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Sandeep Sachdeva, MD

Patients with acute stroke or transient ischemic attack (TIA) should be admitted to a hospital for initial care and assessment; however, a substantial number of these patients will never be seen by a neurologist because of the limited number of physicians in this specialty area. Currently there is only one neurologist per 26,000 people in the United States, and most neurologists prefer to practice in the outpatient setting.1 According to one study, only 11.3% of stroke patients are attended exclusively by a neurologist.2 Hospitalists play a vital role in overcoming this lack of specialized care for stroke patients.

Pharmacotherapy

A significant body of evidence supports secondary prevention as a critical intervention strategy in reducing stroke risk. Identifying specific risk factors remains pivotal to successful secondary prevention. Managing hypertension, diabetes, and hyperlipidemia serves as an effective preventive role; however, preventive management with antithrombotic agents is an important part of the drug regimen for secondary prevention of recurrent ischemic stroke (IS).3

The choice of pharmacologic agents is based on stroke etiology. Anticoagulants such as warfarin are restricted to patients with stroke due to a cardioembolic source, whereas antiplatelet agents are mainly used to treat noncardioembolic and lacunar strokes.4 Currently, four oral antiplatelet agents may be used as therapy to prevent secondary IS: aspirin (acetylsalicylic acid or ASA), ticlopidine, clopidogrel, and ASA plus extended-release dipyridamole.

Currently, four oral antiplatelet agents may be used as therapy to prevent secondary ischemic stroke: aspirin (ASA), ticlopidine, clopidogrel, and ASA plus extended-release dipyridamole.

Aspirin

ASA is the most widely used and cost-effective antiplatelet agent. A salicylate, it blocks platelet activation by inhibiting the cyclo-oxygenase enzymes (COX-1 and COX-2). In several primary prevention trials ASA was associated with a statistically significant reduction in risk of first myocardial infarction (MI). Neither overall cardiovascular mortality nor total number of strokes was reduced by long-term ASA prophylaxis, however.5

ASA was shown to be effective in secondary prevention of noncardioembolic stroke (offering equivalent or better efficacy compared with warfarin) in the Stroke Prevention in Reversible Ischemia Trial and the Warfarin-Aspirin Recurrent Stroke Study.6 The Swedish Aspirin Low-Dose Trial, Dutch TIA Trial, and United Kingdom Transient Ischaemic Attack Aspirin Trial consistently demonstrated the efficacy and reduced gastric toxicity of low-dose ASA.7 A meta-analysis of 197 randomized trials versus control and 90 randomized comparisons between antiplatelet regimens show risk reduction with ASA of approximately 23% in combined vascular events (MI, stroke, and vascular death).8

Ticlopidine

Ticlopidine hydrochloride (thienopyridine) blocks platelet activation by inhibiting adenosine diphosphate-induced fibrinogen binding.7 Ticlopidine was superior to placebo and high-dose ASA in reducing the occurrence of stroke, MI, or vascular death in patients of both genders who had recent cerebral ischemia. This was demonstrated in two major phase 3 multicenter trials: the Ticlopidine Aspirin Stroke Study and the Canadian American Ticlopidine Study.9 Despite ticlopidine’s efficacy in these trials, the drug has been associated with severe adverse effects, including life-threatening neutropenia (1%) and thrombocytopenic purpura (one per 1,600 to 5,000 patients treated).3

Clopidogrel

The ticlopidine analogue clopidogrel is a potent inhibitor of platelet aggregation induced by adenosine diphosphate.7 The efficacy and safety of clopidogrel was evaluated in a randomized, double-blind, multicenter study—the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events trial, the largest clinical study of clopidogrel—of 19,000 patients with stroke, MI, or peripheral arterial disease.10

In this study, clopidogrel showed a more favorable safety and tolerability profile than ticlopidine; however, compared with ASA clopidogrel offered only a modest benefit of 8.7% for all cardiovascular events and showed no significant benefit over ASA for recurrent stroke.

 

 

Findings from two randomized trials—Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO)—have shown sustained benefits of clopidogrel for combined endpoints of MI, stroke, and vascular death.11-12 The incidence of stroke was very small and the risk of serious bleeding was significantly increased.

These trials provided the rationale to undertake the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke study (MATCH).13 This study was designed to determine whether the addition of ASA to clopidogrel would further reduce the risk of recurrent ischemic attacks in high-risk patients after recent IS or TIA, as was observed with coronary manifestations of atherothrombosis in the CURE and CREDO trials.

MATCH, a randomized, double-blind, placebo-controlled trial, involved 7,599 patients and compared clopidogrel with low-dose ASA plus clopidogrel. During an 18-month follow-up, no significant benefit was observed for ASA plus clopidogrel versus clopidogrel monotherapy; however, there was a significant increase in the risk of life-threatening bleeding in the group receiving combined therapy (2.6% versus 1.3%, respectively). Therefore, ASA plus clopidogrel is not a recommended option for prevention of secondary stroke in cerebrovascular patients.

STROKE

The scope of the problem

Stroke is one of the most significant health problems in the United States. Approximately 700,000 strokes and occur each year. Of these, 200,000 are recurrent strokes.18 Extensive studies have identified increasing age as the leading risk factor for stroke.16

Approximately 72% of stroke patients are older than 65; on average, patients with stroke tend to be older than patients with MI.4-19 Thus, the frequency of stroke will increase dramatically with lengthening of life expectancy and advancing age of our population.

A history of TIA poses another strong risk factor for stroke. Each year approximately 300,000 Americans suffer TIAs; about one-third of these people will develop a stroke.20-21 Risk factors include hypertension, cigarette smoking, diabetes mellitus, hyperlipidemia, obesity, and heart disease.—SS

ASA Plus Extended-Release Dipyridamole

The Second European Stroke Prevention Study (ESPS-2), a randomized trial with 2,500 patients, was conducted to compare the efficacy of ASA plus dipyridamole versus placebo. Dipyridamole is a pyrimidopyrimidine derivative from the papaverine family with antithrombotic properties and vasodilatory effects on cells and vasculature.14 It inhibits phosphodiesterases, resulting in increased concentration of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP), which inhibits platelet activation and adhesion.14

ESPS-2 results showed a 38% relative reduction in risk of stroke for the combination versus placebo. The study did not include an ASA-only group. Results prompted reformulation of dipyridamole into a high-dose extended-release capsule combined with low-dose ASA. The higher dose and slower release of dipyridamole combined with ASA provides a more consistent plasma level and is less affected by stomach acidity or concomitant medications.

This combination was tested versus ASA alone in the ESPS-2 trial.15 ESPS-2, a randomized, double-blind, multicenter study, enrolled 6,602 patients with prior stroke or TIA. During the two-year follow-up ASA plus extended-release dipyridamole reduced the risk of recurrent stroke by 37% compared with placebo, and by 22% compared with ASA or dipyridamole alone. Adverse events associated with this combination are similar to those observed with low-dose ASA.

These results were further substantiated by a recent post hoc analysis conducted using data from the ESPS-2 trial. ASA plus extended-release dipyridamole had greater efficacy in preventing stroke than ASA; this difference in efficacy was more pronounced in high-risk patients.16

We need further studies that include direct comparisons to verify the most effective and safe antiplatelet agent for secondary stroke prevention. The Prospective Regimen for Effectively Avoiding Second Strokes (PRoFESS) is a head-to-head trial designed to compare the combination of ASA plus extended-release dipyridamole to clopidogrel in terms of efficacy and safety. This study includes 15,500 patients in more than 20 countries at approximately 600 sites.17

 

 

Conclusions

Stroke remains a major public health concern. Hospitalists play a central role in stroke management by improving the overall quality of hospital care for stroke patients. Still, most residency programs don’t provide sufficient stroke education. Therefore, comprehensive neurology educational programs should be provided for hospitalists so they can provide efficient inpatient care; initiate effective secondary prevention strategies tailored to the specific needs of the patients, starting with appropriate antiplatelet therapy; monitor patients at poststroke rehabilitation centers during recovery period; and educate stroke patients and their caregivers about the disease and its risk factors.

Hospitalists can also initiate effective communication with outpatient primary care providers at the time of discharge to help ensure that the secondary prevention strategies initiated in the hospital are not only continued but strengthened. TH

Dr. Sachdeva is lead hospitalist in the Stroke Program at the Swedish Medical Center, Seattle, and clinical instructor at the University of Washington, Seattle.

References

  1. Kmietowicz Z. United Kingdom needs to double the number of neurologists. BMJ. 2001;322:1508.

  2. Ringel SP. The neurologist’s role in stroke management. Stroke. 1996; 27(11):1935-1936.

  3. Weinberger J. Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke. Drugs. 2005;65(4):461-471.

  4. Weinberger J. Managing and preventing ischemic stroke: Part II—risk assessment and prevention of secondary ischemic stroke. Clin Geriatr. 2004;12(8):41-46.

  5. Patrono C, Coller B, Dalen JF. Platelet-active drugs: the relationship among dose, effectiveness and side effects. Chest. 2001:119(suppl):39S-63S.

  6. Fayad P, Singh SP. Anti-thrombotic therapy for the secondary prevention of ischemic stroke. Chest. 2004;126(3):483S-512S.

  7. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 2001;119(suppl):300S-320S.

  8. Antiplatelet Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;12;324(7329):71-86.

  9. Robert S, Miller AJ, Fagan SC. Ticlopidine: a new antiplatelet agent for cerebrovascular disease. Pharmacotherapy. 1991;11(4):317-322.

  10. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk for ischemic events. Lancet. 1996;348:1329-1339.

  11. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.

  12. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-2420.

  13. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-337.

  14. European Stroke Prevention Study. ESPS Group. Stroke. 1990;21(8):1122-1130.20

  15. Diener HC, Cunha L, Forbes C, et al. European stroke prevention study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1-2):1-13.

  16. Sacco RL, Sivenius J, Diener HC. Efficacy of aspirin plus extended-release dipyridamole in preventing recurrent stroke in high-risk populations. Arch Neurol. 2005;62:403-408.

  17. PRoFESS Web site. Available at: www.profess-study.com/com/Main/newscentre/news_040604.jsp. Last accessed July 18, 2005

  18. Weinberger J. Managing and preventing ischemic stroke: Part I—risk assessment and treatment of primary ischemic stroke. Clin Geriatr. 2004;12(7):48-53.

  19. Heart Disease and Stroke Statistics—2005 Update. Dallas, Texas. American Heart Association; Dallas. 2005

  20. Johnston SC, Gress DR, Browner WS, et al. Short-term prognosis after emergency department diagnosis of TIA. JAMA. 2000;284:2901-2906.

  21. Feinberg WM, Albers GW, Barnett H, et al. Guidelines for the management of transient ischemic attacks. Stroke. 1994;25:1320-1335.

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Author(s)
Sandeep Sachdeva, MD
Author(s)
Sandeep Sachdeva, MD

Patients with acute stroke or transient ischemic attack (TIA) should be admitted to a hospital for initial care and assessment; however, a substantial number of these patients will never be seen by a neurologist because of the limited number of physicians in this specialty area. Currently there is only one neurologist per 26,000 people in the United States, and most neurologists prefer to practice in the outpatient setting.1 According to one study, only 11.3% of stroke patients are attended exclusively by a neurologist.2 Hospitalists play a vital role in overcoming this lack of specialized care for stroke patients.

Pharmacotherapy

A significant body of evidence supports secondary prevention as a critical intervention strategy in reducing stroke risk. Identifying specific risk factors remains pivotal to successful secondary prevention. Managing hypertension, diabetes, and hyperlipidemia serves as an effective preventive role; however, preventive management with antithrombotic agents is an important part of the drug regimen for secondary prevention of recurrent ischemic stroke (IS).3

The choice of pharmacologic agents is based on stroke etiology. Anticoagulants such as warfarin are restricted to patients with stroke due to a cardioembolic source, whereas antiplatelet agents are mainly used to treat noncardioembolic and lacunar strokes.4 Currently, four oral antiplatelet agents may be used as therapy to prevent secondary IS: aspirin (acetylsalicylic acid or ASA), ticlopidine, clopidogrel, and ASA plus extended-release dipyridamole.

Currently, four oral antiplatelet agents may be used as therapy to prevent secondary ischemic stroke: aspirin (ASA), ticlopidine, clopidogrel, and ASA plus extended-release dipyridamole.

Aspirin

ASA is the most widely used and cost-effective antiplatelet agent. A salicylate, it blocks platelet activation by inhibiting the cyclo-oxygenase enzymes (COX-1 and COX-2). In several primary prevention trials ASA was associated with a statistically significant reduction in risk of first myocardial infarction (MI). Neither overall cardiovascular mortality nor total number of strokes was reduced by long-term ASA prophylaxis, however.5

ASA was shown to be effective in secondary prevention of noncardioembolic stroke (offering equivalent or better efficacy compared with warfarin) in the Stroke Prevention in Reversible Ischemia Trial and the Warfarin-Aspirin Recurrent Stroke Study.6 The Swedish Aspirin Low-Dose Trial, Dutch TIA Trial, and United Kingdom Transient Ischaemic Attack Aspirin Trial consistently demonstrated the efficacy and reduced gastric toxicity of low-dose ASA.7 A meta-analysis of 197 randomized trials versus control and 90 randomized comparisons between antiplatelet regimens show risk reduction with ASA of approximately 23% in combined vascular events (MI, stroke, and vascular death).8

Ticlopidine

Ticlopidine hydrochloride (thienopyridine) blocks platelet activation by inhibiting adenosine diphosphate-induced fibrinogen binding.7 Ticlopidine was superior to placebo and high-dose ASA in reducing the occurrence of stroke, MI, or vascular death in patients of both genders who had recent cerebral ischemia. This was demonstrated in two major phase 3 multicenter trials: the Ticlopidine Aspirin Stroke Study and the Canadian American Ticlopidine Study.9 Despite ticlopidine’s efficacy in these trials, the drug has been associated with severe adverse effects, including life-threatening neutropenia (1%) and thrombocytopenic purpura (one per 1,600 to 5,000 patients treated).3

Clopidogrel

The ticlopidine analogue clopidogrel is a potent inhibitor of platelet aggregation induced by adenosine diphosphate.7 The efficacy and safety of clopidogrel was evaluated in a randomized, double-blind, multicenter study—the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events trial, the largest clinical study of clopidogrel—of 19,000 patients with stroke, MI, or peripheral arterial disease.10

In this study, clopidogrel showed a more favorable safety and tolerability profile than ticlopidine; however, compared with ASA clopidogrel offered only a modest benefit of 8.7% for all cardiovascular events and showed no significant benefit over ASA for recurrent stroke.

 

 

Findings from two randomized trials—Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO)—have shown sustained benefits of clopidogrel for combined endpoints of MI, stroke, and vascular death.11-12 The incidence of stroke was very small and the risk of serious bleeding was significantly increased.

These trials provided the rationale to undertake the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke study (MATCH).13 This study was designed to determine whether the addition of ASA to clopidogrel would further reduce the risk of recurrent ischemic attacks in high-risk patients after recent IS or TIA, as was observed with coronary manifestations of atherothrombosis in the CURE and CREDO trials.

MATCH, a randomized, double-blind, placebo-controlled trial, involved 7,599 patients and compared clopidogrel with low-dose ASA plus clopidogrel. During an 18-month follow-up, no significant benefit was observed for ASA plus clopidogrel versus clopidogrel monotherapy; however, there was a significant increase in the risk of life-threatening bleeding in the group receiving combined therapy (2.6% versus 1.3%, respectively). Therefore, ASA plus clopidogrel is not a recommended option for prevention of secondary stroke in cerebrovascular patients.

STROKE

The scope of the problem

Stroke is one of the most significant health problems in the United States. Approximately 700,000 strokes and occur each year. Of these, 200,000 are recurrent strokes.18 Extensive studies have identified increasing age as the leading risk factor for stroke.16

Approximately 72% of stroke patients are older than 65; on average, patients with stroke tend to be older than patients with MI.4-19 Thus, the frequency of stroke will increase dramatically with lengthening of life expectancy and advancing age of our population.

A history of TIA poses another strong risk factor for stroke. Each year approximately 300,000 Americans suffer TIAs; about one-third of these people will develop a stroke.20-21 Risk factors include hypertension, cigarette smoking, diabetes mellitus, hyperlipidemia, obesity, and heart disease.—SS

ASA Plus Extended-Release Dipyridamole

The Second European Stroke Prevention Study (ESPS-2), a randomized trial with 2,500 patients, was conducted to compare the efficacy of ASA plus dipyridamole versus placebo. Dipyridamole is a pyrimidopyrimidine derivative from the papaverine family with antithrombotic properties and vasodilatory effects on cells and vasculature.14 It inhibits phosphodiesterases, resulting in increased concentration of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP), which inhibits platelet activation and adhesion.14

ESPS-2 results showed a 38% relative reduction in risk of stroke for the combination versus placebo. The study did not include an ASA-only group. Results prompted reformulation of dipyridamole into a high-dose extended-release capsule combined with low-dose ASA. The higher dose and slower release of dipyridamole combined with ASA provides a more consistent plasma level and is less affected by stomach acidity or concomitant medications.

This combination was tested versus ASA alone in the ESPS-2 trial.15 ESPS-2, a randomized, double-blind, multicenter study, enrolled 6,602 patients with prior stroke or TIA. During the two-year follow-up ASA plus extended-release dipyridamole reduced the risk of recurrent stroke by 37% compared with placebo, and by 22% compared with ASA or dipyridamole alone. Adverse events associated with this combination are similar to those observed with low-dose ASA.

These results were further substantiated by a recent post hoc analysis conducted using data from the ESPS-2 trial. ASA plus extended-release dipyridamole had greater efficacy in preventing stroke than ASA; this difference in efficacy was more pronounced in high-risk patients.16

We need further studies that include direct comparisons to verify the most effective and safe antiplatelet agent for secondary stroke prevention. The Prospective Regimen for Effectively Avoiding Second Strokes (PRoFESS) is a head-to-head trial designed to compare the combination of ASA plus extended-release dipyridamole to clopidogrel in terms of efficacy and safety. This study includes 15,500 patients in more than 20 countries at approximately 600 sites.17

 

 

Conclusions

Stroke remains a major public health concern. Hospitalists play a central role in stroke management by improving the overall quality of hospital care for stroke patients. Still, most residency programs don’t provide sufficient stroke education. Therefore, comprehensive neurology educational programs should be provided for hospitalists so they can provide efficient inpatient care; initiate effective secondary prevention strategies tailored to the specific needs of the patients, starting with appropriate antiplatelet therapy; monitor patients at poststroke rehabilitation centers during recovery period; and educate stroke patients and their caregivers about the disease and its risk factors.

Hospitalists can also initiate effective communication with outpatient primary care providers at the time of discharge to help ensure that the secondary prevention strategies initiated in the hospital are not only continued but strengthened. TH

Dr. Sachdeva is lead hospitalist in the Stroke Program at the Swedish Medical Center, Seattle, and clinical instructor at the University of Washington, Seattle.

References

  1. Kmietowicz Z. United Kingdom needs to double the number of neurologists. BMJ. 2001;322:1508.

  2. Ringel SP. The neurologist’s role in stroke management. Stroke. 1996; 27(11):1935-1936.

  3. Weinberger J. Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke. Drugs. 2005;65(4):461-471.

  4. Weinberger J. Managing and preventing ischemic stroke: Part II—risk assessment and prevention of secondary ischemic stroke. Clin Geriatr. 2004;12(8):41-46.

  5. Patrono C, Coller B, Dalen JF. Platelet-active drugs: the relationship among dose, effectiveness and side effects. Chest. 2001:119(suppl):39S-63S.

  6. Fayad P, Singh SP. Anti-thrombotic therapy for the secondary prevention of ischemic stroke. Chest. 2004;126(3):483S-512S.

  7. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 2001;119(suppl):300S-320S.

  8. Antiplatelet Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;12;324(7329):71-86.

  9. Robert S, Miller AJ, Fagan SC. Ticlopidine: a new antiplatelet agent for cerebrovascular disease. Pharmacotherapy. 1991;11(4):317-322.

  10. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk for ischemic events. Lancet. 1996;348:1329-1339.

  11. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.

  12. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-2420.

  13. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-337.

  14. European Stroke Prevention Study. ESPS Group. Stroke. 1990;21(8):1122-1130.20

  15. Diener HC, Cunha L, Forbes C, et al. European stroke prevention study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1-2):1-13.

  16. Sacco RL, Sivenius J, Diener HC. Efficacy of aspirin plus extended-release dipyridamole in preventing recurrent stroke in high-risk populations. Arch Neurol. 2005;62:403-408.

  17. PRoFESS Web site. Available at: www.profess-study.com/com/Main/newscentre/news_040604.jsp. Last accessed July 18, 2005

  18. Weinberger J. Managing and preventing ischemic stroke: Part I—risk assessment and treatment of primary ischemic stroke. Clin Geriatr. 2004;12(7):48-53.

  19. Heart Disease and Stroke Statistics—2005 Update. Dallas, Texas. American Heart Association; Dallas. 2005

  20. Johnston SC, Gress DR, Browner WS, et al. Short-term prognosis after emergency department diagnosis of TIA. JAMA. 2000;284:2901-2906.

  21. Feinberg WM, Albers GW, Barnett H, et al. Guidelines for the management of transient ischemic attacks. Stroke. 1994;25:1320-1335.

Patients with acute stroke or transient ischemic attack (TIA) should be admitted to a hospital for initial care and assessment; however, a substantial number of these patients will never be seen by a neurologist because of the limited number of physicians in this specialty area. Currently there is only one neurologist per 26,000 people in the United States, and most neurologists prefer to practice in the outpatient setting.1 According to one study, only 11.3% of stroke patients are attended exclusively by a neurologist.2 Hospitalists play a vital role in overcoming this lack of specialized care for stroke patients.

Pharmacotherapy

A significant body of evidence supports secondary prevention as a critical intervention strategy in reducing stroke risk. Identifying specific risk factors remains pivotal to successful secondary prevention. Managing hypertension, diabetes, and hyperlipidemia serves as an effective preventive role; however, preventive management with antithrombotic agents is an important part of the drug regimen for secondary prevention of recurrent ischemic stroke (IS).3

The choice of pharmacologic agents is based on stroke etiology. Anticoagulants such as warfarin are restricted to patients with stroke due to a cardioembolic source, whereas antiplatelet agents are mainly used to treat noncardioembolic and lacunar strokes.4 Currently, four oral antiplatelet agents may be used as therapy to prevent secondary IS: aspirin (acetylsalicylic acid or ASA), ticlopidine, clopidogrel, and ASA plus extended-release dipyridamole.

Currently, four oral antiplatelet agents may be used as therapy to prevent secondary ischemic stroke: aspirin (ASA), ticlopidine, clopidogrel, and ASA plus extended-release dipyridamole.

Aspirin

ASA is the most widely used and cost-effective antiplatelet agent. A salicylate, it blocks platelet activation by inhibiting the cyclo-oxygenase enzymes (COX-1 and COX-2). In several primary prevention trials ASA was associated with a statistically significant reduction in risk of first myocardial infarction (MI). Neither overall cardiovascular mortality nor total number of strokes was reduced by long-term ASA prophylaxis, however.5

ASA was shown to be effective in secondary prevention of noncardioembolic stroke (offering equivalent or better efficacy compared with warfarin) in the Stroke Prevention in Reversible Ischemia Trial and the Warfarin-Aspirin Recurrent Stroke Study.6 The Swedish Aspirin Low-Dose Trial, Dutch TIA Trial, and United Kingdom Transient Ischaemic Attack Aspirin Trial consistently demonstrated the efficacy and reduced gastric toxicity of low-dose ASA.7 A meta-analysis of 197 randomized trials versus control and 90 randomized comparisons between antiplatelet regimens show risk reduction with ASA of approximately 23% in combined vascular events (MI, stroke, and vascular death).8

Ticlopidine

Ticlopidine hydrochloride (thienopyridine) blocks platelet activation by inhibiting adenosine diphosphate-induced fibrinogen binding.7 Ticlopidine was superior to placebo and high-dose ASA in reducing the occurrence of stroke, MI, or vascular death in patients of both genders who had recent cerebral ischemia. This was demonstrated in two major phase 3 multicenter trials: the Ticlopidine Aspirin Stroke Study and the Canadian American Ticlopidine Study.9 Despite ticlopidine’s efficacy in these trials, the drug has been associated with severe adverse effects, including life-threatening neutropenia (1%) and thrombocytopenic purpura (one per 1,600 to 5,000 patients treated).3

Clopidogrel

The ticlopidine analogue clopidogrel is a potent inhibitor of platelet aggregation induced by adenosine diphosphate.7 The efficacy and safety of clopidogrel was evaluated in a randomized, double-blind, multicenter study—the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events trial, the largest clinical study of clopidogrel—of 19,000 patients with stroke, MI, or peripheral arterial disease.10

In this study, clopidogrel showed a more favorable safety and tolerability profile than ticlopidine; however, compared with ASA clopidogrel offered only a modest benefit of 8.7% for all cardiovascular events and showed no significant benefit over ASA for recurrent stroke.

 

 

Findings from two randomized trials—Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO)—have shown sustained benefits of clopidogrel for combined endpoints of MI, stroke, and vascular death.11-12 The incidence of stroke was very small and the risk of serious bleeding was significantly increased.

These trials provided the rationale to undertake the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke study (MATCH).13 This study was designed to determine whether the addition of ASA to clopidogrel would further reduce the risk of recurrent ischemic attacks in high-risk patients after recent IS or TIA, as was observed with coronary manifestations of atherothrombosis in the CURE and CREDO trials.

MATCH, a randomized, double-blind, placebo-controlled trial, involved 7,599 patients and compared clopidogrel with low-dose ASA plus clopidogrel. During an 18-month follow-up, no significant benefit was observed for ASA plus clopidogrel versus clopidogrel monotherapy; however, there was a significant increase in the risk of life-threatening bleeding in the group receiving combined therapy (2.6% versus 1.3%, respectively). Therefore, ASA plus clopidogrel is not a recommended option for prevention of secondary stroke in cerebrovascular patients.

STROKE

The scope of the problem

Stroke is one of the most significant health problems in the United States. Approximately 700,000 strokes and occur each year. Of these, 200,000 are recurrent strokes.18 Extensive studies have identified increasing age as the leading risk factor for stroke.16

Approximately 72% of stroke patients are older than 65; on average, patients with stroke tend to be older than patients with MI.4-19 Thus, the frequency of stroke will increase dramatically with lengthening of life expectancy and advancing age of our population.

A history of TIA poses another strong risk factor for stroke. Each year approximately 300,000 Americans suffer TIAs; about one-third of these people will develop a stroke.20-21 Risk factors include hypertension, cigarette smoking, diabetes mellitus, hyperlipidemia, obesity, and heart disease.—SS

ASA Plus Extended-Release Dipyridamole

The Second European Stroke Prevention Study (ESPS-2), a randomized trial with 2,500 patients, was conducted to compare the efficacy of ASA plus dipyridamole versus placebo. Dipyridamole is a pyrimidopyrimidine derivative from the papaverine family with antithrombotic properties and vasodilatory effects on cells and vasculature.14 It inhibits phosphodiesterases, resulting in increased concentration of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP), which inhibits platelet activation and adhesion.14

ESPS-2 results showed a 38% relative reduction in risk of stroke for the combination versus placebo. The study did not include an ASA-only group. Results prompted reformulation of dipyridamole into a high-dose extended-release capsule combined with low-dose ASA. The higher dose and slower release of dipyridamole combined with ASA provides a more consistent plasma level and is less affected by stomach acidity or concomitant medications.

This combination was tested versus ASA alone in the ESPS-2 trial.15 ESPS-2, a randomized, double-blind, multicenter study, enrolled 6,602 patients with prior stroke or TIA. During the two-year follow-up ASA plus extended-release dipyridamole reduced the risk of recurrent stroke by 37% compared with placebo, and by 22% compared with ASA or dipyridamole alone. Adverse events associated with this combination are similar to those observed with low-dose ASA.

These results were further substantiated by a recent post hoc analysis conducted using data from the ESPS-2 trial. ASA plus extended-release dipyridamole had greater efficacy in preventing stroke than ASA; this difference in efficacy was more pronounced in high-risk patients.16

We need further studies that include direct comparisons to verify the most effective and safe antiplatelet agent for secondary stroke prevention. The Prospective Regimen for Effectively Avoiding Second Strokes (PRoFESS) is a head-to-head trial designed to compare the combination of ASA plus extended-release dipyridamole to clopidogrel in terms of efficacy and safety. This study includes 15,500 patients in more than 20 countries at approximately 600 sites.17

 

 

Conclusions

Stroke remains a major public health concern. Hospitalists play a central role in stroke management by improving the overall quality of hospital care for stroke patients. Still, most residency programs don’t provide sufficient stroke education. Therefore, comprehensive neurology educational programs should be provided for hospitalists so they can provide efficient inpatient care; initiate effective secondary prevention strategies tailored to the specific needs of the patients, starting with appropriate antiplatelet therapy; monitor patients at poststroke rehabilitation centers during recovery period; and educate stroke patients and their caregivers about the disease and its risk factors.

Hospitalists can also initiate effective communication with outpatient primary care providers at the time of discharge to help ensure that the secondary prevention strategies initiated in the hospital are not only continued but strengthened. TH

Dr. Sachdeva is lead hospitalist in the Stroke Program at the Swedish Medical Center, Seattle, and clinical instructor at the University of Washington, Seattle.

References

  1. Kmietowicz Z. United Kingdom needs to double the number of neurologists. BMJ. 2001;322:1508.

  2. Ringel SP. The neurologist’s role in stroke management. Stroke. 1996; 27(11):1935-1936.

  3. Weinberger J. Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke. Drugs. 2005;65(4):461-471.

  4. Weinberger J. Managing and preventing ischemic stroke: Part II—risk assessment and prevention of secondary ischemic stroke. Clin Geriatr. 2004;12(8):41-46.

  5. Patrono C, Coller B, Dalen JF. Platelet-active drugs: the relationship among dose, effectiveness and side effects. Chest. 2001:119(suppl):39S-63S.

  6. Fayad P, Singh SP. Anti-thrombotic therapy for the secondary prevention of ischemic stroke. Chest. 2004;126(3):483S-512S.

  7. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 2001;119(suppl):300S-320S.

  8. Antiplatelet Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;12;324(7329):71-86.

  9. Robert S, Miller AJ, Fagan SC. Ticlopidine: a new antiplatelet agent for cerebrovascular disease. Pharmacotherapy. 1991;11(4):317-322.

  10. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk for ischemic events. Lancet. 1996;348:1329-1339.

  11. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.

  12. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-2420.

  13. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-337.

  14. European Stroke Prevention Study. ESPS Group. Stroke. 1990;21(8):1122-1130.20

  15. Diener HC, Cunha L, Forbes C, et al. European stroke prevention study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1-2):1-13.

  16. Sacco RL, Sivenius J, Diener HC. Efficacy of aspirin plus extended-release dipyridamole in preventing recurrent stroke in high-risk populations. Arch Neurol. 2005;62:403-408.

  17. PRoFESS Web site. Available at: www.profess-study.com/com/Main/newscentre/news_040604.jsp. Last accessed July 18, 2005

  18. Weinberger J. Managing and preventing ischemic stroke: Part I—risk assessment and treatment of primary ischemic stroke. Clin Geriatr. 2004;12(7):48-53.

  19. Heart Disease and Stroke Statistics—2005 Update. Dallas, Texas. American Heart Association; Dallas. 2005

  20. Johnston SC, Gress DR, Browner WS, et al. Short-term prognosis after emergency department diagnosis of TIA. JAMA. 2000;284:2901-2906.

  21. Feinberg WM, Albers GW, Barnett H, et al. Guidelines for the management of transient ischemic attacks. Stroke. 1994;25:1320-1335.

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