Neurology PDF - Seizure Medications and Treatments

Neurology v. Available in immediate-release (valproic acid [Depakene]) capsules for three- or four-timesdaily dosing; delayed-release (enteric coated) (divalproex sodium [Depakote], valproic acid [Stavzor]) capsules and tablets for twice-daily dosing (if patient is taking an enzyme inducer,...

Neurology v. Available in immediate-release (valproic acid [Depakene]) capsules for three- or four-timesdaily dosing; delayed-release (enteric coated) (divalproex sodium [Depakote], valproic acid [Stavzor]) capsules and tablets for twice-daily dosing (if patient is taking an enzyme inducer, agent is dosed more often); and extended-release (divalproex sodium [Depakote ER]) tablets for once-daily dosing vi. Nonepileptic indications: Manic episodes associated with bipolar disorder, prophylaxis of migraine headaches aa. Vigabatrin (Sabril) i. Mechanism of action: Irreversible inhibition of GABA transaminase ii. Pharmacokinetics: Induces CYP2C9; renal elimination; dose adjustment required for CrCl less than 60 mL/minute/1.73 m2 iii. Adverse effects: Fatigue, somnolence, nystagmus, tremor, blurred vision, vision impairment, weight gain, arthralgia, abnormal coordination, and confusional state iv. Serious adverse effect: Vision loss; increased risk with higher total dose and duration; periodic vision testing necessary; restricted distribution program; only used for refractory complex partial seizures and infantile spasms v. Only available through a REMS program vi. Available as oral powder for solution bb. Zonisamide (Zonegran) i. Mechanism of action: Fast sodium channel blocker, blocks T-type calcium currents, weak carbonic anhydrase inhibitor ii. Non-arylamine sulfonamide: Avoid in patients with sulfa sensitivity; sometimes used in patients with nonserious sulfa allergies, particularly when non-acrylamides (i.e., sulfonylureas) have been used successfully iii. Pharmacokinetics: Long half-life, renal elimination iv. Adverse effects: Depression, rash, psychomotor slowing, paresthesias, kidney stones, blood dyscrasias, hyperthermia (associated with decreased perspiration, or oligohidrosis), metabolic acidosis Table 4. Starting and Maximal Adult Seizure Medication Doses Medication Starting Dose Usual Maximal Dose Brivaracetam 50 mg twice daily 200 mg/day Cannabidiol 2.5 mg/kg twice daily 10 mg/kg twice daily Carbamazepine 200 mg twice daily 1600 mg/day Cenobamate 12.5 mg/day 400 mg/day Clobazam 10 mg/day 40 mg/day Clonazepam 0.5 mg three times/day 20 mg/day Eslicarbazepine 400 mg/day 1200 mg/day Ethosuximide 250 mg twice daily 1.5 g/day Felbamate 400 mg three times/day 3600 mg/day Fenfluramine 0.1 mg/kg twice daily 0.35 mg/kg twice daily to maximum of 26 mg/ day; with stiripentol, 0.2 mg/kg twice daily to maximum of 17 mg/day Gabapentin 300 mg three times/day 3600 mg/day Ganaxolone Weight-based dosing (see text above) Weight-based dosing (see text above) Lacosamide 50 mg twice daily 400 mg/day ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-495 Neurology Table 4. Starting and Maximal Adult Seizure Medication Doses (Cont’d) Medication Starting Dose Usual Maximal Dose Lamotrigine With valproic acid: 25 mg every other day Without carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid: 25 mg/day With carbamazepine, phenytoin, phenobarbital, or primidone and not with valproic acid: 50 mg/day With valproic acid: 200 mg/day Without carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid: 375 mg/day With carbamazepine, phenytoin, phenobarbital, or primidone and not with valproic acid: 500 mg/day Levetiracetam 500 mg twice daily 3000 mg/day Oxcarbazepine 300 mg twice daily 2400 mg/day Perampanel With enzyme-inducing seizure medications: 4 mg/day Without enzyme-inducing seizure medications: 2 mg/day With enzyme-inducing seizure medications: 12 mg/day Without enzyme-inducing seizure medications: 8 mg/day Phenobarbital 1–3 mg/kg/day 300 mg/day Phenytoin 100 mg three times/day 600 mg/day Pregabalin 75 mg twice daily 600 mg/day Primidone 100 mg at bedtime 2000 mg/day Rufinamide 200–400 mg twice daily 3200 mg/day Stiripentol 50 mg/kg/day in two or three divided doses; must be administered with clobazam 3000 mg/day Tiagabine With carbamazepine, phenytoin, primidone, With carbamazepine, phenytoin, primidone, phenobarbital: 4 mg/day phenobarbital: 56 mg/day Without carbamazepine, phenytoin, primidone, phenobarbital: 2 mg/day Topiramate 25–50 mg/day 400 mg/day Valproic acid 10–15 mg/kg/day 60 mg/kg/day Vigabatrin 500 mg twice daily 3000 mg/day Zonisamide 100 mg/day 600 mg/day 2. Surgery: Surgery can sometimes drastically reduce the number of seizures; possible surgical procedures include removal of the seizure focus, corpus callosotomy, or implantation of vagus nerve stimulators. 3. Status epilepticus a. Treatment principles i. Ascertain ABCs (airway, breathing, and circulation). ii. Laboratory values (fingerstick blood glucose, CBC, basic metabolic panel, calcium, magnesium, and seizure medication serum concentrations, if applicable) are sent to determine any reversible causes of status epilepticus. iii. If blood glucose is less than 60 mg/dL, administer thiamine 100 mg intravenously followed by dextrose 50%. iv. Administer an emergency medication to stop the seizure immediately. v. Follow with an urgent medication to prevent the recurrence of seizures. vi. In general, all medications for status epilepticus should be administered parenterally. vii. Neuromuscular-blocking drugs do not stop seizures; they stop only the muscular response to the brain’s electrical activity. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-496 Neurology b. Emergency medications i. Lorazepam: Drug of choice (a) Rapid onset (2–3 minutes) (b) Dosage 0.1 mg/kg (up to 4 mg/dose) at a rate of up to 2 mg/minute; may repeat every 5–10 minutes ii. Diazepam (a) Rapid onset, short duration (b) Dosage 0.15 mg/kg (up to 10 mg/dose) at a rate of up to 5 mg/minute. May repeat every 5 minutes (c) Rectal gel and intranasal formulations are available. iii. Midazolam: Preferred for intramuscular administration (a) Rapid onset, short duration (b) Dosage 0.2 mg/kg (up to 10 mg/dose). Can be administered intramuscularly, intranasally, or buccally c. Urgent medications i. Phenytoin: Dosage 20 mg/kg; administration rate no more than 50 mg/minute ii. Fosphenytoin: Administration rate no more than 150 mg of PE per minute iii. Phenobarbital: Dosage 20 mg/kg at 50–100 mg/minute iv. Valproic acid: Dosage 20–40 mg/kg at up to 6 mg/kg/minute; does not have FDA-labeled approval for status epilepticus v. Levetiracetam: 40–60 mg/kg over 15 minutes (maximum 4.5 g/dose); does not have FDAlabeled approval for status epilepticus vi. Lacosamide: 200- to 400-mg bolus over 15 minutes; does not have FDA-labeled approval for status epilepticus d. Refractory status epilepticus medications i.  Benzodiazepine-resistant status epilepticus: Fosphenytoin = levetiracetam = valproate (N Engl J Med 2019;381:2103-13) ii. Pentobarbital: Load 5–15 mg/kg up to 50 mg/minute; follow with a 0.5- to 5-mg/kg/hour infusion. (a) May have severe hypotension, necessitating treatment with vasopressors; should have continuous blood pressure measurement (b) Must be on ventilator iii. Midazolam: Load 0.2-mg/kg infused up to 2 mg/minute; follow with a 0.05- to 2-mg/kg/hour infusion. (a) May have hypotension, respiratory depression (b) May have tachyphylaxis iv. Propofol: Load a 1- to 2-mg/kg intravenous bolus for 30–60 seconds; follow with a 20- to 200mcg/kg/minute infusion. (a) Significant source of lipids (b) Some reports of seizure exacerbation with propofol (c) Must be on ventilator (d) PRIS (propofol infusion syndrome) with prolonged administration ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-497 Neurology 4. Special populations a. Older adults: Pharmacokinetic changes in older adults that may affect seizure medications include the following: i. Carbamazepine: Decreased clearance ii. Phenytoin: Decreased protein binding if hypoalbuminemic or in renal failure iii. Valproic acid: Decreased protein binding iv. Diazepam: Increased half-life v. Phenylethylmalonamide (active metabolite of primidone): Decreased clearance if CrCl is decreased vi. Lamotrigine: Decreased clearance vii. Seizure medications with renal elimination must be adjusted according to the CrCl value. b. Women’s health i. During their reproductive years, women with epilepsy should: (a) Take the best drug for their seizure type. Women of childbearing age should not be administered valproic acid unless other therapies have failed. (b) Be treated with monotherapy, if possible (c) Discuss the possible decrease in hormonal contraceptive effectiveness if taking enzyme-inducing medications (Table 5) (d) Use folic acid supplementation with no less than 0.4 mg/day ii.  Three practice guidelines exist regarding epilepsy during pregnancy (relevant material excerpted in the text that follows). (a) Avoiding valproic acid monotherapy or polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations, particularly neural tube defects, facial clefts, hypospadias, and poor cognitive outcomes. Valproic acid use has now been associated with lower IQ scores at ages 3 and 4½ years (Neurology 2012;78:1207-14). (b) To reduce the risk of major congenital malformations and poor cognitive outcomes, avoiding the use of seizure medication polytherapy during pregnancy, if possible, should be considered. (c) Limiting the dose of valproic acid (less than 700 mg/day), topiramate, or lamotrigine during the first trimester, if possible, should be considered to reduce the risk of major congenital malformations. (d) Avoiding the use of phenytoin, carbamazepine, and phenobarbital, if possible, may be considered to reduce the risk of cleft palate (phenytoin), posterior cleft palate (carbamazepine), cardiac malformations (phenobarbital), and poor cognitive outcomes (phenytoin, phenobarbital). (e) Women with epilepsy taking seizure medications during pregnancy probably have an elevated risk of small-for-gestational-age infants and 1-minute Apgar scores less than 7. (f) Monitoring of lamotrigine, carbamazepine, and phenytoin serum concentrations during pregnancy should be considered. (g) Monitoring of levetiracetam and oxcarbazepine (as the mono-hydroxylated derivative) serum concentrations during pregnancy may be considered. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-498 Neurology Table 5. Effect of Seizure Medications on Hormonal Contraceptives Seizure Medication Brivaracetam Carbamazepine Cenobamate Clobazam Eslicarbazepine Felbamate Lamotrigine Oxcarbazepine Perampanel Phenobarbital Phenytoin Primidone Rufinamide Topiramatea Benzodiazepines Cannabidiol Ethosuximide Fenfluramine Gabapentin Ganaxolone Lacosamide Levetiracetam Pregabalin Stiripentol Tiagabine Valproic acid Vigabatrin Zonisamide a Oral Contraceptives, Contraceptive Patch, Contraceptive Vaginal Ring, Progestogen Implant Decrease effectiveness Medroxyprogesterone Acetate Depot Injection, Levonorgestrel-Releasing Intrauterine System No effect No effect No effect Doses > 200 mg/day. E. Other Issues 1. Initiating therapy after a first seizure a. Guidance from the American Epilepsy Society and the American Academy of Neurology b. Adults with an unprovoked first seizure (e.g., not meningitis, intoxication) will have a 21%–45% chance of having more seizures within the next 2 years. Higher risks are associated with prior brain insults, EEG with epileptiform abnormalities, and nocturnal seizures. c. Initiating antiseizure medication (ASM) therapy will probably reduce recurrence risk within the first 2 years but may not increase quality of life. d. Initiating ASM therapy early does not change the long-term risk of seizures. 2. Driving: All states place driving restrictions on people with epilepsy; some require mandatory physician reporting to the state department of transportation. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-499 Neurology 3. Medication discontinuation a. The following criteria can be used to determine the possibility of withdrawal from ASM therapy: i. Patient should be seizure free for 2–5 years on seizure medication. ii. Patient should have a single type of focal or generalized seizures. iii. Patient should have a normal neurologic examination and normal IQ. iv. Patient’s EEG should have normalized with seizure medication treatment. b. If a medication is discontinued, it is usually tapered for several months; a typical regimen would reduce the dose by one-third for 1 month, reduce it by another one-third for 1 month, and then discontinue it. 4. Monitoring a. Number of seizures: The goal number of seizures is always zero. b. Signs of toxicity c. Laboratory values: Specific for each agent d. Blood concentrations: Available for many of the medications; commonly used for carbamazepine, phenobarbital, phenytoin, and valproic acid. The ILAE has a position paper on therapeutic drug monitoring, giving situations in which serum concentrations are most likely beneficial: i. When a person has attained the desired clinical outcome, to establish an individual therapeutic concentration that can then be used to assess potential causes for a change in drug response ii. As an aid in diagnosing clinical toxicity iii.  To assess adherence, particularly in patients with uncontrolled seizure or breakthrough seizures iv. To guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, older adults, patients with associated diseases, drug formulation changes) v. When a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when an interacting drug is added or removed) vi. To guide dose adjustments for seizure medications with dose-dependent pharmacokinetics, particularly phenytoin 5. Sexual dysfunction a. Described in 30%–60% of men and women with epilepsy b. Includes hyposexuality, orgasmic dysfunction, and erectile dysfunction c. Mechanism may be induction of CYP isoenzymes to increase testosterone metabolism, increased hepatic synthesis of sex hormone–binding globulin, or induction of aromatase, which converts free testosterone to estradiol. d. Sexual dysfunction has been reported with carbamazepine, phenobarbital, phenytoin, pregabalin, topiramate, and zonisamide. e. Improved sexual functioning has been reported with lamotrigine and oxcarbazepine. 6. Bone health a. Osteopenia or osteoporosis is found in 38%–60% of patients in tertiary epilepsy clinics. b. Increased fractures in patients with epilepsy and with seizure medication use c. Risk is increased with increased treatment duration; there is a dose-response relationship; the medications most often associated with poor bone health are carbamazepine, clonazepam, phenobarbital, phenytoin, and valproic acid. However, evidence now suggests that all seizure medications contribute to osteopenia or osteoporosis. d. Proposed mechanisms: Hepatic induction of CYP isoenzymes leads to increased vitamin D catabolism, impaired calcium absorption, calcitonin deficiency, vitamin K interference, and direct harmful effects on bone cells. e. Proposed treatments: High-dose vitamin D (4000 international units/day for adults and 2000 international units/day for children) improves bone mineral density compared with low doses; estrogen may be helpful for women but may also trigger seizures in some women. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-500 Neurology 7. Suicidality a. Meta-analysis of 199 placebo-controlled clinical trials of 11 drugs (n=43,892 patients older than 5 years) showed that patients who received seizure medications had about twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.22%), and there were four completed suicides in the treatment group versus zero in the placebo group. i. Risk is increased at 1 week and continues through week 24. ii. Patients with epilepsy (RR 3.6), psychiatric disorders (RR 1.6), or other conditions (RR 2.3) were all at elevated risk of suicidality; no differences between drugs; no differences between age groups b. The FDA requires a warning and a medication guide for all seizure medications. c. Recent observational studies show mixed results. When specific ASMs are examined, those most associated with depression and suicidality are levetiracetam, perampanel, phenobarbital, primidone, tiagabine, topiramate, and vigabatrin. d. A 2013 expert consensus statement made the following points: i. Although some (but not all) ASMs can be associated with treatment-emergent psychiatric problems that may lead to suicidal ideation and behavior, the actual suicidal risk has not yet been established; however, it seems to be very low. The risk of discontinuing ASMs or refusing to initiate them is significantly worse and can result in serious harm, including patient death. ii. Suicidality in epilepsy is multifactorial. Primary operant variables include postictal suicidal ideation; a history of psychiatric disorders, particularly mood and anxiety disorders (and above all, when associated with prior suicide attempts); and a family history of mood disorder complicated by suicide attempts. iii. When initiating or changing ASMs, patients should be advised to report any changes in mood and suicidal ideation. e. Self-care seizure plans i. Train patients and caregivers on first aid for seizures. ii. Instruct on when patient should receive emergency care. iii. Provide seizure rescue medication (e.g., intranasal diazepam, intranasal midazolam). Patient Cases Questions 1–3 pertain to the following case. T.M. is a 23-year-old woman with newly diagnosed generalized motor myoclonic-type seizures. She is in good health and takes oral contraceptives. 1. Which is the best medication for T.M.’s seizures? A. Valproate. B. Phenytoin. C. Phenobarbital. D. Levetiracetam. 2. T.M. is concerned about the impact of levetiracetam on her oral contraceptives. Which response is best? A. Levetiracetam does not alter the effectiveness of your oral contraceptives. B. You should use alternative forms of birth control because levetiracetam decreases oral contraceptive effectiveness. C. You may have breakthrough bleeding, but the effectiveness of the oral contraceptive is not changed. D. Oral contraceptives decrease the effectiveness of levetiracetam, so you need another form of birth control. ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-501 Neurology Patient Cases (Cont’d) 8. M.G. has been prescribed levetiracetam. On which adverse effect is it best to counsel M.G.? A. Hepatoxicity. B. Renal stones. C. Depression. D. Word-finding difficulties. Questions 9 and 10 pertain to the following case. G.Z., a 26-year-old woman, presents with a 6-month history of “spells.” The spells are all the same, and all begin with a feeling in the abdomen that is difficult for her to describe. This feeling rises toward the head. The patient believes that she will then lose awareness. After a neurologic workup, she is diagnosed with focal seizures evolving to a bilateral, convulsive seizure. The neurologist is considering initiating either carbamazepine or oxcarbazepine. 9. Which is the most accurate comparison of carbamazepine and oxcarbazepine? A. Oxcarbazepine causes more liver enzyme induction than carbamazepine. B. Oxcarbazepine does not cause rash. C. Oxcarbazepine does not cause hyponatremia. D. Oxcarbazepine does not form an epoxide intermediate in its metabolism. 10. When you see G.Z. 6 months later for a follow-up, she tells you she is about 6 weeks pregnant. She has had no seizures since starting oxcarbazepine. Which strategy is best for G.Z.? A. Discontinue her seizure medication immediately. B. Change her seizure medication to topiramate. C. Continue her seizure medication. D. Change her seizure medication to lamotrigine. II. ISCHEMIC STROKE A. Epidemiology 1. Updated definitions a. CNS infarction: Brain, spinal cord, or retinal cell death attributable to ischemia, according to pathologic evidence, imaging, or other objective evidence of cerebral, spinal cord, or retinal focal ischemic injury in a defined vascular distribution, or clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury, given symptoms persisting for 24 hours or more or until death, and other etiologies excluded b. Ischemic stroke: An episode of neurologic dysfunction caused by focal cerebral, spinal, or retinal infarction 2. Third or fourth most common cause of death in all developed countries 3. More than 795,000 cases per year in the United States (128,842 deaths) 4. Most common cause of adult disability ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-503 Neurology 5. Risk factors a. Nonmodifiable i. Age: Stroke risk doubles each decade after 55 years. ii. Race: Stroke risk for American Indian populations is greater than for African American populations, whose risk is greater than for White populations. iii. Sex: Risks are greater for men than for women; however, about one-half of strokes occur in women. iv. Low birth weight: Odds of stroke for those with birth weights less than 2500 g are twice has high as the odds for those weighing more than 4000 g. v. Family history: Parental history increases risk; some coagulopathies (e.g., protein C and S deficiencies, factor V Leiden mutations) are inherited. vi.  Systemic lupus erythematosus b. Somewhat modifiable: Diabetes increases risk 1.8–6 times; risk reduction has not been shown for glycemic control. c. Modifiable i. Hypertension increases risk 1.4–8 times; 32% risk reduction with control ii. Smoking increases risk 1.9 times; 50% risk reduction in 1 year, baseline risk of stroke at 5 years with smoking cessation; exposure to environmental cigarette smoke also increases risk iii. Oral contraceptives with less than 50 mcg of estrogen double the risk of stroke; those with more than 50 mcg of estrogen have a 4.5 times increased risk; risk increases with age; adding smoking to oral contraceptive use increases the risk of stroke 7.2 times; obesity and hypertension also increase the risk with oral contraceptives. iv. Postmenopausal hormone therapy increases risk 1.4 times. v. Atrial fibrillation increases risk 2.6–4.5 times; 68% risk reduction with warfarin; direct oral anticoagulants have risk reduction similar to warfarin vi. Coronary heart disease increases risk 1.55 times (women) to 1.73 times (men). vii. Asymptomatic carotid stenosis increases risk 2 times; about a 50% risk reduction with endarterectomy viii. Dyslipidemia: High TC increases risk 1.5 times; low HDL (less than 35 mg/dL) increases risk 2 times; 27%–32% risk reduction with statins in patients with coronary heart disease, hypertension, or diabetes. Twenty-five percent risk reduction with high-dose statins compared with low-dose statins ix. Obesity (especially abdominal body fat) increases risk 1.75–2.37 times; risk reduction with weight loss is unknown. x. Physical inactivity increases risk 2.7 times; risk reduction with increased activity is unknown. xi. Sickle cell disease increases risk 200–400 times; 91% risk reduction with transfusion therapy xii. Peripheral artery disease increases risk 3 times; impact of risk reduction strategies is unknown. xiii. Pregnancy increases risk by 2.4 times over nonpregnant women; the risk remains elevated for the first 6 weeks after delivery. xiv. Patent foramen ovale increases the risk of stroke in young patients (younger than 55 years). xv. Risk of stroke is increased 1.35 times in depressed people compared with nondepressed people. d. Less well documented: Alcohol use disorder (5 or more drinks a day), hyperhomocystinemia, drug use disorder (cocaine, amphetamines, and heroin), hypercoagulability, periodontal disease, inflammation and infection, sleep-disordered breathing (sleep apnea and snoring), metabolic syndrome, and migraine with aura ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-504 Neurology B. Primary Prevention 1. Reduction in risk factors (e.g., control of hypertension, smoking cessation, control of diabetes, cholesterol reduction). Control of hypertension produces the greatest benefit in primary prevention of stroke. 2. Patient education: Patients should be educated about stroke warning signs and instructed to seek emergency care if they have any of them. Warning signs: Sudden numbness or weakness of the face, arm, or leg, especially on one side of the body; sudden confusion; trouble speaking or understanding; sudden trouble seeing in one or both eyes; sudden trouble walking; dizziness, loss of balance or coordination; sudden, severe headache with no known cause 3. Treatment of atrial fibrillation: Up to 70% of cases are inappropriately treated. (For a more detailed discussion, see the Anticoagulation chapter.) a. Dabigatran (Pradaxa): When oral anticoagulation is recommended and the patient’s bleeding risk is high, current guidelines suggest dabigatran 150 mg twice daily over warfarin (target INR of 2.5). Dabigatran had similar rates of hemorrhage, but intracranial hemorrhage was less likely with dabigatran and GI hemorrhage was more likely. b. Rivaroxaban (Xarelto) was noninferior to warfarin therapy and had a similar risk of major bleeding. Rivaroxaban had a higher risk of GI bleeding, but a lower risk of intracranial hemorrhage and fatal bleeding, compared with warfarin therapy. c. Apixaban (Eliquis) is more effective than warfarin, with a lower risk of stroke and lower risk of bleeding and mortality. d. Edoxaban (Savaysa) is as effective as warfarin, with a lower risk of bleeding. e. Warfarin (Coumadin) is probably more effective than clopidogrel plus aspirin, but intracranial bleeding is more common. C. Treatment of Acute Event 1. Heparin a. Good data on outcomes are unavailable; not recommended for stroke treatment at therapeutic doses; increases risk of hemorrhagic transformation; heparin is often used for deep venous thrombosis prevention at a dose of 10,000–15,000 units/day administered subcutaneously b. Avoid in hemorrhagic stroke. 2. Tissue plasminogen activator (Alteplase) a. Within 4½ hours of symptom onset b. 90-day outcomes significantly improve (decreased disability). c. Intracerebral hemorrhage increases but mortality does not. d. Dose 0.9 mg/kg intravenously (maximum is 90 mg), with 10% as a bolus and the remainder over 1 hour. The bolus should be administered within 60 minutes of hospital arrival. e. Antiplatelet agents should be held for 24 hours after tissue plasminogen activator administration. f. Exclusion criteria i. Intracranial bleeding (or history) or subarachnoid bleeding ii. Other active internal bleeding iii. Intracranial/spinal surgery, head trauma, stroke within 3 months iv. Major surgery or serious trauma within 2 weeks, if risk of bleeding outweighs the anticipated benefits of reduced stroke-related neurologic deficits v. GI hemorrhage within 3 weeks or structural GI malignancy vi. Blood pressure greater than 185/110 mm Hg. If medications are administered to lower blood pressure, blood pressure should be stabilized before beginning treatment and maintained below 180/105 mm Hg for at least the first 24 hours after treatment. vii. Glucose less than 50 mg/dL or greater than 400 mg/dL, unless subsequently normalized viii. A rterial puncture at a noncompressible site within 1 week ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-505 Neurology ix. Intracranial intra-axial neoplasm, arteriovenous malformation, or giant unruptured and unsecured aneurysm x. INR greater than 1.7, activated PTT greater than 40 seconds, PT greater than 15 seconds, Plt less than 100,000 cells/m3, patients who have received a dose of low-molecular-weight heparin within the previous 24 hours, or patients who have taken direct thrombin inhibitors or direct factor Xa inhibitors in the previous 48 hours xi. Infective endocarditis xii. Pregnancy, if the anticipated benefits of treating moderate to severe stroke do not outweigh the anticipated risks of uterine bleeding xiii. Individuals presenting in the 3- to 4½-hour window may benefit even if they are older than 80, take warfarin, have a history of diabetes with previous stroke, or have severe stroke symptoms (NIHSS [National Institutes of Health Stroke Scale] score greater than 25). 3. In patients with minor strokes or transient ischemic attack (TIA), DAPT with aspirin and clopidogrel should be initiated immediately and continued for 21 days. 4. A clot retriever within 24 hours may be useful in selected patients with or without prior tissue plasminogen activator. D. Secondary Prevention 1. Reduction in all modifiable risk factors (specific changes in the text that follows according to Stroke 2021;52:e364-e467) a. Hypertension: Goal less than 130/less than 80 mm Hg. With lacunar stroke, may target less than 130 mm Hg systolic b. Hyperlipidemia: High-intensity statin therapy should be initiated or continued as first-line therapy in women and men younger than 75 who have had stroke or TIA. 2. Carotid endarterectomy if 70%–99% stenosis. For 50%–69% stenosis, the carotid endarterectomy recommendation depends on age, sex, and comorbidities; use aspirin 50–100 mg/day and statin therapy before and after the procedure. 3. Carotid angioplasty and stenting may be an alternative to carotid endarterectomy in some patients, particularly younger patients. 4. Antiplatelet therapy: DAPT with aspirin and clopidogrel should be initiated within 24 hours of a minor stroke or TIA and continued for 21 days. After a major stroke (e.g., intracranial atherosclerosis, severe stenosis), DAPT with aspirin and clopidogrel should be initiated and continued for 90 days. After these time intervals, therapy should be transitioned to single antiplatelet therapy and continued indefinitely. Each agent has shown efficacy in reducing secondary stroke risk. Guidelines differ slightly on their recommendations. The American Stroke Association suggests that aspirin, aspirin/extended-release dipyridamole, and clopidogrel are all options for ongoing prophylaxis. a. Aspirin i. Dose: 50–100 mg/day ii. If the patient has an additional stroke while taking aspirin, no evidence suggests increasing the aspirin dose will provide additional benefit. b. Aspirin/dipyridamole (Aggrenox) i. Capsule contains dipyridamole extended-release pellets (200 mg) and aspirin tablet (25 mg). ii. Dose: 1 capsule orally twice daily iii. Most common adverse effects: Headache, nausea, and dyspepsia; can increase liver enzymes ACCP Updates in Therapeutics® 2023: The Pharmacotherapy Preparatory Review and Recertification Course 1-506