1 Dr.Hisham Ah. Nematall a Pharmacotherapy of cerebrovascular diseases & peripheral artery disease (PAD) Intended Learning Objectives 1. Understand the types of cerebrovascular disease including transient ischemic attack, cerebral infarction, and cerebral hemorrhage. 2. Identify the modifiable and non - modifiable risk factors associated with ischemic stroke and hemorrhagic stroke. 3. P rovide the appropriate patient education. 4. Discuss the various treatment options for acute ischemic stroke and hemorrhagic stroke. 5. De termine whether thrombolytic therapy is indicated in a patient with acute ischemic stroke. 6. Develop an appropriate patient - specific therapeutic plan for acute ischemic stroke. 7. Identify peripheral artery disease (PAD) and its pharmacotherapeutic approach erebrovascular disease (CVD) or stroke is the leading cause of long - term disability in adults, with 90% of survivors having residual deficits. Moderate to severe disability is seen in 70% of survivors. Strokes can either be ischemic (88% of all str okes) or hemorrhagic (12% of all strokes). Hemorrhagic stroke  Hemorrhagic stroke is a result of bleeding into the brain and other spaces within the central nervous system and includes subarachnoid hemorrhage , intracerebral hemorrhage , and subdural hematomas  Subarachnoid hemorrhage (SAH) results from sudden bleeding into the space between the inner layer and middle layer of the meninges , most often due to trauma or rupture of a cerebral aneurysm or arteriovenous malformation (AVM). c 2 Dr.Hisham Ah. Nematall a  Intracerebral hemorrhage (ICH) is bleeding directly into the brain parenchyma, often as a result of chro nic, uncontrolled hypertension.  Subdural hematomas (SDH) result from bleeding under the dura which covers the brain and most often occur as a result of head trauma Symptoms  Sudd en severe headache , nausea and vomiting, and photophobia may be the fi rst signs and symptoms of hemorrhagic stroke.  Neck pain and stiffness may also be experienced at the time of the hemorrhage.  Patients may complain that the headache is “ the worst headache of my life, ” especially if the cause is an SAH. Treatment of acute hemorrhagic st r oke Desired therapeutic outcomes  T he short - term goals f or the treatment of hemorrhagic stroke include rapid neurointen sive care treatment to maintain adequate oxygenation, breathi ng, and circulation.  Management of increased intracranial press ure and blood pressure (BP) are important in the acute setting  Long - term management includes prevention of complications and prevention of a recurrent bleed and delayed cerebral ischemia ( post - hemorrhagic phase of ischemia due to inflammatory mediators release causing vasospasm of cerebral arteries in the affected area) Supportive Measures  There is no proven treatment for intracerebral hemorrhage. Management is based on neurointensive care treatment and prevention of complications.  Treatment should be provided to manage the needs of the critically ill patient includi ng management of increased intracranial pressure, seizures, infections, and prevention of re - bleeding an d delayed cerebral ischemia. 3 Dr.Hisham Ah. Nematall a  For ICH speci fi cally, uncontrolled hypertension is thought to be the cause of hemorrhage in 60% to 70% of patients.  Blood pressure is often elevated after hem orrhagic stroke and appropriate management is important to prevent re - bleeding and expansion of the hematoma.  B lood pressure can be controlled with IV boluses of labetalol 10 to 80 mg every 10 minutes up to a maximum of 300 mg or with IV infusions of labetalol (0.5 to 2 mg/minute) or nicardipi ne (5 to 15 mg/hour ) Surgical Therapy  In SAH, either clipping of the aneurysm or coil embolization is recommended w ithin 72 hours after the initial event to prevent re - bleeding. Calcium Antagonists  Oral nimodipine (60 mg every 4 hours for 21 days) is recommended in subarachnoid hemorrhage to prevent delayed cerebral ischemia  Delayed cerebral ischemia occurs 4 to 14 days after the initial aneurysm rupture and is a common cause of neurologic deficits and death. Hemostatic Therapy  Recombinant factor VIIa as an IV infusion over 1 to 2 minutes within 4 hours after the onset of symptoms has been shown to have a benefit in the treatment of ICH. 4 Dr.Hisham Ah. Nematall a Ischemic Stroke:  Ischemic stroke is defined as brain cell death attributable to ischemia, based on neuropathological, neuroimaging, and/or clinical evidence of permanent injury.  Caused by large artery atherosclerotic infarction which may be extra - crani al or intra - cranial o r embolism from a cardiac source or small vessels diseases ( l acunar infarction) Transient ischemic attack (TIA)  T ransient episode of neurological dysfunction caused by focal brain ischemia, without acute infarction.  Although a TIA leaves no immediate impairment, affected individuals have a high risk for future ischemic events, particularly in the days and weeks immediately after symptom resolution. Risk factors  A major goal in the long - term treatment of ischemic stroke involves the prevention of a recurrent stroke through the reduction and modification of risk factors.  The major focus of primary prevention (prevention of the f irst stroke) is also reduction and mo dification of risk factors.  Risk factors for ischemic stroke can be divided into mo difiable and non - modifiable factors.  Non - modifiable risk factors include age (> 55 years), gender (male > female) , race/ ethnicity (African - Americans, Hispanics) , and heredity (family history)  Modifiable risk factors include a number of treatable disease states and lifestyle factors that can greatly influence overall stroke risk. 5 Dr.Hisham Ah. Nematall a Modifiable Risk Factors for Ischemic Stroke  Hypertension is one of the major risk factors for ischemic stroke.  Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice with substantial morbidity and mortality.  The risk of stroke is increased two - to seven - fold in patients with AF compared to patients without this arrhythmia. Public stroke education  The chain of events favoring good functional outcome from an acute ischemic stroke begins with the recognition of stroke when it occurs.  Before 2008, the 5 “Suddens” of stroke warning signs (sudden weakness; sudden speech difficulty; sudden visual loss; sudden dizziness; sudden, severe headache) were used widely in public education campaigns  The FAST stroke message campaign, first promoted a decade ago, is being reintroduced in public educa tion efforts.  F acial drooping: A section of the face, usually only on one side, that is drooping and hard to move. This can be recognized by a crooked smile.  A rm weakness: The inability to raise one's arm fully  S peech difficulties: An inability or difficulty to understand or produce speech  T ime: If any of the symptoms above are showing, time is of the essence; call the emergency services or go to the hospital 6 Dr.Hisham Ah. Nematall a Desired therapeutic outcome s:  The short - term goals of treatment for acute ischemic stroke include reducing secondary brain damage by re - establishing and maintaining adequate perfusion to marginally ischemic areas of the brain and to protect these areas from the effects of ischemia (neuroprotection).  The long - term goals of treatment include prevention of a recurrent stroke through reduction and modification of risk factors and by use of appropriate treatments. Diagnosis  All patients should have a brain computed tomography (CT) scan or magnetic resonance imaging (MRI) sca n to differentiate an ischemic stroke from a hemorrhagic stroke, as the treatment will differ accordingly  Thrombolytic (fibrinolytic) therapy must be avoided until a hemorrhagic stroke is ruled out (in other words, until it is determined that it is not a hemorrhagic stroke). 7 Dr.Hisham Ah. Nematall a American Heart Association/American Stroke Association (AHA/ASA) guidelines for e arly m anagement of p atients with a cute i schemic s troke , 201 3 Intravenous rtPA 1. Intra venous Alteplase (rt - PA; Activase) ( 0.9 mg/kg, maximum dose 90 mg ) is recommended for selected patients who may be treated within 3 hours of onset of ischemic stroke (Class I; Level of Evidence A) Physicians should review the criteria to determine the eligibility of the patient for thrombol ytic therapy. 2. In patients eligible for intravenous rtPA, benefit of therapy is time dependent, and treatment should be initiated as quickly as possible. The door - to - needle time (time of bolus administration) should be within 60 minutes from hospital arrival. ( C lass I, Level of evidence A ) 8 Dr.Hisham Ah. Nematall a 3. Intravenous rtPA (0.9 mg/kg, maximum dose 90 mg) is recommended for administration to eligible patients who can be treated in the time period of 3 to 4.5 hours after stroke onset (Class I; Level of Evidence B) . The eligibility criteria for treatment in this time period are similar to those for people treated at earlier time periods within 3 hours, with the following additional exclusion criteria:  patients >80 years old,  severe stroke  those taking oral anticoagulants regardless of INR,  or those with a history of both stroke and diabetes mellitus. 4. Intravenous rtPA is reasonable in patients whose blood pressure can be lowered safely (to below 185/110 mm Hg) with antihypertensive agents, with the physician assessing the stability of the b lood pressure b efore starting intravenous rtPA. 5. In patients undergoing fibrinolytic therapy, physicians should be aware of and prepared to emergently treat potential side effects, including bleeding complications (ICH) and angioedema that may cause partia l airway obstruction 6. The usefulness of intravenous administration of tenecteplase, reteplase, desmoteplase, urokinase, or other fibrinolytic agents and the intravenous administration of ancrod is not well established. 7. The intravenous administration of streptokinase for treatment of stroke is not recommended (Class III; Level of Evidence A) 8. The use of intravenous rtPA in patients taking direct thrombin inhibitors or direct factor Xa inhibitors may be harmful and is not recommended unless sensitive laboratory tests such as aPTT, INR, platelet count, are normal, or the patient has not received a dose of these agents for >2 days (assuming normal renal metabolizing function). 9 Dr.Hisham Ah. Nematall a Endovascular intervention:  The number of options for endovascular treatment of ischemic stroke has increased substantially over the past decade to include intra - arterial fibrinolysis, mechanical clot retrieval  Intra - arterial fibrinolysis is beneficial for treatment of carefully selected patients with major ischemic strokes of <6 hours’ duration caused by occlusions who are not otherwise candidates for intravenous rtPA (4.5 - 6 hours, major surgical procedure ). Anticoagulant  The results of several clinical trials demonstrate there is an increased ri sk of bleeding complications with early administration of either UFH or LMWH. Early administration of anticoagulants does not lessen the risk of early neurological worsening  Data indicate that early administration of UFH or LMWH does not lower the risk o f early recurrent stroke, including among people with cardioembolic sources.  At present, the usefulness of thrombin inhibitors for treatment of patients with acute ischemic stroke is not well established  Urgent anticoagulation, with the goal of preventing early recurrent stroke, halting neurological worsening, or improving outcomes after acute ischemic stroke, is not recommended for treatment of patients with acute ischemic stroke ( Class III, Level of E vidence A ) Antiplatelets  Currently available data demonstrate a small but sta tistically significant decline in mortality and unfavorable outcomes with the administration of aspirin within 48 hours after stroke.  It appears that the primary effects of aspirin are attributable to a reduction in early recurrent stroke.  Oral administration of aspirin (initial dose is 325 mg) within 24 to 48 hours after stroke onset is recommended for treatment of most patients ( C lass I, Level of Evidence A)  The usefulness of clopidogrel for the treatment of acute ischemic stroke is not well established 10 Dr.Hisham Ah. Nematall a  The administra tion of aspirin (or other antiplatelet agents) as an adjunctive therapy within 24 hours of intravenous fibrinolysis is not recommended Risk factors control for all pati ent with TIA or ischemic stroke according to AHA/ASA guidelines 2013 Hypertension  Treatment of hypertension is possibly the most important intervention for secondary prevention of ischemic stroke  The prevalence among patients with a recent ischemic stroke is ≈70%.  The risk for a first ischemic stroke is directly related to blood pressur e (BP) starting with an SBP as low as 115 mm Hg.  Large reductions in SBP tended to be associated with greater reduction in risk of recurrent stroke  A significant reduction in recurrent stroke was seen with diuretics (alone or in combination with angiotens in converting enzyme inhibitors Hypertension Recommendations  Initiation of BP therapy is indicated for previously untreated patients with ischemic stroke or TIA who, after the first several days, have an established BP ≥140 mm Hg systolic or ≥90 mm Hg diastolic  Initiation of therapy for patients with BP <140 mm Hg systolic and <90 mm Hg diastolic is of uncertain benefit Goals for target BP level or reduction from pretreatment baseline are uncertain and should be individualized, but it is reasonable to achieve a systolic pressure <140 mm Hg and a diastolic pressure <90mm Hg  For patients with a recent lacunar stroke, it might be reasonable to target an SBP of <130 mm Hg (Class IIb; Level of Evidence B)  The available data indicate that diuretics or the c ombination of diuretics and an angiotensin - converting enzyme inhibitor is useful (Class I; Level of Evidence A ). 11 Dr.Hisham Ah. Nematall a Medical t reatments for p atients w ith Cardiogenic Embolism Atrial Fibrillation  The principal adverse consequence of AF is ischemic stroke.  Thus, treatment of AF among patients with prior ischemic stroke is a major focus of preventive care in neurology.  Warfarin is the mainstay treatment of non - valvular atrial fibrillation due to its superiority to aspirin and the antiplatelet combination aspi rin & clopidogrel.  NOACs have been approved & indicated for the prevention of recurrent stroke in patients with non - valvular AF. AF recommendations  F or patients who have experienced and acute ischemic stroke or TIA with no apparent cause, prolonged rhythm monitoring (30 days) for AF is reasonable.  VKA therapy ( Class I; Level of Evidence A) , apixaban (Class I; Level o f Evidence A) , a nd dabigatran (Class I; Level of Evidence B) are all indicated for the prevention of recurrent stroke in patients with non - valvular AF, whether paroxysmal or permanent.  The selection of an antithrombotic agent should be individualized on the basis of risk fac tors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including renal function and time in INR therapeutic range (TTR) if the patient has been taking VKA therapy.  Ri varoxaban is reasonable for the prevention of recurrent stroke in patients with non - valvular AF (Class IIa; Level of Evidence B)  For patients with ischemic stroke or TIA with paroxysmal (intermittent), persistent, or permanent AF in whom VKA therapy is begun, a target INR of 2.5 is recommended (range, 2.0 – 3.0) (Class I; Level of Evidence A ).  The combination of oral anticoagulat ion (warfarin or one of the newer agents) with antiplatelet therapy is not recommended for all patients after ischemic stroke or TIA but is reasonable in patients with clinically apparent CAD, particularly an acute coronary syndrome or sten t placement. 12 Dr.Hisham Ah. Nematall a Peripheral Artery diseases (PAD) S ymptomatic PAD is defined as the presence of typical claudication symptoms ( claudication: pain in the muscles of the leg with ambula tion ) in combination with an abnormal ankle: brachial index (ABI) In contrast, asymptomatic PAD is defined as the finding of an abnormal ABI ( < 0.9) alone without limb symptoms. ABI:  Ankle - brachial index (ABI) is the ratio of the blood press ure at the ankle to the blood pressure in the upper arm (brachium).  Compared to the arm, lower blood pressure in the leg is an indication of blocked arteries due to peripheral artery dise ase (PAD).  The ABI is calculated by dividing the systolic blood pressure at the ankle by the systolic blood pressure in the arm  ABI > 1. 4 : Calcified & incompressible arteries (DM)  ABI: 1 - 1. 4 : normal range  ABI: 0.9 - 0.99 : acceptable  ABI < 0.9: PAD Pharmacotherapy  The risk of MI, stroke, and death are increased in patients with atherosclerotic PAD,  Risk factor modifying therapies and antiplatelet drugs are recommended in patients with PAD, as they are in patients with coronary artery disease (CAD) and cerebrovascul ar disease  The most important of these are age and sex; atherosclerosis of the lower extremities is more common in elderly individuals and in men.  Diabetes mellitus is a most important risk factor for large vessel atherosclerotic occlusive disease. 13 Dr.Hisham Ah. Nematall a Therapies to Reduce Systemic Cardiovascular Events Antiplatelet therapy  Patients with PAD have a high r isk of atherothrombotic events.  Antithrombotic therapy, and particularly antiplatelet monotherapy, has shown benefit for atherothrombotic risk reduction in patients with symptomatic PAD.  Symptomatic patients with an ABI ≤0.85 benefit from monotherapy with aspirin or clopidogrel, and there is some data suggesting that dual antiplatelet therapy with both drugs may be effective.  Vorapaxar in combination wit h either aspirin, clopidogrel, or both reduces cardiovascular events in PAD patients who have no prior history of stroke or TIA, but is contraindicated if a history of stroke or TIA is present.  The use of warfarin in preference to antiplatelet therapy is not recommended unless another indication is present, such as atrial fibrillation or mechanical prosthetic heart valve and has been associated with high rates of bleeding. Smoking Cessation  Smoking is also closely linked to PAD, where the risk of intermittent claudication was reported to be three times greater in smokers. Lipid l owering t herapy  The American College of Cardiology/American Heart Association (ACC/AHA) for PAD Guidelines recommend lipid lowering therapy with a statin for patients with PAD, targeting an LDL - cholesterol < 100mg/dl and suggest that lower target < 70 mg/dl may be beneficial in high - risk patient. Antihypertensive therapy  In general, it is recommended th at patients with PAD have blood pressure controlled to s tandard targets of ≤140/90 mmHg. 14 Dr.Hisham Ah. Nematall a  Broad potential vascular benefits have been described as possible mechanisms of benefit for ACE I or ARB therapy, beyond blood pressure lowering alone.  These mechanisms include enhancement in endothelial function, reductions in oxidative s tress, and other vascular protective effects.  RCT study showed that Ramipril increased maximal walking distance & improved pain - free wa lking distance. Hypoglycemic therapy  Recent guideline statements have recommended a patient - centered approach recognizing the potential harms of hypoglycemia on cardiovascular health  Recommendations include latitude with mor e stringent glycemic targets for young patients with long life expectancy and no established vascular complications and less stringent targets for patients with established vascular disease Therapies to Reduce Limb Morbidity Exercise training  E xercise training has multiple benefits in patients with PAD, including the reduction of limb symptoms, improvement in functional capacity, and the reduction of systemic cardiovascular risk. Cilo stazol  S pecific inhibitor of phosphodiesterase - 3, reported to have a b road range of potentially beneficial actions, including reducing platelet aggregation and smooth muscle proliferation, as well as enhancing vasodilation.  Overall, cilostazol increased maximal and pain - free walking distances Pentoxifylline  P entoxifylline, may improve claudication symptoms by reducing blood viscosity through increasing deformability of erythrocytes and leukocytes.  Although pentoxifylline has been shown to improve symptoms of claudication, the overall benefit is small. 15 Dr.Hisham Ah. Nematall a  Accordin gly, pentoxifylline is considered for therapy only in patients who are not able to receive or tolerate cilostazol

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Hisham Nematalla