracranial large artery stenosis, we suggest dual antiplatelet therapy with aspirin plus clopidogrel for 90 days, followed by antiplatelet monotherapy. • parenteral anticoagulation rather than aspirin only for select patients with acute cardioembolic ischemic stroke or TIA who have intracardiac thrombus, as these patients are at high risk for recurrent ischemic stroke.
- 24. • Secondary hemorrhagic transformation of an ischemic infarct vs. aspirin use? • Early anticoagulation is associated with a higher mortality and worse outcomes compared with aspirin treatment initiated within 48 hours of ischemic stroke onset
- 25. • Early anticoagulation : – no proven benefit. – If used: • Heparin: administer as IV infusion rather than bolus. • Enoxaparin: 1 mg/kg dose every 12 hours
- 27. • ASA vs. ASA & ERDP – the combination demonstrated a significant advantage over the ASA-alone therapy. – High dc rate because of headache (15%) • ERDP-ASA vs. clopidogrel – the risk of recurrent stroke was similar for the two antiplatelet agents, but clopidogrel was better tolerated with less bleeding and headache.
- 28. • ASA vs. clopidogrel: – clopidogrel is slightly more effective than ASA and had a similar incidence of adverse effects.
- 29. • ASA Plus Clopidogrel for secondary prevention: – No add benefit, increased bleeding risk
- 30. Aspirin • lowest effective dose is 50 mg/day. • most common adverse effects: Upper GI discomfort and bleeding (both are dose related). • Caution when used with NSAIDs.
- 31. Extended-Release Dipyridamole Plus ASA • MOA: – inhibit platelet aggregation by inhibiting phosphodiesterase, leading to accumulation of cAMP and cGMP intracellularly, which prevent platelet activation. – dipyridamole also enhances the antithrombotic potential of the vascular wall. – High dc rate because of headache
- 32. Oral Anticoagulants • The treatment of choice for the prevention of stroke in patients with atrial fibrillation • target INR of 2.5 • NOAC including dabigatran, rivaroxaban, and apixaban have significant advantages over warfarin in terms of ease of dosing and less food and drug interactions. Also all three agents have been shown to be as effective as, and in some cases, superior to, warfarin in reducing recurrent events and intracranial hemorrhage.
- 33. Statins • Use regardless of lipid profile – high intensity statin (atorvastatin 40-80mg). – If not tolerated use moderate intensity statins. (eg: atorvastatin 10-20 mg, rosuvastatin 5-10mg,..)
- 34. Heparin • Use low dose. • Potential but unproven uses for treatment doses of heparins include: – bridge therapy in patients being initiated on warfarin – carotid dissection – continuous worsening of ischemia despite adequate antiplatelet therapy.
- 35. Dosing aspirin: 50 to 100 mg daily clopidogrel: 75 mg daily Aspirin-extended release dipyridamole: 25mg- 200mg BID.
- 36. Glycemic control: Patients with diabetes mellitus have approximately twice the risk of ischemic stroke compared with those without diabetes. Tight glycemic control reduces microvascular complications. A goal of therapy for most people should be A1C less than or equal to 7.
- 37. GI ulcer prophylaxis When to administer prophylaxis? If on mechanical ventilation for >48 hours. Coagulopathy. History of GI ulceration or bleeding within the past year. Traumatic brain injury, traumatic spinal cord injury, or severe burn injury. Two or more of the following risk factors: sepsis, intensive care unit stay lasting >1 week, occult GI bleeding lasting ≥6 days, or high-dose glucocorticoid therapy. Prophylaxis is through proton pump inhibitors or H2 antagonists.
- 38. DVT prophylaxis: DVT is common in patients after stroke, and more common for those who suffer hemiparesis. It can lead to PE which holds a high risk for mortality. DVT prophylaxis could be through intermittent pneumatic compression (IPC) starting at presentation , for patients within 72 hours of acute ischemic stroke onset who have restricted mobility. C/I to IPC: leg ischemia because of PVD, leg ulceration, dermatitis or severe leg edema. If patient has already been at bed rest or immobilized without VTE prophylaxis for >72 hours, don’t use IPC. They can also take anticoagulants starting at presentation and within 48 hours such as heparin 5000 units BID or TID or enoxaparin 40mg daily.
- 39. • Smoking cessation is also important. • Carotid endarterectomy.
Editor's Notes
- #3: SAH occurs when blood enters the subarachnoid space (where cerebrospinal fluid is housed) owing to trauma, rupture of an intracranial aneurysm, or rupture of an arteriovenous malformation (AVM). By contrast, ICH occurs when a blood vessel ruptures within the brain parenchyma itself, resulting in the formation of a hematoma.
- #7: Ischemic stroke results from an occlusion of a cerebral artery, leading to a reduction in cerebral blood flow. The pathophysiologic mechanisms of ischemic stroke are given in Fig. 20-1. Normal cerebral blood flow averages 50 mL/100 g per minute, and this is maintained over a wide range of blood pressures (mean arterial pressures of 50-150 mm Hg) by a process called cerebral autoregulation. Cerebral blood vessels dilate and constrict in response to changes in blood pressure, but this process can be impaired by atherosclerosis, chronic hypertension, and acute injury, such as stroke. Arterial occlusion leads to severe reductions in cerebral blood flow leading to infarction. Tissue that is ischemic but maintains membrane integrity is referred to as the ischemic penumbra because it usually surrounds the infarct core.6 This penumbra is potentially salvageable through therapeutic intervention and is assessed urgently prior to endovascular intervention with a stent retriever. Reduction in the provision of nutrients to the ischemic cell eventually leads to depletion of the high-energy phosphates (eg, adenosine triphosphate [ATP]) and accumulation of extracellular potassium, intracellular sodium, and water, leading to cell swelling and eventual lysis. The increase in intracellular calcium that follows results in the activation of lipases, proteases, and endonucleases and the release of free fatty acids from membrane phospholipids. In addition, there is a release of excitatory amino acids, such as glutamate and aspartate, which perpetuate the neuronal damage and the accumulation of free fatty acids, including arachidonic acid, and result in the formation of prostaglandins, leukotrienes, and free radicals. In ischemia, the magnitude of free radical production overwhelms normal scavenging systems, leaving these reactive molecules to attack cell membranes and contribute to the mounting intracellular acidosis. All these events occur within 2 to 3 hours of the onset of ischemia and contribute to the ultimate cell death. Later targets for intervention in the pathophysiologic process involved after cerebral ischemia include inflammation and apoptosis, or programmed cell death, occurring many hours after the acute insult and can interfere with recovery and repair of brain tissue.6
- #12: Patients with decreased consciousness may be unable to protect their airway, and those with increased intracranial pressure due to hemorrhage can present with vomiting, decreased respiratory drive, or muscular airway obstruction. Hypoventilation, with a resulting increase in carbon dioxide, may lead to cerebral vasodilation and elevate intracranial pressure. In these cases, intubation may be necessary to restore adequate ventilation and to protect the airway from aspiration. Patients with adequate ventilation should have the oxygen saturation monitored. Patients who are hypoxic should receive supplemental oxygen to maintain oxygen saturation >94 percent. Supplemental oxygen should not routinely be given to nonhypoxic patients with acute ischemic stroke. Time of ischemic stroke symptom onset is critical because it is the main determinant of eligibility for treatment with intravenous thrombolysis and endovascular thrombectomy. For patients who are unable to provide a reliable onset time, symptom onset is defined as the time the patient was last known to be normal or at baseline neurologic status. contraindications to thrombolytic treatment should also be assessed. The history and physical examination should be used to distinguish between other disorders in the differential diagnosis of brain ischemia. As examples, seizures, syncope, migraine, hypoglycemia, hyperglycemia, or drug toxicity can mimic acute ischemia. It is important to ask the patient, relative, or any reliable informant whether the patient takes insulin or oral hypoglycemic agents, has a history of epilepsy, drug overdose or abuse, or recent trauma. The presence of onset headache and vomiting favor the diagnosis of ICH or SAH compared with a thromboembolic stroke, while the abrupt onset of impaired cerebral function without focal symptoms favors the diagnosis of SAH. Another important element of the history is whether the patient takes anticoagulant drugs. Even with these clues, diagnosing intracranial hemorrhage on clinical grounds is very imprecise, so early neuroimaging with a CT or MRI scan is critical. CT is preferred at most centers, as it can be obtained very rapidly and is effective at distinguishing between ischemic and hemorrhagic stroke. The physical examination:The lungs should be assessed for abnormal breath sounds, bronchospasm, fluid overload, or stridor. The head should be examined for signs of trauma. A tongue laceration may suggest a seizure. In cases where there is a report or suspicion of a fall, the neck should be immobilized until evaluated radiographically for evidence of serious trauma. Examination of the extremities is important to look for evidence of systemic arterial emboli, distal ischemic, cellulitis, and deep vein thrombosis; the latter should raise the possibility that the patient is receiving anticoagulant treatment. One of the most widely used and validated scales is the National Institutes of Health Stroke Scale (NIHSS), composed of 11 items adding up to a total score of 0 to 42, cut-points of NIHSS score <5 for mild, 5 to 9 for moderate, and ≥10 for severe stroke may be reasonable. The three most predictive examination findings for the diagnosis of acute stroke are facial paresis, arm drift/weakness, and abnormal speech (a combination of dysarthria and language items derived from the NIHSS). The NIHSS score on admission has been correlated to stroke outcome and its use is recommended for all patients with suspected stroke. Urgent brain imaging with CT or MRI is mandatory in all patients with sudden neurologic deterioration or acute stroke. All patients with suspected stroke should have the following studies urgently as part of the acute stroke evaluation: Noncontrast brain CT or brain MRI, Finger stick blood glucose, Oxygen saturation. Other immediate tests for the evaluation of ischemic and hemorrhagic stroke include the following: ECG, CBC, Troponin, INR, PT, APTT, factor Xa activity assay if known or suspected that the patient is taking direct thrombin inhibitor or direct factor Xa inhibitor. However, thrombolytic therapy for acute ischemic stroke should not be delayed while awaiting the results of hematologic studies unless the patient has received anticoagulants or there is suspicion of a bleeding abnormality or thrombocytopenia. The only test that is mandatory before initiation of intravenous alteplase is blood glucose. Chest radiography, urinalysis and blood cultures are indicated if fever is present. We also suggest blood for type and cross match in case fresh frozen plasma is needed to reverse a coagulopathy if ICH is present. In order to limit medication dosage errors, particularly with the use of alteplase, an accurate body weight should be obtained early during the urgent evaluation.
- #13: Intravascular volume depletion may worsen cerebral blood flow. b. because hypotonic fluids may exacerbate cerebral edema and are less useful than isotonic solutions for replacing intravascular volume. c. which may exacerbate hyperglycemia.
- #14: — Hypoglycemia can cause focal neurologic deficits mimicking stroke, and severe hypoglycemia alone can cause neuronal injury. It is important to check the blood sugar and rapidly correct low serum glucose (<60 mg/dL [3.3 mmol/L]) at the first opportunity --- Hyperglycemia:associated with poor functional outcome. May augment brain injury by several mechanisms including: increased tissue acidosis from anaerobic metabolism, free radical generation, and increased blood brain barrier permeability.
- #15: 4. It is important to assess swallowing function prior to administering oral medications or food. Thus, prevention of aspiration in patients with acute stroke includes initial nulla per os (NPO) status until swallowing function is evaluated
- #16: In addition, there is a potential increased risk of aspiration if a flat position is maintained for a prolonged period. very early mobilization and early rehabilitative therapies reduced the odds of a favorable outcome at three months.
- #17: it seems unlikely that acetaminophen will be effective by itself.
- #18: Acutely elevated blood pressure is necessary to maintain brain perfusion in borderline ischemic areas. The blood pressure should be stabilized and maintained at or below 180/105 mmHg for at least 24 hours after thrombolytic treatment -- if the patient has active ischemic coronary disease, heart failure, aortic dissection, hypertensive encephalopathy, or pre-eclampsia/eclampsia and BP > 220/120 mmHg treat but cautious lowering of blood pressure by approximately 15 percent during the first 24 hours after stroke onset is suggested. Rapid acting formulations of Nifedipine should be avoided (prolonged or precipitous decline in BP, increased risk of stroke).
- #20: An “excellent outcome” was defined as minimal or no disability by several different neurologic scales.
- #21: Stent retriver
- #23: However, in a prespecified exploratory analysis, ticagrelor was superior to aspirin in the subgroup of patients who had stroke of possible atherosclerotic origin (defined as ipsilateral atherosclerotic stenosis of an extracranial or intracranial artery (including <50 percent stenosis), or mobile thrombus or thick plaque (≥4 mm) in the aortic arch). These data suggest that patients with atherosclerotic stroke may benefit from antiplatelet therapy other than aspirin. However, the optimal definition of "atherosclerotic" stroke and the optimal treatment strategy are uncertain --- with the exception that short-term treatment with clopidogrel plus aspirin appears to be beneficial for high-risk TIA and minor stroke in China.
- #25: it may be wise to delay initiation if aspirin has not yet been started in patients who develop parenchymal hematoma. Aspirin can then be given once the patient's neurologic condition becomes stable.
- #26: For patients with acute cardioembolic ischemic stroke or TIA who have intracardiac thrombus, either in the left ventricle or associated with mechanical or native heart valves, we suggest early parenteral anticoagulation rather than aspirin (Grade 2C). This approach is controversial. Other experts favor early treatment with aspirin rather than anticoagulation in this setting for patients with an infarct. Our suggestion to use early parenteral anticoagulation for these selected patients applies only to those with a small brain infarct or TIA and no evidence of hemorrhage on brain imaging. While parenteral anticoagulation is not recommended during the first 48 hours after acute ischemic stroke, oral anticoagulation is recommended for secondary stroke prevention in patients with atrial fibrillation and other high-risk sources of cardiogenic embolism. The timing of its initiation for such patients is mainly dependent on the size of the infarct, which is presumed to correlate with the risk of hemorrhagic transformation. Thus, for medically stable patients with a small or moderate-sized infarct, warfarin can be initiated soon (after 24 hours) after admission with minimal risk of transformation to hemorrhagic stroke, while withholding anticoagulation for two weeks is generally recommended for those with large infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension.
- #30: However, the combination has been studied in patients with TIA or minor stroke, and short-term (3-month) use of the combination of clopidogrel and ASA was associated with improved outcomes.
- #31: administration of ibuprofen prior to the administration of a daily aspirin dose inhibits the ASA from binding irreversibly to the cyclooxygenase and can decrease its antiplatelet effect.45 Current recommendations are to administer ASA at least 2 hours before ibuprofen or to wait at least 4 hours after an ibuprofen dose.
- #32: The extended-release formulation allows twice-daily administration and higher doses to be tolerated in patients. The use of immediate-release formulation with ASA, in order to reduce costs, is unproven and should be discouraged.
- #37: 1% A1C reduction --- 12% stroke reduction
- #39: after 24h post tPA.