Background Skin reactions and pain are commonly reported side effects of radiation therapy (RT).

Objective To characterize RT-induced symptoms according to treatment site subgroups and identify skin symptoms that correlate with pain.

Methods A self-report survey—adapted from the MD Anderson Symptom Inventory and the McGill Pain Questionnaire—assessed RT-induced skin problems, pain, and specific skin symptoms. Wilcoxon Sign Ranked tests compared mean severity of pre- and post-RT pain and skin problems within each RT-site subgroup. Multiple linear regression (MLR) investigated associations between skin symptoms and pain.

Results Survey respondents (N = 106) were 58% female and on average 64 years old. RT sites included lung, breast, lower abdomen, head/neck/brain, and upper abdomen. Only patients receiving breast RT reported significant increases in treatment site pain and skin problems (P ≤ .007). Patients receiving head/neck/brain RT reported increased skin problems (P < .0009). MLR showed that post-RT skin tenderness and tightness were most strongly associated with post-RT pain (P = .066 and P = .122, respectively).

Limitations Small sample size, exploratory analyses, and nonvalidated measure.

Conclusions Only patients receiving breast RT reported significant increases in pain and skin problems at the RT site while patients receiving head/neck/brain RT had increased skin problems but not pain. These findings suggest that the severity of skin problems is not the only factor that contributes to pain and that interventions should be tailored to specifically target pain at the RT site, possibly by targeting tenderness and tightness. These findings should be confirmed in a larger sampling of RT patients.

Click on the PDF icon at the top of this introduction to read the full article.

Background Skin reactions and pain are commonly reported side effects of radiation therapy (RT).

Objective To characterize RT-induced symptoms according to treatment site subgroups and identify skin symptoms that correlate with pain.

Methods A self-report survey—adapted from the MD Anderson Symptom Inventory and the McGill Pain Questionnaire—assessed RT-induced skin problems, pain, and specific skin symptoms. Wilcoxon Sign Ranked tests compared mean severity of pre- and post-RT pain and skin problems within each RT-site subgroup. Multiple linear regression (MLR) investigated associations between skin symptoms and pain.

Results Survey respondents (N = 106) were 58% female and on average 64 years old. RT sites included lung, breast, lower abdomen, head/neck/brain, and upper abdomen. Only patients receiving breast RT reported significant increases in treatment site pain and skin problems (P ≤ .007). Patients receiving head/neck/brain RT reported increased skin problems (P < .0009). MLR showed that post-RT skin tenderness and tightness were most strongly associated with post-RT pain (P = .066 and P = .122, respectively).

Limitations Small sample size, exploratory analyses, and nonvalidated measure.

Conclusions Only patients receiving breast RT reported significant increases in pain and skin problems at the RT site while patients receiving head/neck/brain RT had increased skin problems but not pain. These findings suggest that the severity of skin problems is not the only factor that contributes to pain and that interventions should be tailored to specifically target pain at the RT site, possibly by targeting tenderness and tightness. These findings should be confirmed in a larger sampling of RT patients.

Click on the PDF icon at the top of this introduction to read the full article.

Background Skin reactions and pain are commonly reported side effects of radiation therapy (RT).

Objective To characterize RT-induced symptoms according to treatment site subgroups and identify skin symptoms that correlate with pain.

Methods A self-report survey—adapted from the MD Anderson Symptom Inventory and the McGill Pain Questionnaire—assessed RT-induced skin problems, pain, and specific skin symptoms. Wilcoxon Sign Ranked tests compared mean severity of pre- and post-RT pain and skin problems within each RT-site subgroup. Multiple linear regression (MLR) investigated associations between skin symptoms and pain.

Results Survey respondents (N = 106) were 58% female and on average 64 years old. RT sites included lung, breast, lower abdomen, head/neck/brain, and upper abdomen. Only patients receiving breast RT reported significant increases in treatment site pain and skin problems (P ≤ .007). Patients receiving head/neck/brain RT reported increased skin problems (P < .0009). MLR showed that post-RT skin tenderness and tightness were most strongly associated with post-RT pain (P = .066 and P = .122, respectively).

Limitations Small sample size, exploratory analyses, and nonvalidated measure.

Conclusions Only patients receiving breast RT reported significant increases in pain and skin problems at the RT site while patients receiving head/neck/brain RT had increased skin problems but not pain. These findings suggest that the severity of skin problems is not the only factor that contributes to pain and that interventions should be tailored to specifically target pain at the RT site, possibly by targeting tenderness and tightness. These findings should be confirmed in a larger sampling of RT patients.

Click on the PDF icon at the top of this introduction to read the full article.

Over 170,000 cases of metastatic brain tumors are diagnosed in the United States each year; and the length of survival for patients with brain metastases is often quite limited, ranging from a few weeks to several months.¹ The Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) and the Graded Prognostic Assessment (GPA) are 2 prognostic indices that have been validated to predict survival and guide the treatment of these patients.^2-5 The RPA and GPA indices were formulated by comparing survival to patient and tumor characteristics compiled from RTOG brain metastasis treatment protocols spanning greater than 3 decades. The RPA has 3 classes of patients enumerated as “I”, “II”, and “III,” with class I patients having the longest predicted survival and class III patients having the worst prognosis. The RPA classes are based upon factors that include patient age and Karnofsky Performance Status (KPS) as well as control of the primary tumor and evidence of extra-cranial metastases (Table 1).² The GPA has 4 classes of patients with a score that may be considered analogous to a grade point average achieved by students in school. The classes are arranged into 4 groupings, which are divided from best to worst prognosis as follows: 3.5 to 4.0, 3.0, 1.5 to 2.5, and 0.0 to 1.0. The GPA employs criteria similar to but slightly different from those used in the RPA, estimating survival by patient age and performance status as well as the number of brain metastases and evidence of extracranial metastases (Table 2).⁴

Treatment options for patients with brain metastases include surgery, stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), supportive measures such as corticosteroids, or a combination of these modalities. The survival of the worst prognosis brain metastases patients treated with WBRT and steroids is estimated by the RPA and GPA tools to be 2.3 months and 2.6 months, respectively.^2,4 As noted above, the patient data from which the RPA and GPA indices were created included patients treated on clinical trials. This could have resulted in the selection of patients more fit than average patients and lead to an overestimation of survival when applied to all patients. The clinical trial data used were drawn from over 3 decades, during which supportive care and chemotherapy treatments improved. This could result in an underestimation of survival when applied to patients treated with current systemic therapies and supportive care. It is important for physicians to have an accurate method to predict survival in patients to ensure that appropriate treatments can be recommended.

Over 170,000 cases of metastatic brain tumors are diagnosed in the United States each year; and the length of survival for patients with brain metastases is often quite limited, ranging from a few weeks to several months.¹ The Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) and the Graded Prognostic Assessment (GPA) are 2 prognostic indices that have been validated to predict survival and guide the treatment of these patients.^2-5 The RPA and GPA indices were formulated by comparing survival to patient and tumor characteristics compiled from RTOG brain metastasis treatment protocols spanning greater than 3 decades. The RPA has 3 classes of patients enumerated as “I”, “II”, and “III,” with class I patients having the longest predicted survival and class III patients having the worst prognosis. The RPA classes are based upon factors that include patient age and Karnofsky Performance Status (KPS) as well as control of the primary tumor and evidence of extra-cranial metastases (Table 1).² The GPA has 4 classes of patients with a score that may be considered analogous to a grade point average achieved by students in school. The classes are arranged into 4 groupings, which are divided from best to worst prognosis as follows: 3.5 to 4.0, 3.0, 1.5 to 2.5, and 0.0 to 1.0. The GPA employs criteria similar to but slightly different from those used in the RPA, estimating survival by patient age and performance status as well as the number of brain metastases and evidence of extracranial metastases (Table 2).⁴

Treatment options for patients with brain metastases include surgery, stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), supportive measures such as corticosteroids, or a combination of these modalities. The survival of the worst prognosis brain metastases patients treated with WBRT and steroids is estimated by the RPA and GPA tools to be 2.3 months and 2.6 months, respectively.^2,4 As noted above, the patient data from which the RPA and GPA indices were created included patients treated on clinical trials. This could have resulted in the selection of patients more fit than average patients and lead to an overestimation of survival when applied to all patients. The clinical trial data used were drawn from over 3 decades, during which supportive care and chemotherapy treatments improved. This could result in an underestimation of survival when applied to patients treated with current systemic therapies and supportive care. It is important for physicians to have an accurate method to predict survival in patients to ensure that appropriate treatments can be recommended.

Over 170,000 cases of metastatic brain tumors are diagnosed in the United States each year; and the length of survival for patients with brain metastases is often quite limited, ranging from a few weeks to several months.¹ The Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) and the Graded Prognostic Assessment (GPA) are 2 prognostic indices that have been validated to predict survival and guide the treatment of these patients.^2-5 The RPA and GPA indices were formulated by comparing survival to patient and tumor characteristics compiled from RTOG brain metastasis treatment protocols spanning greater than 3 decades. The RPA has 3 classes of patients enumerated as “I”, “II”, and “III,” with class I patients having the longest predicted survival and class III patients having the worst prognosis. The RPA classes are based upon factors that include patient age and Karnofsky Performance Status (KPS) as well as control of the primary tumor and evidence of extra-cranial metastases (Table 1).² The GPA has 4 classes of patients with a score that may be considered analogous to a grade point average achieved by students in school. The classes are arranged into 4 groupings, which are divided from best to worst prognosis as follows: 3.5 to 4.0, 3.0, 1.5 to 2.5, and 0.0 to 1.0. The GPA employs criteria similar to but slightly different from those used in the RPA, estimating survival by patient age and performance status as well as the number of brain metastases and evidence of extracranial metastases (Table 2).⁴

Treatment options for patients with brain metastases include surgery, stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), supportive measures such as corticosteroids, or a combination of these modalities. The survival of the worst prognosis brain metastases patients treated with WBRT and steroids is estimated by the RPA and GPA tools to be 2.3 months and 2.6 months, respectively.^2,4 As noted above, the patient data from which the RPA and GPA indices were created included patients treated on clinical trials. This could have resulted in the selection of patients more fit than average patients and lead to an overestimation of survival when applied to all patients. The clinical trial data used were drawn from over 3 decades, during which supportive care and chemotherapy treatments improved. This could result in an underestimation of survival when applied to patients treated with current systemic therapies and supportive care. It is important for physicians to have an accurate method to predict survival in patients to ensure that appropriate treatments can be recommended.

Palliative care quality indicators should be part of oncology performance assessment initiatives. Palliative care programs should also include initiatives to address the overall quality of palliative care issues, such as pain management, in the settings where the programs are located.1 Measuring quality facilitates justifying palliative care initiatives and documenting their impact, targeting quality improvement efforts, monitoring care for deficiencies, and evaluating providers (Table 1). However, measurement in this field is often not straightforward. Potential challenges include defining the population to measure and data sources, collection and analysis, as well as choosing among many potentially relevant issues and quality measures. This article describes an approach to quality measurement in palliative care, beginning with a description of key frameworks to guide the measurement approach. The article also reviews key steps in designing a quality measurement program, which include defining the quality problem and population to measure and choosing domains and specific measures. Finally, the article addresses other key considerations, such as considering unintended consequences and using data for quality improvement.

Frameworks for evaluating quality

The Donabedian framework of structure (stable elements of the health care system), process (what health care services are provided), and outcome (end results for the patient and family) can be
applied to relevant domains to guide evaluation design (Table 2).^2-8 Key structural elements may include characteristics of programs (eg, palliative clinic availability), providers (eg, multidisciplinary members of the palliative care team), and tools (eg, do-not-resuscitate policies). Processes may include technical aspects of care, such as appropriate prescribing and interpersonal aspects of care (eg, coordination among providers). Outcomes may include patient quality of life or symptoms, perceptions of care, or caregiver outcomes such as burden. Outcomes may also be categorized as overuse (eg, use of chemotherapy at the end of life compared to national benchmarks), underuse (eg, lower rates of hospice care or use of antinausea drugs), or appropriateness of care (eg, accurately documenting patients’ preferences for care).

Palliative care quality indicators should be part of oncology performance assessment initiatives. Palliative care programs should also include initiatives to address the overall quality of palliative care issues, such as pain management, in the settings where the programs are located.1 Measuring quality facilitates justifying palliative care initiatives and documenting their impact, targeting quality improvement efforts, monitoring care for deficiencies, and evaluating providers (Table 1). However, measurement in this field is often not straightforward. Potential challenges include defining the population to measure and data sources, collection and analysis, as well as choosing among many potentially relevant issues and quality measures. This article describes an approach to quality measurement in palliative care, beginning with a description of key frameworks to guide the measurement approach. The article also reviews key steps in designing a quality measurement program, which include defining the quality problem and population to measure and choosing domains and specific measures. Finally, the article addresses other key considerations, such as considering unintended consequences and using data for quality improvement.

Frameworks for evaluating quality

The Donabedian framework of structure (stable elements of the health care system), process (what health care services are provided), and outcome (end results for the patient and family) can be
applied to relevant domains to guide evaluation design (Table 2).^2-8 Key structural elements may include characteristics of programs (eg, palliative clinic availability), providers (eg, multidisciplinary members of the palliative care team), and tools (eg, do-not-resuscitate policies). Processes may include technical aspects of care, such as appropriate prescribing and interpersonal aspects of care (eg, coordination among providers). Outcomes may include patient quality of life or symptoms, perceptions of care, or caregiver outcomes such as burden. Outcomes may also be categorized as overuse (eg, use of chemotherapy at the end of life compared to national benchmarks), underuse (eg, lower rates of hospice care or use of antinausea drugs), or appropriateness of care (eg, accurately documenting patients’ preferences for care).

Palliative care quality indicators should be part of oncology performance assessment initiatives. Palliative care programs should also include initiatives to address the overall quality of palliative care issues, such as pain management, in the settings where the programs are located.1 Measuring quality facilitates justifying palliative care initiatives and documenting their impact, targeting quality improvement efforts, monitoring care for deficiencies, and evaluating providers (Table 1). However, measurement in this field is often not straightforward. Potential challenges include defining the population to measure and data sources, collection and analysis, as well as choosing among many potentially relevant issues and quality measures. This article describes an approach to quality measurement in palliative care, beginning with a description of key frameworks to guide the measurement approach. The article also reviews key steps in designing a quality measurement program, which include defining the quality problem and population to measure and choosing domains and specific measures. Finally, the article addresses other key considerations, such as considering unintended consequences and using data for quality improvement.

Frameworks for evaluating quality

The Donabedian framework of structure (stable elements of the health care system), process (what health care services are provided), and outcome (end results for the patient and family) can be
applied to relevant domains to guide evaluation design (Table 2).^2-8 Key structural elements may include characteristics of programs (eg, palliative clinic availability), providers (eg, multidisciplinary members of the palliative care team), and tools (eg, do-not-resuscitate policies). Processes may include technical aspects of care, such as appropriate prescribing and interpersonal aspects of care (eg, coordination among providers). Outcomes may include patient quality of life or symptoms, perceptions of care, or caregiver outcomes such as burden. Outcomes may also be categorized as overuse (eg, use of chemotherapy at the end of life compared to national benchmarks), underuse (eg, lower rates of hospice care or use of antinausea drugs), or appropriateness of care (eg, accurately documenting patients’ preferences for care).

To the Editor: We would like to raise the following points about the paper by Dr. Aggarwal et al¹ interpreting the Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial.²

The patients enrolled in the FREEDOM trial do not in our opinion completely reflect the real patients that we meet in our daily “real-world” practice.² The patients in the FREEDOM trial did not have a high-risk profile. Rather, the mean European System for Cardiac Operative Risk Evaluation score (EuroSCORE) was 2.7 ± 2.4 in the percutaneous coronary intervention (PCI) group and 2.8 ± 2.5 in the coronary artery bypass grafting group—whereas a score of 5 or more on the EuroSCORE is associated with decreased rates of survival.²

Furthermore, patients with left main coronary artery stenosis were completely excluded from the FREEDOM trial,² but this type of stenosis, with different grades, is found in about 30% of diabetic patients with multivessel coronary artery disease, a fact that may significantly influence the decision regarding the revascularization strategy (bypass grafting or PCI), especially in a clinical setting such as acute coronary syndrome.^3–5

In addition, the authors did not clearly highlight that diabetes mellitus is an independent risk factor for coronary lesion progression, coronary bypass graft occlusion, and cardiac mortality after bypass grafting surgery.^6–8 Clinical outcomes after bypass grafting in diabetic patients are worse than in nondiabetic patients; diabetic patients have higher rates of morbidity (deep sternal instability, wound infection, stroke, renal dysfunction, and respiratory problems), longer intensive care unit and hospital stays, and poorer postoperative physical functioning and quality of life.^6–8

The authors correctly explain the reasons for the superiority of coronary artery bypass grafting vs PCI in diabetic patients, either by the ability to achieve complete revascularization or by using more arterial grafts, and especially the left internal thoracic artery.¹ However, clarifying details on the strategy of revascularization in the FREEDOM trial are scarcely provided.² All we know from the provided details in this regard is that “for CABG surgery, arterial revascularization was encouraged” and 94.4% of the patients undergoing bypass grafting received left internal thoracic artery grafts.²

In addition, whereas off-pump coronary artery bypass grafting surgery is superior to conventional bypass grafting in terms of lower rates of death and major adverse cardiac and cerebrovascular events in diabetic patients with multivessel coronary artery disease,³ only 165 (18.5%) of the 893 patients who underwent bypass grafting in the FREEDOM trial underwent an off-pump procedure.^2,3

Therefore, all these considerations should be taken into account as the physician team discusses the therapeutic options (PCI and bypass grafting surgery) with diabetic patients who have multivessel coronary artery disease.

To the Editor: We would like to raise the following points about the paper by Dr. Aggarwal et al¹ interpreting the Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial.²

The patients enrolled in the FREEDOM trial do not in our opinion completely reflect the real patients that we meet in our daily “real-world” practice.² The patients in the FREEDOM trial did not have a high-risk profile. Rather, the mean European System for Cardiac Operative Risk Evaluation score (EuroSCORE) was 2.7 ± 2.4 in the percutaneous coronary intervention (PCI) group and 2.8 ± 2.5 in the coronary artery bypass grafting group—whereas a score of 5 or more on the EuroSCORE is associated with decreased rates of survival.²

Furthermore, patients with left main coronary artery stenosis were completely excluded from the FREEDOM trial,² but this type of stenosis, with different grades, is found in about 30% of diabetic patients with multivessel coronary artery disease, a fact that may significantly influence the decision regarding the revascularization strategy (bypass grafting or PCI), especially in a clinical setting such as acute coronary syndrome.^3–5

In addition, the authors did not clearly highlight that diabetes mellitus is an independent risk factor for coronary lesion progression, coronary bypass graft occlusion, and cardiac mortality after bypass grafting surgery.^6–8 Clinical outcomes after bypass grafting in diabetic patients are worse than in nondiabetic patients; diabetic patients have higher rates of morbidity (deep sternal instability, wound infection, stroke, renal dysfunction, and respiratory problems), longer intensive care unit and hospital stays, and poorer postoperative physical functioning and quality of life.^6–8

The authors correctly explain the reasons for the superiority of coronary artery bypass grafting vs PCI in diabetic patients, either by the ability to achieve complete revascularization or by using more arterial grafts, and especially the left internal thoracic artery.¹ However, clarifying details on the strategy of revascularization in the FREEDOM trial are scarcely provided.² All we know from the provided details in this regard is that “for CABG surgery, arterial revascularization was encouraged” and 94.4% of the patients undergoing bypass grafting received left internal thoracic artery grafts.²

In addition, whereas off-pump coronary artery bypass grafting surgery is superior to conventional bypass grafting in terms of lower rates of death and major adverse cardiac and cerebrovascular events in diabetic patients with multivessel coronary artery disease,³ only 165 (18.5%) of the 893 patients who underwent bypass grafting in the FREEDOM trial underwent an off-pump procedure.^2,3

Therefore, all these considerations should be taken into account as the physician team discusses the therapeutic options (PCI and bypass grafting surgery) with diabetic patients who have multivessel coronary artery disease.

To the Editor: We would like to raise the following points about the paper by Dr. Aggarwal et al¹ interpreting the Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial.²

The patients enrolled in the FREEDOM trial do not in our opinion completely reflect the real patients that we meet in our daily “real-world” practice.² The patients in the FREEDOM trial did not have a high-risk profile. Rather, the mean European System for Cardiac Operative Risk Evaluation score (EuroSCORE) was 2.7 ± 2.4 in the percutaneous coronary intervention (PCI) group and 2.8 ± 2.5 in the coronary artery bypass grafting group—whereas a score of 5 or more on the EuroSCORE is associated with decreased rates of survival.²

Furthermore, patients with left main coronary artery stenosis were completely excluded from the FREEDOM trial,² but this type of stenosis, with different grades, is found in about 30% of diabetic patients with multivessel coronary artery disease, a fact that may significantly influence the decision regarding the revascularization strategy (bypass grafting or PCI), especially in a clinical setting such as acute coronary syndrome.^3–5

In addition, the authors did not clearly highlight that diabetes mellitus is an independent risk factor for coronary lesion progression, coronary bypass graft occlusion, and cardiac mortality after bypass grafting surgery.^6–8 Clinical outcomes after bypass grafting in diabetic patients are worse than in nondiabetic patients; diabetic patients have higher rates of morbidity (deep sternal instability, wound infection, stroke, renal dysfunction, and respiratory problems), longer intensive care unit and hospital stays, and poorer postoperative physical functioning and quality of life.^6–8

The authors correctly explain the reasons for the superiority of coronary artery bypass grafting vs PCI in diabetic patients, either by the ability to achieve complete revascularization or by using more arterial grafts, and especially the left internal thoracic artery.¹ However, clarifying details on the strategy of revascularization in the FREEDOM trial are scarcely provided.² All we know from the provided details in this regard is that “for CABG surgery, arterial revascularization was encouraged” and 94.4% of the patients undergoing bypass grafting received left internal thoracic artery grafts.²

In addition, whereas off-pump coronary artery bypass grafting surgery is superior to conventional bypass grafting in terms of lower rates of death and major adverse cardiac and cerebrovascular events in diabetic patients with multivessel coronary artery disease,³ only 165 (18.5%) of the 893 patients who underwent bypass grafting in the FREEDOM trial underwent an off-pump procedure.^2,3

Therefore, all these considerations should be taken into account as the physician team discusses the therapeutic options (PCI and bypass grafting surgery) with diabetic patients who have multivessel coronary artery disease.

In Reply: We appreciate the comments of Dr. Saeed and colleagues. As stated in our article, given that the patients included in the FREEDOM trial represent a select group with diabetes and multivessel coronary artery disease, they may not represent all patients encountered in a real-world setting. We highlighted that only 10% of the patients screened were included for randomization, which limits the generalizability of the results. Also, the overall patient population may not be at high risk, as evidenced by low mean EuroSCORE and SYNTAX scores and by the low proportion of patients with ejection fractions less than 40%. However, patients with left main coronary artery disease (even without diabetes) have been shown to have better outcomes with coronary artery bypass grafting than with PCI, although a head-to-head trial in a diabetic subgroup is currently not available.^1,2 In addition, it is important to realize that the FREEDOM trial deals with stable angina; therefore, the results may not extend to patients with acute coronary syndrome wherein primary PCI remains the most feasible option in most cases.

Diabetes mellitus is independently associated with complex, accelerated, and multifocal coronary artery disease. Therefore, outcomes after revascularization (with bypass grafting or PCI) are worse in diabetic patients than in those without diabetes. However, this association does not prove the superiority of PCI over bypass grafting.

As we stated in our paper, the FREEDOM trial did not clearly define the strategy for arterial grafts in patients undergoing bypass grafting. The mean number of coronary lesions in the bypass grafting group was high (mean = 5.74), but the average number of grafts used was only 2.9, and data were not provided on the use of sequential grafting and multiple arterial conduits. Lastly, it is true that the FREEDOM trial had relatively fewer patients (18.5%) that underwent off-pump bypass grafting surgery; however, this approach has never been shown to be superior in large randomized trials.^3,4

In conclusion, no randomized trial should replace clinical judgment to define the targeted revascularization strategy for an individual patient. Rather, results from the FREEDOM trial should help support clinical decision-making in the context of the patient and the institution.

In Reply: We appreciate the comments of Dr. Saeed and colleagues. As stated in our article, given that the patients included in the FREEDOM trial represent a select group with diabetes and multivessel coronary artery disease, they may not represent all patients encountered in a real-world setting. We highlighted that only 10% of the patients screened were included for randomization, which limits the generalizability of the results. Also, the overall patient population may not be at high risk, as evidenced by low mean EuroSCORE and SYNTAX scores and by the low proportion of patients with ejection fractions less than 40%. However, patients with left main coronary artery disease (even without diabetes) have been shown to have better outcomes with coronary artery bypass grafting than with PCI, although a head-to-head trial in a diabetic subgroup is currently not available.^1,2 In addition, it is important to realize that the FREEDOM trial deals with stable angina; therefore, the results may not extend to patients with acute coronary syndrome wherein primary PCI remains the most feasible option in most cases.

Diabetes mellitus is independently associated with complex, accelerated, and multifocal coronary artery disease. Therefore, outcomes after revascularization (with bypass grafting or PCI) are worse in diabetic patients than in those without diabetes. However, this association does not prove the superiority of PCI over bypass grafting.

As we stated in our paper, the FREEDOM trial did not clearly define the strategy for arterial grafts in patients undergoing bypass grafting. The mean number of coronary lesions in the bypass grafting group was high (mean = 5.74), but the average number of grafts used was only 2.9, and data were not provided on the use of sequential grafting and multiple arterial conduits. Lastly, it is true that the FREEDOM trial had relatively fewer patients (18.5%) that underwent off-pump bypass grafting surgery; however, this approach has never been shown to be superior in large randomized trials.^3,4

In conclusion, no randomized trial should replace clinical judgment to define the targeted revascularization strategy for an individual patient. Rather, results from the FREEDOM trial should help support clinical decision-making in the context of the patient and the institution.

In Reply: We appreciate the comments of Dr. Saeed and colleagues. As stated in our article, given that the patients included in the FREEDOM trial represent a select group with diabetes and multivessel coronary artery disease, they may not represent all patients encountered in a real-world setting. We highlighted that only 10% of the patients screened were included for randomization, which limits the generalizability of the results. Also, the overall patient population may not be at high risk, as evidenced by low mean EuroSCORE and SYNTAX scores and by the low proportion of patients with ejection fractions less than 40%. However, patients with left main coronary artery disease (even without diabetes) have been shown to have better outcomes with coronary artery bypass grafting than with PCI, although a head-to-head trial in a diabetic subgroup is currently not available.^1,2 In addition, it is important to realize that the FREEDOM trial deals with stable angina; therefore, the results may not extend to patients with acute coronary syndrome wherein primary PCI remains the most feasible option in most cases.

Diabetes mellitus is independently associated with complex, accelerated, and multifocal coronary artery disease. Therefore, outcomes after revascularization (with bypass grafting or PCI) are worse in diabetic patients than in those without diabetes. However, this association does not prove the superiority of PCI over bypass grafting.

As we stated in our paper, the FREEDOM trial did not clearly define the strategy for arterial grafts in patients undergoing bypass grafting. The mean number of coronary lesions in the bypass grafting group was high (mean = 5.74), but the average number of grafts used was only 2.9, and data were not provided on the use of sequential grafting and multiple arterial conduits. Lastly, it is true that the FREEDOM trial had relatively fewer patients (18.5%) that underwent off-pump bypass grafting surgery; however, this approach has never been shown to be superior in large randomized trials.^3,4

In conclusion, no randomized trial should replace clinical judgment to define the targeted revascularization strategy for an individual patient. Rather, results from the FREEDOM trial should help support clinical decision-making in the context of the patient and the institution.

To the Editor: The July 2013 Cleveland Clinic Journal of Medicine includes timely articles addressing the problems of electronic health records (EHRs). At least to this reader, there is little that is surprising in the observations.

A common inside joke among programmers, sometimes displayed at one’s cubicle, is: “Fast, good, or cheap (pick two).” In other words, there is always a compromise to be had between a good product and one that is punched out on a given timetable and inexpensive. Economists call this the “second best.”

Any truly great software product accomplishes three goals. First, it allows the user to do everything previously doable at least as well or as easily as before. Second, it eliminates drudgery. And third, ideally, it provides new functionality, which previously was difficult or impossible to accomplish or to afford.

The reality is that much software is sold on the basis of the third goal, whereas goal number 1 and sometimes goal number 2 get short shrift. And for EHRs in particular, it is a fallacy for physicians to think that EHRs were brought out primarily for their benefit rather than for the benefit of the front office. This was all the more true a decade ago, when very few physicians were employed by hospitals. Thus, if the physician’s workload was increased because of the hospital’s choice of EHR, the hospital felt no financial pain. With greater reliance on an employment model, we can hope that hospitals will recognize that physicians should not be turned into very expensive secretaries.

To the Editor: The July 2013 Cleveland Clinic Journal of Medicine includes timely articles addressing the problems of electronic health records (EHRs). At least to this reader, there is little that is surprising in the observations.

A common inside joke among programmers, sometimes displayed at one’s cubicle, is: “Fast, good, or cheap (pick two).” In other words, there is always a compromise to be had between a good product and one that is punched out on a given timetable and inexpensive. Economists call this the “second best.”

Any truly great software product accomplishes three goals. First, it allows the user to do everything previously doable at least as well or as easily as before. Second, it eliminates drudgery. And third, ideally, it provides new functionality, which previously was difficult or impossible to accomplish or to afford.

The reality is that much software is sold on the basis of the third goal, whereas goal number 1 and sometimes goal number 2 get short shrift. And for EHRs in particular, it is a fallacy for physicians to think that EHRs were brought out primarily for their benefit rather than for the benefit of the front office. This was all the more true a decade ago, when very few physicians were employed by hospitals. Thus, if the physician’s workload was increased because of the hospital’s choice of EHR, the hospital felt no financial pain. With greater reliance on an employment model, we can hope that hospitals will recognize that physicians should not be turned into very expensive secretaries.

To the Editor: The July 2013 Cleveland Clinic Journal of Medicine includes timely articles addressing the problems of electronic health records (EHRs). At least to this reader, there is little that is surprising in the observations.

A common inside joke among programmers, sometimes displayed at one’s cubicle, is: “Fast, good, or cheap (pick two).” In other words, there is always a compromise to be had between a good product and one that is punched out on a given timetable and inexpensive. Economists call this the “second best.”

Any truly great software product accomplishes three goals. First, it allows the user to do everything previously doable at least as well or as easily as before. Second, it eliminates drudgery. And third, ideally, it provides new functionality, which previously was difficult or impossible to accomplish or to afford.

The reality is that much software is sold on the basis of the third goal, whereas goal number 1 and sometimes goal number 2 get short shrift. And for EHRs in particular, it is a fallacy for physicians to think that EHRs were brought out primarily for their benefit rather than for the benefit of the front office. This was all the more true a decade ago, when very few physicians were employed by hospitals. Thus, if the physician’s workload was increased because of the hospital’s choice of EHR, the hospital felt no financial pain. With greater reliance on an employment model, we can hope that hospitals will recognize that physicians should not be turned into very expensive secretaries.

Research on symptom management and monitoring of health-related quality of life (HRQOL) among cancer patients has typically focused on the active treatment phase.^1-7 More recently, greater attention has been given to the psychosocial needs and follow-up care plans for survivors.⁸ Several technology-assisted symptom/HRQOL monitoring systems with routine assessments have been shown to be easy to use,^1,3,5,9-16 readily accepted by patients,^{3,9,11,14,15,17,18} helpful in communication between patients and providers, ^3,9,11,13,15 and a means of overcoming numerous barriers to conducting routine assessments.^16,19-23 Real-time clinician feedback at the point-of-care appears to be a crucial component of these systems, giving patients and providers a systematic way of discussing symptoms and aspects of HRQOL that are often addressed only informally or not at all.

To date, 6 randomized controlled trials (RCTs) have assessed the impact of technology-assisted interventions among cancer patients.^6,23-27 There was significant variability across these studies, including differing sample sizes, number of intervention contacts, tumor site (eg, breast, lung, colon), outcomes assessed (eg, symptom distress, communication, and HRQOL), and types of technology used (eg, touch-screen computers, telephone systems). The methodological differences make it difficult to compare these studies, although a common thread was that patients found the systems easy to use and they generally perceived the systems as beneficial.^6,23-27 

Despite the positive response from participants, only 2 of the 6 RCTs demonstrated positive outcomes for the intervention over the control group.^23,25 In a study of 286 cancer patients and 28 oncologists, Velikova et al (2004) found that both the intervention and the attentioncontrol groups had better HRQOL than the control group over a 6-month period.²³ Among the intervention patients, the HRQOL improvement was related to clear use of the HRQOL data by physicians, and to physician/ patient discussion of pain and role function. A positive effect on emotional well-being was associated with feedback of the data to physicians. However, there were no significant differences between the intervention and attention-control groups.

Research on symptom management and monitoring of health-related quality of life (HRQOL) among cancer patients has typically focused on the active treatment phase.^1-7 More recently, greater attention has been given to the psychosocial needs and follow-up care plans for survivors.⁸ Several technology-assisted symptom/HRQOL monitoring systems with routine assessments have been shown to be easy to use,^1,3,5,9-16 readily accepted by patients,^{3,9,11,14,15,17,18} helpful in communication between patients and providers, ^3,9,11,13,15 and a means of overcoming numerous barriers to conducting routine assessments.^16,19-23 Real-time clinician feedback at the point-of-care appears to be a crucial component of these systems, giving patients and providers a systematic way of discussing symptoms and aspects of HRQOL that are often addressed only informally or not at all.

To date, 6 randomized controlled trials (RCTs) have assessed the impact of technology-assisted interventions among cancer patients.^6,23-27 There was significant variability across these studies, including differing sample sizes, number of intervention contacts, tumor site (eg, breast, lung, colon), outcomes assessed (eg, symptom distress, communication, and HRQOL), and types of technology used (eg, touch-screen computers, telephone systems). The methodological differences make it difficult to compare these studies, although a common thread was that patients found the systems easy to use and they generally perceived the systems as beneficial.^6,23-27 

Despite the positive response from participants, only 2 of the 6 RCTs demonstrated positive outcomes for the intervention over the control group.^23,25 In a study of 286 cancer patients and 28 oncologists, Velikova et al (2004) found that both the intervention and the attentioncontrol groups had better HRQOL than the control group over a 6-month period.²³ Among the intervention patients, the HRQOL improvement was related to clear use of the HRQOL data by physicians, and to physician/ patient discussion of pain and role function. A positive effect on emotional well-being was associated with feedback of the data to physicians. However, there were no significant differences between the intervention and attention-control groups.

Research on symptom management and monitoring of health-related quality of life (HRQOL) among cancer patients has typically focused on the active treatment phase.^1-7 More recently, greater attention has been given to the psychosocial needs and follow-up care plans for survivors.⁸ Several technology-assisted symptom/HRQOL monitoring systems with routine assessments have been shown to be easy to use,^1,3,5,9-16 readily accepted by patients,^{3,9,11,14,15,17,18} helpful in communication between patients and providers, ^3,9,11,13,15 and a means of overcoming numerous barriers to conducting routine assessments.^16,19-23 Real-time clinician feedback at the point-of-care appears to be a crucial component of these systems, giving patients and providers a systematic way of discussing symptoms and aspects of HRQOL that are often addressed only informally or not at all.

To date, 6 randomized controlled trials (RCTs) have assessed the impact of technology-assisted interventions among cancer patients.^6,23-27 There was significant variability across these studies, including differing sample sizes, number of intervention contacts, tumor site (eg, breast, lung, colon), outcomes assessed (eg, symptom distress, communication, and HRQOL), and types of technology used (eg, touch-screen computers, telephone systems). The methodological differences make it difficult to compare these studies, although a common thread was that patients found the systems easy to use and they generally perceived the systems as beneficial.^6,23-27 

Despite the positive response from participants, only 2 of the 6 RCTs demonstrated positive outcomes for the intervention over the control group.^23,25 In a study of 286 cancer patients and 28 oncologists, Velikova et al (2004) found that both the intervention and the attentioncontrol groups had better HRQOL than the control group over a 6-month period.²³ Among the intervention patients, the HRQOL improvement was related to clear use of the HRQOL data by physicians, and to physician/ patient discussion of pain and role function. A positive effect on emotional well-being was associated with feedback of the data to physicians. However, there were no significant differences between the intervention and attention-control groups.

Background Patients with late-stage cancer are living longer, making it important to understand factors that contribute to maintaining quality of life (QOL) and completing advanced illness behaviors (eg, advance directives).

Objective To examine whether illness perceptions—the cognitive beliefs that patients form about their cancer—may be more important guides to adjustment than clinical characteristics of the cancer.

Methods In a cross-sectional study, 105 female patients diagnosed with stage III (n 66) or IV (n 39) breast (n 44), gynecological (n 38), or lung (n 23) cancer completed self-report measures of illness perceptions, QOL, and advanced illness behaviors. Clinical data was obtained from medical records.

Results Despite modest associations, patients’ beliefs about the cancer were clearly unique from the clinical characteristics of the cancer. Illness perception variables accounted for a large portion of the variance (PS .01) for QOL and advanced illness behaviors, whereas clinical characteristics did not. QOL scores were predicted by patients’ reports of experiencing more cancer related symptoms (ie, illness identity), believing that their cancer is central to their self-identity, and higher income. Higher completion of advanced illness behaviors was predicted by higher income, the cancer being recurrent, and participants perceiving their cancer as more severe but also more understandable.

Limitations This study was limited by a cross-sectional design, small sample size, and focus on female patients.

Conclusion Addressing patients’ beliefs about their cancer diagnosis may provide important targets for intervention to improve QOL and illness behaviors in patients with late-stage cancer.

Click on the PDF icon at the top of this introduction to read the full article.

Background Patients with late-stage cancer are living longer, making it important to understand factors that contribute to maintaining quality of life (QOL) and completing advanced illness behaviors (eg, advance directives).

Objective To examine whether illness perceptions—the cognitive beliefs that patients form about their cancer—may be more important guides to adjustment than clinical characteristics of the cancer.

Methods In a cross-sectional study, 105 female patients diagnosed with stage III (n 66) or IV (n 39) breast (n 44), gynecological (n 38), or lung (n 23) cancer completed self-report measures of illness perceptions, QOL, and advanced illness behaviors. Clinical data was obtained from medical records.

Results Despite modest associations, patients’ beliefs about the cancer were clearly unique from the clinical characteristics of the cancer. Illness perception variables accounted for a large portion of the variance (PS .01) for QOL and advanced illness behaviors, whereas clinical characteristics did not. QOL scores were predicted by patients’ reports of experiencing more cancer related symptoms (ie, illness identity), believing that their cancer is central to their self-identity, and higher income. Higher completion of advanced illness behaviors was predicted by higher income, the cancer being recurrent, and participants perceiving their cancer as more severe but also more understandable.

Limitations This study was limited by a cross-sectional design, small sample size, and focus on female patients.

Conclusion Addressing patients’ beliefs about their cancer diagnosis may provide important targets for intervention to improve QOL and illness behaviors in patients with late-stage cancer.

Click on the PDF icon at the top of this introduction to read the full article.

Background Patients with late-stage cancer are living longer, making it important to understand factors that contribute to maintaining quality of life (QOL) and completing advanced illness behaviors (eg, advance directives).

Objective To examine whether illness perceptions—the cognitive beliefs that patients form about their cancer—may be more important guides to adjustment than clinical characteristics of the cancer.

Methods In a cross-sectional study, 105 female patients diagnosed with stage III (n 66) or IV (n 39) breast (n 44), gynecological (n 38), or lung (n 23) cancer completed self-report measures of illness perceptions, QOL, and advanced illness behaviors. Clinical data was obtained from medical records.

Results Despite modest associations, patients’ beliefs about the cancer were clearly unique from the clinical characteristics of the cancer. Illness perception variables accounted for a large portion of the variance (PS .01) for QOL and advanced illness behaviors, whereas clinical characteristics did not. QOL scores were predicted by patients’ reports of experiencing more cancer related symptoms (ie, illness identity), believing that their cancer is central to their self-identity, and higher income. Higher completion of advanced illness behaviors was predicted by higher income, the cancer being recurrent, and participants perceiving their cancer as more severe but also more understandable.

Limitations This study was limited by a cross-sectional design, small sample size, and focus on female patients.

Conclusion Addressing patients’ beliefs about their cancer diagnosis may provide important targets for intervention to improve QOL and illness behaviors in patients with late-stage cancer.

Click on the PDF icon at the top of this introduction to read the full article.

Venous thromboembolism (VTE) and its associated complications account for significant morbidity and mortality. Each year between 100 and 180 persons per 100,000 develop a VTE in the Western countries. The majority of VTEs are classified as either pulmonary embolism (PE), which accounts for one third of the events, or deep vein thrombosis (DVT), which is responsible for the remaining two thirds. Between 20% and 30% of patients diagnosed with thrombotic events will die within the first month after diagnosis. PE is a common consequence of DVT; 40% of patients who are diagnosed with a DVT will be subsequently found to have a PE upon further imaging. The high rate of association is also seen in those who present with a PE, 70% of whom will also be found to have a concomitant DVT.

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Venous thromboembolism (VTE) and its associated complications account for significant morbidity and mortality. Each year between 100 and 180 persons per 100,000 develop a VTE in the Western countries. The majority of VTEs are classified as either pulmonary embolism (PE), which accounts for one third of the events, or deep vein thrombosis (DVT), which is responsible for the remaining two thirds. Between 20% and 30% of patients diagnosed with thrombotic events will die within the first month after diagnosis. PE is a common consequence of DVT; 40% of patients who are diagnosed with a DVT will be subsequently found to have a PE upon further imaging. The high rate of association is also seen in those who present with a PE, 70% of whom will also be found to have a concomitant DVT.

To read the full article in PDF:

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Venous thromboembolism (VTE) and its associated complications account for significant morbidity and mortality. Each year between 100 and 180 persons per 100,000 develop a VTE in the Western countries. The majority of VTEs are classified as either pulmonary embolism (PE), which accounts for one third of the events, or deep vein thrombosis (DVT), which is responsible for the remaining two thirds. Between 20% and 30% of patients diagnosed with thrombotic events will die within the first month after diagnosis. PE is a common consequence of DVT; 40% of patients who are diagnosed with a DVT will be subsequently found to have a PE upon further imaging. The high rate of association is also seen in those who present with a PE, 70% of whom will also be found to have a concomitant DVT.

To read the full article in PDF:

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After a stroke, an important goal is to prevent another one.^1,2 And for patients who have had an ischemic stroke or transient ischemic attack (TIA) due to atherosclerosis, an important part of secondary preventive therapy is a drug that inhibits platelets—ie, aspirin, extended-release dipyridamole, or clopidogrel. This has taken years to establish.

In the following pages, we discuss the antiplatelet agents that have been shown to be beneficial after stroke of atherosclerotic origin, and we briefly review the indications for surgery and stenting for the subset of patients whose strokes are caused by symptomatic carotid disease.

(Although managing modifiable risk factors such as smoking, hypertension, diabetes, and dyslipidemia is also important, we will not cover this topic here, nor will we talk about hemorrhagic stroke or stroke due to atrial fibrillation. Also not discussed here is cilostazol, which, although shown to be effective in preventing recurrent stroke when compared with placebo and aspirin,^3,4 has not been approved for this use by the US Food and Drug Administration, as of this writing.)

HOW WE REVIEWED THE LITERATURE

We searched PubMed using the terms aspirin, acetylsalicylic acid, clopidogrel, and/or dipyridamole, in combination with stroke, cerebral ische(ae)mia, transient ische(ae)mic attacks, or retinal artery occlusion. We reviewed only clinical trials or meta-analyses of these drugs for either primary or secondary prevention of cerebrovascular disease.

As our aim was to review the topic and not to perform a meta-analysis, no cutoffs were used to exclude trials. The references in the selected papers were also reviewed to expand the articles. Finally, the references in the current American Heart Association and American Stroke Association secondary stroke prevention guideline were also reviewed.

For a summary of the trials included in our review, see the Data Supplement as an appendix to the online version of this article.

ASPIRIN: THE GOLD STANDARD

Prescribed by Hippocrates in the form of willow bark extract, aspirin has long been known for its antipyretic and anti-inflammatory properties. Its antiplatelet and antithrombotic properties, first described in 1967 by Weiss and Aledort,⁵ are mediated by irreversible inhibition of cyclooxygenase, leading to decreased thromboxane A2, a platelet-aggregation activator.

Fields et al,^6,7 in 1977 and 1978, reported that in a controlled trial in patients with TIA or monocular blindness, fewer subsequent TIAs occurred in patients who received aspirin, although the difference was not statistically significant, with lower rates of events only in nonsurgical patients. Over the next 20 years, the results remained mixed.

The Danish Cooperative study⁸ (1983) found no significant difference in the rate of recurrent stroke with aspirin vs placebo.

AICLA.⁹ The Accidents Ischémiques Cérébraux Liés à l’Athérosclérose study of 1983 did find a difference. However, both the Danish Cooperative study and the AICLA were limited by lacking standardized computed tomographic imaging to rule out hemorrhagic stroke and by being relatively small.

The Swedish Cooperative Study¹⁰ (1987) found no statistical difference between high-dose aspirin and placebo in preventing recurrent vascular events (stroke, TIA, or myocardial infarction [MI]) 1 to 3 weeks after a stroke. However, it had several limitations: the aspirin group contained more patients with ischemic heart disease (who are more likely to die of cardiac causes), there were significantly more men in the aspirin group, and nearly one-fourth of the deaths were a result of the initial stroke, potentially masking the effect of aspirin in secondary prevention.

Later studies began to show a consistently favorable effect of aspirin.

Boysen et al¹¹ in 1988 reported a nonsignificant trend toward fewer adverse events with aspirin.

UK-TIA.¹² The United Kingdom Transient Ischaemic Attack trial in 1991 found a similar trend.

SALT.¹³ The Swedish Aspirin Low-dose Trial, also in 1991, showed a significant 18% lower rate of stroke or death in patients with recent TIA, minor stroke, or retinal occlusion treated with low-dose aspirin. The inclusion of patients with TIA helped broaden the population that might benefit. However, the study may have favored the aspirin group by having a run-in period in which patients were nonrandomly treated either with aspirin or with anticoagulation at the discretion of the patient’s physician and, if they suffered “several” TIAs, a stroke, retinal artery occlusion, or MI, were removed from the study.

ESPS-2.¹⁴ The second European Stroke Prevention Study in 1996 added to the evidence that aspirin prevents recurrent stroke. Patients with a history of TIA or stroke were randomized in double-blind fashion to four treatment groups: placebo, low-dose aspirin, dipyridamole, or aspirin plus dipyridamole. At 2 years, strokes had occurred in 18% fewer patients in the aspirin group than in the placebo group, and TIAs had occurred in 21.9% fewer. However, aspirin was associated with an absolute 0.5% increase in severe and fatal bleeding. The power of the study was limited because patients from one center were excluded because of “serious inconsistencies in patient case record forms and compliance assay determinations.” ¹⁴

Comment. The mixed results with aspirin in studies predating ESPS-2 were partly because the study populations were too small to show benefit.

ATT.¹⁵ The Antithrombotic Trialists’ Collaboration performed a meta-analysis that conclusively confirmed the benefit of aspirin after stroke or TIA. The investigators analyzed individual patient data pooled from randomized controlled trials published before 1997 that compared antiplatelet regimens (mostly aspirin) against placebo and against each other. The rates of vascular events were 10.7% with treatment vs 13.2% with placebo (P < .0001). Antiplatelet therapy was particularly effective in preventing ischemic stroke, with a 25% reduction in the rate of nonfatal stroke, and with an overall absolute benefit in stroke prevention across all high-risk patient groups. This translated to 25 fewer nonfatal strokes per 1,000 patients treated with antiplatelet therapy.

Studies of aspirin have used different daily doses—the earliest studies used large doses of 1,000 to 1,500 mg.^6–10

Boysen et al¹¹ in 1988 found a trend toward benefit (not statistically significant) with doses ranging from 50 mg to 100 mg.

In 1991, three separate studies found that higher doses of aspirin were no more effective than lower doses.

The UK-TIA trial¹² compared aspirin 300 mg vs 1,200 mg and found a higher risk of gastrointestinal bleeding with the higher dose.

The SALT Collaborative Group¹³ found 75 mg to be effective.

The Dutch TIA trial¹⁶ compared 30 mg vs 283 mg; end point outcomes were similar but the rate of adverse events was higher with 283 mg.

ESPS-2 was able to show efficacy at a dose of only 50 mg.¹⁴

Taylor et al¹⁷ compared lower doses (81 or 325 mg) vs higher doses (650 or 1,300 mg) for patients undergoing carotid endarterectomy and found that the risk of adverse events was twice as high with the higher doses.

The ATT Collaboration¹⁵ found that efficacy was 40% lower with the highest dose of aspirin than with the lowest doses.

Algra and van Gijn¹⁸ performed a meta-analysis of all these studies and found no difference in risk reduction between low-dose and high-dose aspirin, with an overall relative risk reduction of 13% at any dose above 30 mg.

Campbell et al,¹⁹ in a 2007 review, found that doses greater than 300 mg conferred no benefit, and that rapid and maximum suppression of thromboxane A2 can be achieved by chewing or ingesting dissolved forms of aspirin 162 mg.

Conclusion. Aspirin doses higher than 81 mg (the US standard) confer no greater benefit and may even decrease the efficacy of aspirin. In an emergency, rapid suppression of thromboxane A2 can be achieved by chewing a minimum dose of 162 mg.

DIPYRIDAMOLE CAN BE ADDED TO ASPIRIN

In 1967, Weiss and Aledort⁵ found that aspirin’s antiplatelet effect could be blocked by adenosine diphosphate, which is released by activated platelet cells and is an essential part of thrombus formation. Adjacent platelets are then activated, leading to up-regulation of thromboxane A2 and glycoprotein IIb/IIIa receptors and resulting in a cascade of platelet activation and clot formation.²⁰ Dipyridamole inhibits aggregation of platelets by inhibiting their ability to take up adenosine diphosphate.

Studies of dipyridamole

AICLA.⁹ Bousser et al⁹ randomized patients who suffered one or more cerebral or retinal infarctions to receive placebo, aspirin 1 g, or aspirin 1 g plus dipyridamole 225 mg. Aspirin was significantly better than placebo in preventing a recurrence of stroke. The event rate with aspirin plus dipyridamole was similar to the rate with aspirin alone, although on 2-by-2 analysis, the difference between placebo and aspirin plus dipyridamole did not reach statistical significance. However, the rate of carotid-origin stroke was 17% with aspirin alone and 6% with aspirin plus dipyridamole, a statistically significant difference.

Thus, this study confirmed the benefit of aspirin in preventing ischemic events but did not fully support the addition of dipyridamole, except in preventing stroke of carotid origin. The study had a number of limitations: the sample size was small, TIA was not included as an end point, computed tomography was not required for entry, and many patients were lost to follow-up, decreasing the statistical power of the trial.

The ESPS study²¹ was also a randomized controlled trial of aspirin plus dipyridamole vs placebo. But unlike AICLA, ESPS included patients with TIA.

ESPS found a 38.1% relative risk reduction in stroke with aspirin plus dipyridamole compared with placebo, and a 30.6% reduction in death from all causes. Interestingly, patients who had a TIA as the qualifying event had a lower end-point incidence and larger end-point reduction than those who had a stroke as the qualifying event. However, ESPS did not resolve the question of whether adding dipyridamole to aspirin affords any benefit over aspirin alone.

ESPS-2¹⁴ hoped to answer this question. Patients were randomized to placebo, aspirin, dipyridamole, or aspirin plus dipyridamole. On 2 × 2 analysis, the dipyridamole group had a 16% lower rate of recurrent stroke than the placebo group, and patients on aspirin plus dipyridamole had a 37% lower rate. Aspirin plus dipyridamole yielded a 23.1% reduction compared with aspirin alone, and a 24.7% reduction compared with dipyridamole alone. Similar benefit was reported for the end point of TIA with combination therapy compared with either agent alone.

However, nearly 25% of patients had to withdraw because of side effects, particularly in the dipyridamole-alone and aspirin-dipyridamole groups, and, as mentioned above, verification of compliance in the aspirin group was an issue.^14,22 Nevertheless, ESPS-2 clearly showed that aspirin plus dipyridamole was better than either drug alone in preventing recurrent stroke. It also showed the effectiveness of dipyridamole, which AICLA and ESPS could not do, because it had a larger study population, used a lower dose of aspirin, and perhaps because it used an extended-release form of dipyridamole.²³

The ATT meta-analysis¹⁵ showed a clear benefit of antiplatelet therapy. However, much of this benefit was derived from aspirin therapy, with the addition of dipyridamole resulting in a nonsignificant 6% reduction of vascular events. Most of the patients on dipyridamole were from the ESPS-2 study. In effect, the ATT was a meta-analysis of aspirin, as aspirin studies dominated at that time.

A Cochrane review²⁴ publsihed in 2003 attempted to rectify this by analyzing randomized controlled trials of dipyridamole vs placebo.²⁴ Like the ATT meta-analysis, it did not bear out the benefits of dipyridamole: compared with placebo, there was no effect on the rate of vascular death, and only a minimal benefit in reduction of vascular events—and this latter point is only because of the inclusion of ESPS-2.

Directly comparing aspirin plus dipyridamole vs aspirin alone, the reviewers found no effect on the rate of vascular death, and with the exclusion of ESPS-2, no effect on vascular events.

The Cochrane review had the same limitation as the ATT meta-analysis, ie, dependence on a single trial (ESPS-2) to show benefit, and perhaps the fact that ESPS-2 was the only study that used an extended-release form of dipyridamole.

Leonardi-Bee et al²⁵ performed a meta-analysis that overcame the limitation of ESPS-2 being the only study at the time with positive findings: they used pooled individual patient data from randomized trials and analyzed them en masse. Patients on aspirin plus dipyridamole had a 39% lower risk than with placebo and a 22% lower risk than with aspirin alone. Unlike the ATT and the Cochrane review, excluding ESPS-2 did not alter the statistically significant lower stroke rate with aspirin plus dipyridamole compared with controls. This meta-analysis helped to confirm ESPS-2’s finding of the additive effect of aspirin plus dipyridamole compared with aspirin and placebo control.

ESPRIT.^26,27 The European/Australasian Stroke Prevention in Reversible Ischaemia Trial confirmed these findings. This randomized controlled trial compared aspirin plus dipyridamole against aspirin alone in patients with a TIA or minor ischemic stroke of arterial origin within the past 6 months. For the primary end point (death from all vascular causes, nonfatal stroke, nonfatal MI, nonfatal major bleeding complication), the hazard ratio was 0.80 favoring aspirin plus dipyridamole, with a number needed to treat of 104 over a mean of 3.5 years (absolute risk reduction of 1% per year). Importantly, twice as many patients taking aspirin plus dipyridamole discontinued the medication.

Caveats to interpreting this study are that it was not blinded, the aspirin doses varied (although the median aspirin dose—75 mg—was the same between the two groups), and not all patients received the extended-release form of dipyridamole.

ESPS-2, ESPRIT, and the meta-analysis by Leonardi-Bee et al showed that aspirin plus dipyridamole is more effective than placebo or aspirin alone in secondary prevention of vascular events, including stroke. Also, extended-release dipyridamole appears to be more effective.

Unfortunately, many patients stop taking dipyridamole because of side effects (primarily headache).

Based on the results of ESPRIT, the absolute benefit of dipyridamole used alone may be small.

CLOPIDOGREL: SIMILAR TO ASPIRIN IN EFFICACY?

Like dipyridamole, clopidogrel targets adenosine diphosphate to prevent clot formation, blocking its ability to bind to its receptor on platelets. It is a thienopyridine and, unlike its sister drug ticlopidine, does not seem to be associated with the potentially serious side effects of neutropenia. However, a few cases of thrombotic thrombocytopenic purpura have been reported.²⁸ The other drugs in this class have not been evaluated in clinical trials for secondary stroke prophylaxis.

Trials of clopidogrel

CAPRIE.²⁹ The Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events trial, in 1996, was one of the first to compare the clinical use of clopidogrel against aspirin. It was a randomized controlled noninferiority trial in patients over age 21 (inclusion criteria: ischemic stroke, MI, or peripheral arterial disease) randomized to aspirin 325 mg once daily or clopidogrel 75 mg once daily. Patients were followed for 1 to 3 years.

Patients on clopidogrel had a relative risk reduction of 8.7% in primary events (ischemic stroke, MI, or vascular death); patients on aspirin were at significantly higher risk of gastrointestinal hemorrhage. Patients with peripheral arterial disease as the qualifying event did particularly well on clopidogrel, with a significant relative risk reduction of 23.8%.

Limitations of the CAPRIE trial included its inability to measure the effect of treatment on individual outcomes, particularly stroke, and the fact that the relative risk reduction for patients with stroke as the qualifying event was not significant (P = .66). Another limitation was that it did not use TIA as an entry criterion or as part of the composite outcome. Also, the relative risk reduction had a wide confidence interval, and a large number of patients discontinued therapy for reasons other than the defined outcomes.

Nevertheless, the CAPRIE trial showed clopidogrel to be an effective antiplatelet prophylactic, particularly in patients with peripheral artery disease, but with no discernible difference from aspirin for those patients with MI or stroke as a qualifying event.

MATCH.³⁰ The Management of Atherothrombosis With Clopidogrel in High-risk Patients trial hoped to better assess clopidogrel’s efficacy, particularly in patients with ischemic cerebral events. Cardiac studies leading up to MATCH suggested that adding a thienopyridine to aspirin might offer additive benefit in reducing the rate of vascular outcomes.^15,31 MATCH randomized high-risk patients (inclusion criteria were ischemic stroke or TIA and a history of vascular disease) to clopidogrel or to aspirin plus clopidogrel.

There was a nonsignificant 6.4% relative risk reduction in the combined primary outcome of MI, ischemic stroke, vascular death, other vascular death, and re-hospitalization for acute ischemic events in the aspirin-plus-clopidogrel group compared with clopidogrel alone. However, this came at the cost of double the number of bleeding events in the combination group, mitigating most of the benefit of combination therapy.

An important caveat in interpreting the results of MATCH, as compared with the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, is that aspirin was being added to clopidogrel, not vice versa. CURE, which looked at the addition of clopidogrel to aspirin vs aspirin alone in cardiac patients, found a significant reduction of ischemic events taken as a group (relative risk 0.8), and a trend toward a lower rate of stroke (relative risk 0.86, but 95% confidence interval encompassing 1) for aspirin plus clopidogrel vs aspirin alone.³¹ However, patients in the CURE trial did not have high-risk vasculopathy per se but rather non-ST-elevation MI, perhaps skewing the benefit of combination therapy and lessening the risk of intracranial bleeding.

CHARISMA.³² The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, like the CURE trial, compared aspirin plus clopidogrel vs aspirin in patients with established cardiovascular, cerebrovascular, or peripheral arterial disease, or who were at high risk of events. As in the MATCH study, the findings for combination therapy were a nonsignificant relative risk of 0.93 for primary events (MI, stroke, or death from cardiovascular causes), and a significant reduction of secondary end points (primary end point event plus TIA or hospitalization for unstable angina) (relative risk 0.92, P = .04).

Importantly, combination therapy significantly increased the rate of bleeding events. In asymptomatic patients (those without documented vascular disease but with multiple atherothrombotic risk factors), there was actually harm with combined treatment. Conversely, for symptomatic patients (those with documented vascular disease), there was a negligible, but significant reduction in primary end points.

The result was that in patients with documented vascular disease, aspirin plus clopidogrel combination therapy provided little or no benefit over aspirin alone. For patients with elevated risk factors but no documented vascular burden, there may actually be harm from combination therapy.

PRoFESS.³³ Logically following is the question of whether aspirin plus dipyridamole offers any benefit over clopidogrel as a stroke prophylactic. The Prevention Regimen for Effectively Avoiding Second Strokes trial hoped to answer this by comparing clopidogrel against aspirin plus dipyridamole, both with and without telmisartan, in patients with recent stroke.

The rate of recurrent stroke was similar in the two groups, but there were 25 fewer ischemic strokes in patients on aspirin plus dipyridamole, offset by an increase in hemorrhagic strokes. Rates of secondary outcomes of stroke, death, or MI were nearly identical between the groups. Early discontinuation of treatment was significantly more frequent in those patients taking aspirin plus dipyridamole, meaning better compliance for those taking clopidogrel.

Initially, patients were to be randomized to either aspirin plus dipyridamole or aspirin plus clopidogrel. However, after MATCH³⁰ demonstrated a significantly higher bleeding risk with aspirin plus clopidogrel, patients were changed to clopidogrel alone. But despite this, the bleeding risk was still higher with aspirin plus dipyridamole.

During the trial, the entry criteria were expanded, allowing for the inclusion of younger patients and those with less recent strokes; but despite this change, the study remained underpowered to demonstrate its goal of noninferiority. Thus, it showed only a trend of noninferiority of clopidogrel vs aspirin plus dipyridamole.

What the clopidogrel trials tell us

Clopidogrel confers a benefit similar to that of aspirin (as shown in the CAPRIE study).²⁹ Although aspirin plus dipyridamole confers greater benefit than aspirin alone (as shown in the ESPS-2,¹⁴ Leonardi-Bee,²⁵ and ESPRIT²⁶ studies), aspirin plus dipyridamole is not superior to clopidogrel, and may even be inferior.³⁴

WARFARIN FOR ATRIAL FIBRILLATION ONLY

Warfarin acts by disrupting the coagulation cascade rather than acting at the site of platelet plug formation. In theory, warfarin should be as effective as the antiplatelet drugs in preventing clot formation, and so it was thought to possibly be effective in preventing stroke of arterial origin.

However, in at least three studies, warfarin increased the risk of death, MI, and hemorrhage, with perhaps a slight decrease in the risk of recurrent stroke in patients with suspected stroke or TIA.^35–37 This should be differentiated from stroke originating from cardiac dysrhythmias, for which warfarin has clearly been shown to be beneficial.²⁸

THREE GOOD MEDICAL OPTIONS FOR PREVENTING STROKE RECURRENCE

Antiplatelet therapy offers benefit in the primary and secondary prevention of stroke, with a 25% reduction in the rate of nonfatal stroke and a 17% reduction in the rate of death due to vascular causes.¹⁵

Aspirin is the best established, best tolerated, and least expensive of the three contemporary agents. Further, it is also the agent of choice for acute stroke care, to be given within 48 hours of a stroke to mitigate the risk of death and morbidity. The data for other agents in acute stroke management remain limited.³⁸

Aspirin plus dipyridamole

Aspirin plus dipyridamole is slightly more efficacious than aspirin alone, and it is an alternative when aspirin is ineffective and when the patient can afford the additional cost. Aspirin plus dipyridamole offers up to a 22% relative risk reduction (but a small reduction in absolute risk) of stroke compared with aspirin alone, as demonstrated by ESPS-2,¹⁴ Leonardi-Bee et al,²⁵ and ESPRIT.²⁶

When is clopidogrel appropriate?

Up to one-third of patients may not tolerate aspirin plus dipyridamole because of side effects. Clopidogrel is an option for these patients. The CAPRIE study²⁹ showed clopidogrel similar in efficacy to aspirin.

In contrast to aspirin plus dipyridamole, there is clearly no benefit to combining aspirin and clopidogrel for ischemic stroke prophylaxis. And data from PRoFESS³³ suggested the combination was qualitatively inferior to aspirin plus dipyridamole. However, the PRoFESS trial was underpowered to fully bear this out.

Therefore, current guidelines consider all three agents as appropriate for secondary prevention of stroke. One is not preferred over another, and the selection should be based on individual patient characteristics and affordability.²⁸

CAROTID SURGERY OR STENTING: BENEFITS AND LIMITATIONS

Atherosclerosis is the most common cause of stroke, and atherosclerosis of the common carotid bifurcation accounts for a small but significant percentage of all strokes.^39–41

The degree of carotid stenosis and whether it is producing symptoms influence how it should be managed. For patients with symptomatic carotid stenosis of more than 70%, multicenter randomized trials have shown that surgery (ie, carotid endarterectomy) added to medical therapy decreases the rate of recurrent stroke by up to 17% and the rate of combined stroke and death by 10% to 12% over a 2- to 3-year follow-up period (level of evidence A).^42–44 No study has proven the efficacy of surgery in patients with symptomatic stenosis of less than 50%.^43,44

Similarly, in asymptomatic carotid disease, preventive surgery is a beneficial adjunct to medical therapy in certain patients. An approximate 6% reduction in the rate of stroke or death over 5 years has been shown in patients with moderate stenosis (> 60%), with men younger than age 75 and with greater than 70% stenosis deriving the most benefit.^45–47

However, these robust, positive results with surgical intervention should not overshadow the importance of intensive and guided medical therapy, which has been shown to mitigate the risk of stroke.^48,49

Is stenting as good as surgery? In the multicenter randomized Carotid Revascularization Endarterectomy vs Stenting Trial (CREST), stenting resulted in similar rates of stroke and MI in patients with symptomatic and asymptomatic disease.⁵⁰ However, stenting carried a greater risk of perioperative stroke, and endarterectomy carried a greater risk of MI. Those under age 70 benefited more from stenting, and those over age 70 benefited more from endarterectomy.

But another fact to keep in mind is that the relationship between carotid narrowing and an ipsilateral stroke is not necessarily direct. Two follow-up studies in patients from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) found that up to 45% of strokes that occurred after intervention in the distribution of the asymptomatic stenosed carotid artery were unrelated to the stenosis.^51,52 Moreover, up to 20% of subsequent strokes in the distribution of the symptomatic artery were not of large-artery origin, increasing up to 35% for those with stenosis of less than 70%.⁵¹ Clearly, thorough screening of those with presumed symptomatic stenosis is needed to eliminate other possible causes.

After a stroke, an important goal is to prevent another one.^1,2 And for patients who have had an ischemic stroke or transient ischemic attack (TIA) due to atherosclerosis, an important part of secondary preventive therapy is a drug that inhibits platelets—ie, aspirin, extended-release dipyridamole, or clopidogrel. This has taken years to establish.

In the following pages, we discuss the antiplatelet agents that have been shown to be beneficial after stroke of atherosclerotic origin, and we briefly review the indications for surgery and stenting for the subset of patients whose strokes are caused by symptomatic carotid disease.

(Although managing modifiable risk factors such as smoking, hypertension, diabetes, and dyslipidemia is also important, we will not cover this topic here, nor will we talk about hemorrhagic stroke or stroke due to atrial fibrillation. Also not discussed here is cilostazol, which, although shown to be effective in preventing recurrent stroke when compared with placebo and aspirin,^3,4 has not been approved for this use by the US Food and Drug Administration, as of this writing.)

HOW WE REVIEWED THE LITERATURE

We searched PubMed using the terms aspirin, acetylsalicylic acid, clopidogrel, and/or dipyridamole, in combination with stroke, cerebral ische(ae)mia, transient ische(ae)mic attacks, or retinal artery occlusion. We reviewed only clinical trials or meta-analyses of these drugs for either primary or secondary prevention of cerebrovascular disease.

As our aim was to review the topic and not to perform a meta-analysis, no cutoffs were used to exclude trials. The references in the selected papers were also reviewed to expand the articles. Finally, the references in the current American Heart Association and American Stroke Association secondary stroke prevention guideline were also reviewed.

For a summary of the trials included in our review, see the Data Supplement as an appendix to the online version of this article.

ASPIRIN: THE GOLD STANDARD

Prescribed by Hippocrates in the form of willow bark extract, aspirin has long been known for its antipyretic and anti-inflammatory properties. Its antiplatelet and antithrombotic properties, first described in 1967 by Weiss and Aledort,⁵ are mediated by irreversible inhibition of cyclooxygenase, leading to decreased thromboxane A2, a platelet-aggregation activator.

Fields et al,^6,7 in 1977 and 1978, reported that in a controlled trial in patients with TIA or monocular blindness, fewer subsequent TIAs occurred in patients who received aspirin, although the difference was not statistically significant, with lower rates of events only in nonsurgical patients. Over the next 20 years, the results remained mixed.

The Danish Cooperative study⁸ (1983) found no significant difference in the rate of recurrent stroke with aspirin vs placebo.

AICLA.⁹ The Accidents Ischémiques Cérébraux Liés à l’Athérosclérose study of 1983 did find a difference. However, both the Danish Cooperative study and the AICLA were limited by lacking standardized computed tomographic imaging to rule out hemorrhagic stroke and by being relatively small.

The Swedish Cooperative Study¹⁰ (1987) found no statistical difference between high-dose aspirin and placebo in preventing recurrent vascular events (stroke, TIA, or myocardial infarction [MI]) 1 to 3 weeks after a stroke. However, it had several limitations: the aspirin group contained more patients with ischemic heart disease (who are more likely to die of cardiac causes), there were significantly more men in the aspirin group, and nearly one-fourth of the deaths were a result of the initial stroke, potentially masking the effect of aspirin in secondary prevention.

Later studies began to show a consistently favorable effect of aspirin.

Boysen et al¹¹ in 1988 reported a nonsignificant trend toward fewer adverse events with aspirin.

UK-TIA.¹² The United Kingdom Transient Ischaemic Attack trial in 1991 found a similar trend.

SALT.¹³ The Swedish Aspirin Low-dose Trial, also in 1991, showed a significant 18% lower rate of stroke or death in patients with recent TIA, minor stroke, or retinal occlusion treated with low-dose aspirin. The inclusion of patients with TIA helped broaden the population that might benefit. However, the study may have favored the aspirin group by having a run-in period in which patients were nonrandomly treated either with aspirin or with anticoagulation at the discretion of the patient’s physician and, if they suffered “several” TIAs, a stroke, retinal artery occlusion, or MI, were removed from the study.

ESPS-2.¹⁴ The second European Stroke Prevention Study in 1996 added to the evidence that aspirin prevents recurrent stroke. Patients with a history of TIA or stroke were randomized in double-blind fashion to four treatment groups: placebo, low-dose aspirin, dipyridamole, or aspirin plus dipyridamole. At 2 years, strokes had occurred in 18% fewer patients in the aspirin group than in the placebo group, and TIAs had occurred in 21.9% fewer. However, aspirin was associated with an absolute 0.5% increase in severe and fatal bleeding. The power of the study was limited because patients from one center were excluded because of “serious inconsistencies in patient case record forms and compliance assay determinations.” ¹⁴

Comment. The mixed results with aspirin in studies predating ESPS-2 were partly because the study populations were too small to show benefit.

ATT.¹⁵ The Antithrombotic Trialists’ Collaboration performed a meta-analysis that conclusively confirmed the benefit of aspirin after stroke or TIA. The investigators analyzed individual patient data pooled from randomized controlled trials published before 1997 that compared antiplatelet regimens (mostly aspirin) against placebo and against each other. The rates of vascular events were 10.7% with treatment vs 13.2% with placebo (P < .0001). Antiplatelet therapy was particularly effective in preventing ischemic stroke, with a 25% reduction in the rate of nonfatal stroke, and with an overall absolute benefit in stroke prevention across all high-risk patient groups. This translated to 25 fewer nonfatal strokes per 1,000 patients treated with antiplatelet therapy.

Studies of aspirin have used different daily doses—the earliest studies used large doses of 1,000 to 1,500 mg.^6–10

Boysen et al¹¹ in 1988 found a trend toward benefit (not statistically significant) with doses ranging from 50 mg to 100 mg.

In 1991, three separate studies found that higher doses of aspirin were no more effective than lower doses.

The UK-TIA trial¹² compared aspirin 300 mg vs 1,200 mg and found a higher risk of gastrointestinal bleeding with the higher dose.

The SALT Collaborative Group¹³ found 75 mg to be effective.

The Dutch TIA trial¹⁶ compared 30 mg vs 283 mg; end point outcomes were similar but the rate of adverse events was higher with 283 mg.

ESPS-2 was able to show efficacy at a dose of only 50 mg.¹⁴

Taylor et al¹⁷ compared lower doses (81 or 325 mg) vs higher doses (650 or 1,300 mg) for patients undergoing carotid endarterectomy and found that the risk of adverse events was twice as high with the higher doses.

The ATT Collaboration¹⁵ found that efficacy was 40% lower with the highest dose of aspirin than with the lowest doses.

Algra and van Gijn¹⁸ performed a meta-analysis of all these studies and found no difference in risk reduction between low-dose and high-dose aspirin, with an overall relative risk reduction of 13% at any dose above 30 mg.

Campbell et al,¹⁹ in a 2007 review, found that doses greater than 300 mg conferred no benefit, and that rapid and maximum suppression of thromboxane A2 can be achieved by chewing or ingesting dissolved forms of aspirin 162 mg.

Conclusion. Aspirin doses higher than 81 mg (the US standard) confer no greater benefit and may even decrease the efficacy of aspirin. In an emergency, rapid suppression of thromboxane A2 can be achieved by chewing a minimum dose of 162 mg.

DIPYRIDAMOLE CAN BE ADDED TO ASPIRIN

In 1967, Weiss and Aledort⁵ found that aspirin’s antiplatelet effect could be blocked by adenosine diphosphate, which is released by activated platelet cells and is an essential part of thrombus formation. Adjacent platelets are then activated, leading to up-regulation of thromboxane A2 and glycoprotein IIb/IIIa receptors and resulting in a cascade of platelet activation and clot formation.²⁰ Dipyridamole inhibits aggregation of platelets by inhibiting their ability to take up adenosine diphosphate.

Studies of dipyridamole

AICLA.⁹ Bousser et al⁹ randomized patients who suffered one or more cerebral or retinal infarctions to receive placebo, aspirin 1 g, or aspirin 1 g plus dipyridamole 225 mg. Aspirin was significantly better than placebo in preventing a recurrence of stroke. The event rate with aspirin plus dipyridamole was similar to the rate with aspirin alone, although on 2-by-2 analysis, the difference between placebo and aspirin plus dipyridamole did not reach statistical significance. However, the rate of carotid-origin stroke was 17% with aspirin alone and 6% with aspirin plus dipyridamole, a statistically significant difference.

Thus, this study confirmed the benefit of aspirin in preventing ischemic events but did not fully support the addition of dipyridamole, except in preventing stroke of carotid origin. The study had a number of limitations: the sample size was small, TIA was not included as an end point, computed tomography was not required for entry, and many patients were lost to follow-up, decreasing the statistical power of the trial.

The ESPS study²¹ was also a randomized controlled trial of aspirin plus dipyridamole vs placebo. But unlike AICLA, ESPS included patients with TIA.

ESPS found a 38.1% relative risk reduction in stroke with aspirin plus dipyridamole compared with placebo, and a 30.6% reduction in death from all causes. Interestingly, patients who had a TIA as the qualifying event had a lower end-point incidence and larger end-point reduction than those who had a stroke as the qualifying event. However, ESPS did not resolve the question of whether adding dipyridamole to aspirin affords any benefit over aspirin alone.

ESPS-2¹⁴ hoped to answer this question. Patients were randomized to placebo, aspirin, dipyridamole, or aspirin plus dipyridamole. On 2 × 2 analysis, the dipyridamole group had a 16% lower rate of recurrent stroke than the placebo group, and patients on aspirin plus dipyridamole had a 37% lower rate. Aspirin plus dipyridamole yielded a 23.1% reduction compared with aspirin alone, and a 24.7% reduction compared with dipyridamole alone. Similar benefit was reported for the end point of TIA with combination therapy compared with either agent alone.

However, nearly 25% of patients had to withdraw because of side effects, particularly in the dipyridamole-alone and aspirin-dipyridamole groups, and, as mentioned above, verification of compliance in the aspirin group was an issue.^14,22 Nevertheless, ESPS-2 clearly showed that aspirin plus dipyridamole was better than either drug alone in preventing recurrent stroke. It also showed the effectiveness of dipyridamole, which AICLA and ESPS could not do, because it had a larger study population, used a lower dose of aspirin, and perhaps because it used an extended-release form of dipyridamole.²³

The ATT meta-analysis¹⁵ showed a clear benefit of antiplatelet therapy. However, much of this benefit was derived from aspirin therapy, with the addition of dipyridamole resulting in a nonsignificant 6% reduction of vascular events. Most of the patients on dipyridamole were from the ESPS-2 study. In effect, the ATT was a meta-analysis of aspirin, as aspirin studies dominated at that time.

A Cochrane review²⁴ publsihed in 2003 attempted to rectify this by analyzing randomized controlled trials of dipyridamole vs placebo.²⁴ Like the ATT meta-analysis, it did not bear out the benefits of dipyridamole: compared with placebo, there was no effect on the rate of vascular death, and only a minimal benefit in reduction of vascular events—and this latter point is only because of the inclusion of ESPS-2.

Directly comparing aspirin plus dipyridamole vs aspirin alone, the reviewers found no effect on the rate of vascular death, and with the exclusion of ESPS-2, no effect on vascular events.

The Cochrane review had the same limitation as the ATT meta-analysis, ie, dependence on a single trial (ESPS-2) to show benefit, and perhaps the fact that ESPS-2 was the only study that used an extended-release form of dipyridamole.

Leonardi-Bee et al²⁵ performed a meta-analysis that overcame the limitation of ESPS-2 being the only study at the time with positive findings: they used pooled individual patient data from randomized trials and analyzed them en masse. Patients on aspirin plus dipyridamole had a 39% lower risk than with placebo and a 22% lower risk than with aspirin alone. Unlike the ATT and the Cochrane review, excluding ESPS-2 did not alter the statistically significant lower stroke rate with aspirin plus dipyridamole compared with controls. This meta-analysis helped to confirm ESPS-2’s finding of the additive effect of aspirin plus dipyridamole compared with aspirin and placebo control.

ESPRIT.^26,27 The European/Australasian Stroke Prevention in Reversible Ischaemia Trial confirmed these findings. This randomized controlled trial compared aspirin plus dipyridamole against aspirin alone in patients with a TIA or minor ischemic stroke of arterial origin within the past 6 months. For the primary end point (death from all vascular causes, nonfatal stroke, nonfatal MI, nonfatal major bleeding complication), the hazard ratio was 0.80 favoring aspirin plus dipyridamole, with a number needed to treat of 104 over a mean of 3.5 years (absolute risk reduction of 1% per year). Importantly, twice as many patients taking aspirin plus dipyridamole discontinued the medication.

Caveats to interpreting this study are that it was not blinded, the aspirin doses varied (although the median aspirin dose—75 mg—was the same between the two groups), and not all patients received the extended-release form of dipyridamole.

ESPS-2, ESPRIT, and the meta-analysis by Leonardi-Bee et al showed that aspirin plus dipyridamole is more effective than placebo or aspirin alone in secondary prevention of vascular events, including stroke. Also, extended-release dipyridamole appears to be more effective.

Unfortunately, many patients stop taking dipyridamole because of side effects (primarily headache).

Based on the results of ESPRIT, the absolute benefit of dipyridamole used alone may be small.

CLOPIDOGREL: SIMILAR TO ASPIRIN IN EFFICACY?

Like dipyridamole, clopidogrel targets adenosine diphosphate to prevent clot formation, blocking its ability to bind to its receptor on platelets. It is a thienopyridine and, unlike its sister drug ticlopidine, does not seem to be associated with the potentially serious side effects of neutropenia. However, a few cases of thrombotic thrombocytopenic purpura have been reported.²⁸ The other drugs in this class have not been evaluated in clinical trials for secondary stroke prophylaxis.

Trials of clopidogrel

CAPRIE.²⁹ The Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events trial, in 1996, was one of the first to compare the clinical use of clopidogrel against aspirin. It was a randomized controlled noninferiority trial in patients over age 21 (inclusion criteria: ischemic stroke, MI, or peripheral arterial disease) randomized to aspirin 325 mg once daily or clopidogrel 75 mg once daily. Patients were followed for 1 to 3 years.

Patients on clopidogrel had a relative risk reduction of 8.7% in primary events (ischemic stroke, MI, or vascular death); patients on aspirin were at significantly higher risk of gastrointestinal hemorrhage. Patients with peripheral arterial disease as the qualifying event did particularly well on clopidogrel, with a significant relative risk reduction of 23.8%.

Limitations of the CAPRIE trial included its inability to measure the effect of treatment on individual outcomes, particularly stroke, and the fact that the relative risk reduction for patients with stroke as the qualifying event was not significant (P = .66). Another limitation was that it did not use TIA as an entry criterion or as part of the composite outcome. Also, the relative risk reduction had a wide confidence interval, and a large number of patients discontinued therapy for reasons other than the defined outcomes.

Nevertheless, the CAPRIE trial showed clopidogrel to be an effective antiplatelet prophylactic, particularly in patients with peripheral artery disease, but with no discernible difference from aspirin for those patients with MI or stroke as a qualifying event.

MATCH.³⁰ The Management of Atherothrombosis With Clopidogrel in High-risk Patients trial hoped to better assess clopidogrel’s efficacy, particularly in patients with ischemic cerebral events. Cardiac studies leading up to MATCH suggested that adding a thienopyridine to aspirin might offer additive benefit in reducing the rate of vascular outcomes.^15,31 MATCH randomized high-risk patients (inclusion criteria were ischemic stroke or TIA and a history of vascular disease) to clopidogrel or to aspirin plus clopidogrel.

There was a nonsignificant 6.4% relative risk reduction in the combined primary outcome of MI, ischemic stroke, vascular death, other vascular death, and re-hospitalization for acute ischemic events in the aspirin-plus-clopidogrel group compared with clopidogrel alone. However, this came at the cost of double the number of bleeding events in the combination group, mitigating most of the benefit of combination therapy.

An important caveat in interpreting the results of MATCH, as compared with the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, is that aspirin was being added to clopidogrel, not vice versa. CURE, which looked at the addition of clopidogrel to aspirin vs aspirin alone in cardiac patients, found a significant reduction of ischemic events taken as a group (relative risk 0.8), and a trend toward a lower rate of stroke (relative risk 0.86, but 95% confidence interval encompassing 1) for aspirin plus clopidogrel vs aspirin alone.³¹ However, patients in the CURE trial did not have high-risk vasculopathy per se but rather non-ST-elevation MI, perhaps skewing the benefit of combination therapy and lessening the risk of intracranial bleeding.

CHARISMA.³² The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, like the CURE trial, compared aspirin plus clopidogrel vs aspirin in patients with established cardiovascular, cerebrovascular, or peripheral arterial disease, or who were at high risk of events. As in the MATCH study, the findings for combination therapy were a nonsignificant relative risk of 0.93 for primary events (MI, stroke, or death from cardiovascular causes), and a significant reduction of secondary end points (primary end point event plus TIA or hospitalization for unstable angina) (relative risk 0.92, P = .04).

Importantly, combination therapy significantly increased the rate of bleeding events. In asymptomatic patients (those without documented vascular disease but with multiple atherothrombotic risk factors), there was actually harm with combined treatment. Conversely, for symptomatic patients (those with documented vascular disease), there was a negligible, but significant reduction in primary end points.

The result was that in patients with documented vascular disease, aspirin plus clopidogrel combination therapy provided little or no benefit over aspirin alone. For patients with elevated risk factors but no documented vascular burden, there may actually be harm from combination therapy.

PRoFESS.³³ Logically following is the question of whether aspirin plus dipyridamole offers any benefit over clopidogrel as a stroke prophylactic. The Prevention Regimen for Effectively Avoiding Second Strokes trial hoped to answer this by comparing clopidogrel against aspirin plus dipyridamole, both with and without telmisartan, in patients with recent stroke.

The rate of recurrent stroke was similar in the two groups, but there were 25 fewer ischemic strokes in patients on aspirin plus dipyridamole, offset by an increase in hemorrhagic strokes. Rates of secondary outcomes of stroke, death, or MI were nearly identical between the groups. Early discontinuation of treatment was significantly more frequent in those patients taking aspirin plus dipyridamole, meaning better compliance for those taking clopidogrel.

Initially, patients were to be randomized to either aspirin plus dipyridamole or aspirin plus clopidogrel. However, after MATCH³⁰ demonstrated a significantly higher bleeding risk with aspirin plus clopidogrel, patients were changed to clopidogrel alone. But despite this, the bleeding risk was still higher with aspirin plus dipyridamole.

During the trial, the entry criteria were expanded, allowing for the inclusion of younger patients and those with less recent strokes; but despite this change, the study remained underpowered to demonstrate its goal of noninferiority. Thus, it showed only a trend of noninferiority of clopidogrel vs aspirin plus dipyridamole.

What the clopidogrel trials tell us

Clopidogrel confers a benefit similar to that of aspirin (as shown in the CAPRIE study).²⁹ Although aspirin plus dipyridamole confers greater benefit than aspirin alone (as shown in the ESPS-2,¹⁴ Leonardi-Bee,²⁵ and ESPRIT²⁶ studies), aspirin plus dipyridamole is not superior to clopidogrel, and may even be inferior.³⁴

WARFARIN FOR ATRIAL FIBRILLATION ONLY

Warfarin acts by disrupting the coagulation cascade rather than acting at the site of platelet plug formation. In theory, warfarin should be as effective as the antiplatelet drugs in preventing clot formation, and so it was thought to possibly be effective in preventing stroke of arterial origin.

However, in at least three studies, warfarin increased the risk of death, MI, and hemorrhage, with perhaps a slight decrease in the risk of recurrent stroke in patients with suspected stroke or TIA.^35–37 This should be differentiated from stroke originating from cardiac dysrhythmias, for which warfarin has clearly been shown to be beneficial.²⁸

THREE GOOD MEDICAL OPTIONS FOR PREVENTING STROKE RECURRENCE

Antiplatelet therapy offers benefit in the primary and secondary prevention of stroke, with a 25% reduction in the rate of nonfatal stroke and a 17% reduction in the rate of death due to vascular causes.¹⁵

Aspirin is the best established, best tolerated, and least expensive of the three contemporary agents. Further, it is also the agent of choice for acute stroke care, to be given within 48 hours of a stroke to mitigate the risk of death and morbidity. The data for other agents in acute stroke management remain limited.³⁸

Aspirin plus dipyridamole

Aspirin plus dipyridamole is slightly more efficacious than aspirin alone, and it is an alternative when aspirin is ineffective and when the patient can afford the additional cost. Aspirin plus dipyridamole offers up to a 22% relative risk reduction (but a small reduction in absolute risk) of stroke compared with aspirin alone, as demonstrated by ESPS-2,¹⁴ Leonardi-Bee et al,²⁵ and ESPRIT.²⁶

When is clopidogrel appropriate?

Up to one-third of patients may not tolerate aspirin plus dipyridamole because of side effects. Clopidogrel is an option for these patients. The CAPRIE study²⁹ showed clopidogrel similar in efficacy to aspirin.

In contrast to aspirin plus dipyridamole, there is clearly no benefit to combining aspirin and clopidogrel for ischemic stroke prophylaxis. And data from PRoFESS³³ suggested the combination was qualitatively inferior to aspirin plus dipyridamole. However, the PRoFESS trial was underpowered to fully bear this out.

Therefore, current guidelines consider all three agents as appropriate for secondary prevention of stroke. One is not preferred over another, and the selection should be based on individual patient characteristics and affordability.²⁸

CAROTID SURGERY OR STENTING: BENEFITS AND LIMITATIONS

Atherosclerosis is the most common cause of stroke, and atherosclerosis of the common carotid bifurcation accounts for a small but significant percentage of all strokes.^39–41

The degree of carotid stenosis and whether it is producing symptoms influence how it should be managed. For patients with symptomatic carotid stenosis of more than 70%, multicenter randomized trials have shown that surgery (ie, carotid endarterectomy) added to medical therapy decreases the rate of recurrent stroke by up to 17% and the rate of combined stroke and death by 10% to 12% over a 2- to 3-year follow-up period (level of evidence A).^42–44 No study has proven the efficacy of surgery in patients with symptomatic stenosis of less than 50%.^43,44

Similarly, in asymptomatic carotid disease, preventive surgery is a beneficial adjunct to medical therapy in certain patients. An approximate 6% reduction in the rate of stroke or death over 5 years has been shown in patients with moderate stenosis (> 60%), with men younger than age 75 and with greater than 70% stenosis deriving the most benefit.^45–47

However, these robust, positive results with surgical intervention should not overshadow the importance of intensive and guided medical therapy, which has been shown to mitigate the risk of stroke.^48,49

Is stenting as good as surgery? In the multicenter randomized Carotid Revascularization Endarterectomy vs Stenting Trial (CREST), stenting resulted in similar rates of stroke and MI in patients with symptomatic and asymptomatic disease.⁵⁰ However, stenting carried a greater risk of perioperative stroke, and endarterectomy carried a greater risk of MI. Those under age 70 benefited more from stenting, and those over age 70 benefited more from endarterectomy.

But another fact to keep in mind is that the relationship between carotid narrowing and an ipsilateral stroke is not necessarily direct. Two follow-up studies in patients from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) found that up to 45% of strokes that occurred after intervention in the distribution of the asymptomatic stenosed carotid artery were unrelated to the stenosis.^51,52 Moreover, up to 20% of subsequent strokes in the distribution of the symptomatic artery were not of large-artery origin, increasing up to 35% for those with stenosis of less than 70%.⁵¹ Clearly, thorough screening of those with presumed symptomatic stenosis is needed to eliminate other possible causes.

After a stroke, an important goal is to prevent another one.^1,2 And for patients who have had an ischemic stroke or transient ischemic attack (TIA) due to atherosclerosis, an important part of secondary preventive therapy is a drug that inhibits platelets—ie, aspirin, extended-release dipyridamole, or clopidogrel. This has taken years to establish.

In the following pages, we discuss the antiplatelet agents that have been shown to be beneficial after stroke of atherosclerotic origin, and we briefly review the indications for surgery and stenting for the subset of patients whose strokes are caused by symptomatic carotid disease.

(Although managing modifiable risk factors such as smoking, hypertension, diabetes, and dyslipidemia is also important, we will not cover this topic here, nor will we talk about hemorrhagic stroke or stroke due to atrial fibrillation. Also not discussed here is cilostazol, which, although shown to be effective in preventing recurrent stroke when compared with placebo and aspirin,^3,4 has not been approved for this use by the US Food and Drug Administration, as of this writing.)

HOW WE REVIEWED THE LITERATURE

We searched PubMed using the terms aspirin, acetylsalicylic acid, clopidogrel, and/or dipyridamole, in combination with stroke, cerebral ische(ae)mia, transient ische(ae)mic attacks, or retinal artery occlusion. We reviewed only clinical trials or meta-analyses of these drugs for either primary or secondary prevention of cerebrovascular disease.

As our aim was to review the topic and not to perform a meta-analysis, no cutoffs were used to exclude trials. The references in the selected papers were also reviewed to expand the articles. Finally, the references in the current American Heart Association and American Stroke Association secondary stroke prevention guideline were also reviewed.

For a summary of the trials included in our review, see the Data Supplement as an appendix to the online version of this article.

ASPIRIN: THE GOLD STANDARD

Prescribed by Hippocrates in the form of willow bark extract, aspirin has long been known for its antipyretic and anti-inflammatory properties. Its antiplatelet and antithrombotic properties, first described in 1967 by Weiss and Aledort,⁵ are mediated by irreversible inhibition of cyclooxygenase, leading to decreased thromboxane A2, a platelet-aggregation activator.

Fields et al,^6,7 in 1977 and 1978, reported that in a controlled trial in patients with TIA or monocular blindness, fewer subsequent TIAs occurred in patients who received aspirin, although the difference was not statistically significant, with lower rates of events only in nonsurgical patients. Over the next 20 years, the results remained mixed.

The Danish Cooperative study⁸ (1983) found no significant difference in the rate of recurrent stroke with aspirin vs placebo.

AICLA.⁹ The Accidents Ischémiques Cérébraux Liés à l’Athérosclérose study of 1983 did find a difference. However, both the Danish Cooperative study and the AICLA were limited by lacking standardized computed tomographic imaging to rule out hemorrhagic stroke and by being relatively small.

The Swedish Cooperative Study¹⁰ (1987) found no statistical difference between high-dose aspirin and placebo in preventing recurrent vascular events (stroke, TIA, or myocardial infarction [MI]) 1 to 3 weeks after a stroke. However, it had several limitations: the aspirin group contained more patients with ischemic heart disease (who are more likely to die of cardiac causes), there were significantly more men in the aspirin group, and nearly one-fourth of the deaths were a result of the initial stroke, potentially masking the effect of aspirin in secondary prevention.

Later studies began to show a consistently favorable effect of aspirin.

Boysen et al¹¹ in 1988 reported a nonsignificant trend toward fewer adverse events with aspirin.

UK-TIA.¹² The United Kingdom Transient Ischaemic Attack trial in 1991 found a similar trend.

SALT.¹³ The Swedish Aspirin Low-dose Trial, also in 1991, showed a significant 18% lower rate of stroke or death in patients with recent TIA, minor stroke, or retinal occlusion treated with low-dose aspirin. The inclusion of patients with TIA helped broaden the population that might benefit. However, the study may have favored the aspirin group by having a run-in period in which patients were nonrandomly treated either with aspirin or with anticoagulation at the discretion of the patient’s physician and, if they suffered “several” TIAs, a stroke, retinal artery occlusion, or MI, were removed from the study.

ESPS-2.¹⁴ The second European Stroke Prevention Study in 1996 added to the evidence that aspirin prevents recurrent stroke. Patients with a history of TIA or stroke were randomized in double-blind fashion to four treatment groups: placebo, low-dose aspirin, dipyridamole, or aspirin plus dipyridamole. At 2 years, strokes had occurred in 18% fewer patients in the aspirin group than in the placebo group, and TIAs had occurred in 21.9% fewer. However, aspirin was associated with an absolute 0.5% increase in severe and fatal bleeding. The power of the study was limited because patients from one center were excluded because of “serious inconsistencies in patient case record forms and compliance assay determinations.” ¹⁴

Comment. The mixed results with aspirin in studies predating ESPS-2 were partly because the study populations were too small to show benefit.

ATT.¹⁵ The Antithrombotic Trialists’ Collaboration performed a meta-analysis that conclusively confirmed the benefit of aspirin after stroke or TIA. The investigators analyzed individual patient data pooled from randomized controlled trials published before 1997 that compared antiplatelet regimens (mostly aspirin) against placebo and against each other. The rates of vascular events were 10.7% with treatment vs 13.2% with placebo (P < .0001). Antiplatelet therapy was particularly effective in preventing ischemic stroke, with a 25% reduction in the rate of nonfatal stroke, and with an overall absolute benefit in stroke prevention across all high-risk patient groups. This translated to 25 fewer nonfatal strokes per 1,000 patients treated with antiplatelet therapy.

Studies of aspirin have used different daily doses—the earliest studies used large doses of 1,000 to 1,500 mg.^6–10

Boysen et al¹¹ in 1988 found a trend toward benefit (not statistically significant) with doses ranging from 50 mg to 100 mg.

In 1991, three separate studies found that higher doses of aspirin were no more effective than lower doses.

The UK-TIA trial¹² compared aspirin 300 mg vs 1,200 mg and found a higher risk of gastrointestinal bleeding with the higher dose.

The SALT Collaborative Group¹³ found 75 mg to be effective.

The Dutch TIA trial¹⁶ compared 30 mg vs 283 mg; end point outcomes were similar but the rate of adverse events was higher with 283 mg.

ESPS-2 was able to show efficacy at a dose of only 50 mg.¹⁴

Taylor et al¹⁷ compared lower doses (81 or 325 mg) vs higher doses (650 or 1,300 mg) for patients undergoing carotid endarterectomy and found that the risk of adverse events was twice as high with the higher doses.

The ATT Collaboration¹⁵ found that efficacy was 40% lower with the highest dose of aspirin than with the lowest doses.

Algra and van Gijn¹⁸ performed a meta-analysis of all these studies and found no difference in risk reduction between low-dose and high-dose aspirin, with an overall relative risk reduction of 13% at any dose above 30 mg.

Campbell et al,¹⁹ in a 2007 review, found that doses greater than 300 mg conferred no benefit, and that rapid and maximum suppression of thromboxane A2 can be achieved by chewing or ingesting dissolved forms of aspirin 162 mg.

Conclusion. Aspirin doses higher than 81 mg (the US standard) confer no greater benefit and may even decrease the efficacy of aspirin. In an emergency, rapid suppression of thromboxane A2 can be achieved by chewing a minimum dose of 162 mg.

DIPYRIDAMOLE CAN BE ADDED TO ASPIRIN

In 1967, Weiss and Aledort⁵ found that aspirin’s antiplatelet effect could be blocked by adenosine diphosphate, which is released by activated platelet cells and is an essential part of thrombus formation. Adjacent platelets are then activated, leading to up-regulation of thromboxane A2 and glycoprotein IIb/IIIa receptors and resulting in a cascade of platelet activation and clot formation.²⁰ Dipyridamole inhibits aggregation of platelets by inhibiting their ability to take up adenosine diphosphate.

Studies of dipyridamole

AICLA.⁹ Bousser et al⁹ randomized patients who suffered one or more cerebral or retinal infarctions to receive placebo, aspirin 1 g, or aspirin 1 g plus dipyridamole 225 mg. Aspirin was significantly better than placebo in preventing a recurrence of stroke. The event rate with aspirin plus dipyridamole was similar to the rate with aspirin alone, although on 2-by-2 analysis, the difference between placebo and aspirin plus dipyridamole did not reach statistical significance. However, the rate of carotid-origin stroke was 17% with aspirin alone and 6% with aspirin plus dipyridamole, a statistically significant difference.

Thus, this study confirmed the benefit of aspirin in preventing ischemic events but did not fully support the addition of dipyridamole, except in preventing stroke of carotid origin. The study had a number of limitations: the sample size was small, TIA was not included as an end point, computed tomography was not required for entry, and many patients were lost to follow-up, decreasing the statistical power of the trial.

The ESPS study²¹ was also a randomized controlled trial of aspirin plus dipyridamole vs placebo. But unlike AICLA, ESPS included patients with TIA.

ESPS found a 38.1% relative risk reduction in stroke with aspirin plus dipyridamole compared with placebo, and a 30.6% reduction in death from all causes. Interestingly, patients who had a TIA as the qualifying event had a lower end-point incidence and larger end-point reduction than those who had a stroke as the qualifying event. However, ESPS did not resolve the question of whether adding dipyridamole to aspirin affords any benefit over aspirin alone.

ESPS-2¹⁴ hoped to answer this question. Patients were randomized to placebo, aspirin, dipyridamole, or aspirin plus dipyridamole. On 2 × 2 analysis, the dipyridamole group had a 16% lower rate of recurrent stroke than the placebo group, and patients on aspirin plus dipyridamole had a 37% lower rate. Aspirin plus dipyridamole yielded a 23.1% reduction compared with aspirin alone, and a 24.7% reduction compared with dipyridamole alone. Similar benefit was reported for the end point of TIA with combination therapy compared with either agent alone.

However, nearly 25% of patients had to withdraw because of side effects, particularly in the dipyridamole-alone and aspirin-dipyridamole groups, and, as mentioned above, verification of compliance in the aspirin group was an issue.^14,22 Nevertheless, ESPS-2 clearly showed that aspirin plus dipyridamole was better than either drug alone in preventing recurrent stroke. It also showed the effectiveness of dipyridamole, which AICLA and ESPS could not do, because it had a larger study population, used a lower dose of aspirin, and perhaps because it used an extended-release form of dipyridamole.²³

The ATT meta-analysis¹⁵ showed a clear benefit of antiplatelet therapy. However, much of this benefit was derived from aspirin therapy, with the addition of dipyridamole resulting in a nonsignificant 6% reduction of vascular events. Most of the patients on dipyridamole were from the ESPS-2 study. In effect, the ATT was a meta-analysis of aspirin, as aspirin studies dominated at that time.

A Cochrane review²⁴ publsihed in 2003 attempted to rectify this by analyzing randomized controlled trials of dipyridamole vs placebo.²⁴ Like the ATT meta-analysis, it did not bear out the benefits of dipyridamole: compared with placebo, there was no effect on the rate of vascular death, and only a minimal benefit in reduction of vascular events—and this latter point is only because of the inclusion of ESPS-2.

Directly comparing aspirin plus dipyridamole vs aspirin alone, the reviewers found no effect on the rate of vascular death, and with the exclusion of ESPS-2, no effect on vascular events.

The Cochrane review had the same limitation as the ATT meta-analysis, ie, dependence on a single trial (ESPS-2) to show benefit, and perhaps the fact that ESPS-2 was the only study that used an extended-release form of dipyridamole.

Leonardi-Bee et al²⁵ performed a meta-analysis that overcame the limitation of ESPS-2 being the only study at the time with positive findings: they used pooled individual patient data from randomized trials and analyzed them en masse. Patients on aspirin plus dipyridamole had a 39% lower risk than with placebo and a 22% lower risk than with aspirin alone. Unlike the ATT and the Cochrane review, excluding ESPS-2 did not alter the statistically significant lower stroke rate with aspirin plus dipyridamole compared with controls. This meta-analysis helped to confirm ESPS-2’s finding of the additive effect of aspirin plus dipyridamole compared with aspirin and placebo control.

ESPRIT.^26,27 The European/Australasian Stroke Prevention in Reversible Ischaemia Trial confirmed these findings. This randomized controlled trial compared aspirin plus dipyridamole against aspirin alone in patients with a TIA or minor ischemic stroke of arterial origin within the past 6 months. For the primary end point (death from all vascular causes, nonfatal stroke, nonfatal MI, nonfatal major bleeding complication), the hazard ratio was 0.80 favoring aspirin plus dipyridamole, with a number needed to treat of 104 over a mean of 3.5 years (absolute risk reduction of 1% per year). Importantly, twice as many patients taking aspirin plus dipyridamole discontinued the medication.

Caveats to interpreting this study are that it was not blinded, the aspirin doses varied (although the median aspirin dose—75 mg—was the same between the two groups), and not all patients received the extended-release form of dipyridamole.

ESPS-2, ESPRIT, and the meta-analysis by Leonardi-Bee et al showed that aspirin plus dipyridamole is more effective than placebo or aspirin alone in secondary prevention of vascular events, including stroke. Also, extended-release dipyridamole appears to be more effective.

Unfortunately, many patients stop taking dipyridamole because of side effects (primarily headache).

Based on the results of ESPRIT, the absolute benefit of dipyridamole used alone may be small.

CLOPIDOGREL: SIMILAR TO ASPIRIN IN EFFICACY?

Like dipyridamole, clopidogrel targets adenosine diphosphate to prevent clot formation, blocking its ability to bind to its receptor on platelets. It is a thienopyridine and, unlike its sister drug ticlopidine, does not seem to be associated with the potentially serious side effects of neutropenia. However, a few cases of thrombotic thrombocytopenic purpura have been reported.²⁸ The other drugs in this class have not been evaluated in clinical trials for secondary stroke prophylaxis.

Trials of clopidogrel

CAPRIE.²⁹ The Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events trial, in 1996, was one of the first to compare the clinical use of clopidogrel against aspirin. It was a randomized controlled noninferiority trial in patients over age 21 (inclusion criteria: ischemic stroke, MI, or peripheral arterial disease) randomized to aspirin 325 mg once daily or clopidogrel 75 mg once daily. Patients were followed for 1 to 3 years.

Patients on clopidogrel had a relative risk reduction of 8.7% in primary events (ischemic stroke, MI, or vascular death); patients on aspirin were at significantly higher risk of gastrointestinal hemorrhage. Patients with peripheral arterial disease as the qualifying event did particularly well on clopidogrel, with a significant relative risk reduction of 23.8%.

Limitations of the CAPRIE trial included its inability to measure the effect of treatment on individual outcomes, particularly stroke, and the fact that the relative risk reduction for patients with stroke as the qualifying event was not significant (P = .66). Another limitation was that it did not use TIA as an entry criterion or as part of the composite outcome. Also, the relative risk reduction had a wide confidence interval, and a large number of patients discontinued therapy for reasons other than the defined outcomes.

Nevertheless, the CAPRIE trial showed clopidogrel to be an effective antiplatelet prophylactic, particularly in patients with peripheral artery disease, but with no discernible difference from aspirin for those patients with MI or stroke as a qualifying event.

MATCH.³⁰ The Management of Atherothrombosis With Clopidogrel in High-risk Patients trial hoped to better assess clopidogrel’s efficacy, particularly in patients with ischemic cerebral events. Cardiac studies leading up to MATCH suggested that adding a thienopyridine to aspirin might offer additive benefit in reducing the rate of vascular outcomes.^15,31 MATCH randomized high-risk patients (inclusion criteria were ischemic stroke or TIA and a history of vascular disease) to clopidogrel or to aspirin plus clopidogrel.

There was a nonsignificant 6.4% relative risk reduction in the combined primary outcome of MI, ischemic stroke, vascular death, other vascular death, and re-hospitalization for acute ischemic events in the aspirin-plus-clopidogrel group compared with clopidogrel alone. However, this came at the cost of double the number of bleeding events in the combination group, mitigating most of the benefit of combination therapy.

An important caveat in interpreting the results of MATCH, as compared with the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, is that aspirin was being added to clopidogrel, not vice versa. CURE, which looked at the addition of clopidogrel to aspirin vs aspirin alone in cardiac patients, found a significant reduction of ischemic events taken as a group (relative risk 0.8), and a trend toward a lower rate of stroke (relative risk 0.86, but 95% confidence interval encompassing 1) for aspirin plus clopidogrel vs aspirin alone.³¹ However, patients in the CURE trial did not have high-risk vasculopathy per se but rather non-ST-elevation MI, perhaps skewing the benefit of combination therapy and lessening the risk of intracranial bleeding.

CHARISMA.³² The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, like the CURE trial, compared aspirin plus clopidogrel vs aspirin in patients with established cardiovascular, cerebrovascular, or peripheral arterial disease, or who were at high risk of events. As in the MATCH study, the findings for combination therapy were a nonsignificant relative risk of 0.93 for primary events (MI, stroke, or death from cardiovascular causes), and a significant reduction of secondary end points (primary end point event plus TIA or hospitalization for unstable angina) (relative risk 0.92, P = .04).

Importantly, combination therapy significantly increased the rate of bleeding events. In asymptomatic patients (those without documented vascular disease but with multiple atherothrombotic risk factors), there was actually harm with combined treatment. Conversely, for symptomatic patients (those with documented vascular disease), there was a negligible, but significant reduction in primary end points.

The result was that in patients with documented vascular disease, aspirin plus clopidogrel combination therapy provided little or no benefit over aspirin alone. For patients with elevated risk factors but no documented vascular burden, there may actually be harm from combination therapy.

PRoFESS.³³ Logically following is the question of whether aspirin plus dipyridamole offers any benefit over clopidogrel as a stroke prophylactic. The Prevention Regimen for Effectively Avoiding Second Strokes trial hoped to answer this by comparing clopidogrel against aspirin plus dipyridamole, both with and without telmisartan, in patients with recent stroke.

The rate of recurrent stroke was similar in the two groups, but there were 25 fewer ischemic strokes in patients on aspirin plus dipyridamole, offset by an increase in hemorrhagic strokes. Rates of secondary outcomes of stroke, death, or MI were nearly identical between the groups. Early discontinuation of treatment was significantly more frequent in those patients taking aspirin plus dipyridamole, meaning better compliance for those taking clopidogrel.

Initially, patients were to be randomized to either aspirin plus dipyridamole or aspirin plus clopidogrel. However, after MATCH³⁰ demonstrated a significantly higher bleeding risk with aspirin plus clopidogrel, patients were changed to clopidogrel alone. But despite this, the bleeding risk was still higher with aspirin plus dipyridamole.

During the trial, the entry criteria were expanded, allowing for the inclusion of younger patients and those with less recent strokes; but despite this change, the study remained underpowered to demonstrate its goal of noninferiority. Thus, it showed only a trend of noninferiority of clopidogrel vs aspirin plus dipyridamole.

What the clopidogrel trials tell us

Clopidogrel confers a benefit similar to that of aspirin (as shown in the CAPRIE study).²⁹ Although aspirin plus dipyridamole confers greater benefit than aspirin alone (as shown in the ESPS-2,¹⁴ Leonardi-Bee,²⁵ and ESPRIT²⁶ studies), aspirin plus dipyridamole is not superior to clopidogrel, and may even be inferior.³⁴

WARFARIN FOR ATRIAL FIBRILLATION ONLY

Warfarin acts by disrupting the coagulation cascade rather than acting at the site of platelet plug formation. In theory, warfarin should be as effective as the antiplatelet drugs in preventing clot formation, and so it was thought to possibly be effective in preventing stroke of arterial origin.

However, in at least three studies, warfarin increased the risk of death, MI, and hemorrhage, with perhaps a slight decrease in the risk of recurrent stroke in patients with suspected stroke or TIA.^35–37 This should be differentiated from stroke originating from cardiac dysrhythmias, for which warfarin has clearly been shown to be beneficial.²⁸

THREE GOOD MEDICAL OPTIONS FOR PREVENTING STROKE RECURRENCE

Antiplatelet therapy offers benefit in the primary and secondary prevention of stroke, with a 25% reduction in the rate of nonfatal stroke and a 17% reduction in the rate of death due to vascular causes.¹⁵

Aspirin is the best established, best tolerated, and least expensive of the three contemporary agents. Further, it is also the agent of choice for acute stroke care, to be given within 48 hours of a stroke to mitigate the risk of death and morbidity. The data for other agents in acute stroke management remain limited.³⁸

Aspirin plus dipyridamole

Aspirin plus dipyridamole is slightly more efficacious than aspirin alone, and it is an alternative when aspirin is ineffective and when the patient can afford the additional cost. Aspirin plus dipyridamole offers up to a 22% relative risk reduction (but a small reduction in absolute risk) of stroke compared with aspirin alone, as demonstrated by ESPS-2,¹⁴ Leonardi-Bee et al,²⁵ and ESPRIT.²⁶

When is clopidogrel appropriate?

Up to one-third of patients may not tolerate aspirin plus dipyridamole because of side effects. Clopidogrel is an option for these patients. The CAPRIE study²⁹ showed clopidogrel similar in efficacy to aspirin.

In contrast to aspirin plus dipyridamole, there is clearly no benefit to combining aspirin and clopidogrel for ischemic stroke prophylaxis. And data from PRoFESS³³ suggested the combination was qualitatively inferior to aspirin plus dipyridamole. However, the PRoFESS trial was underpowered to fully bear this out.

Therefore, current guidelines consider all three agents as appropriate for secondary prevention of stroke. One is not preferred over another, and the selection should be based on individual patient characteristics and affordability.²⁸

CAROTID SURGERY OR STENTING: BENEFITS AND LIMITATIONS

Atherosclerosis is the most common cause of stroke, and atherosclerosis of the common carotid bifurcation accounts for a small but significant percentage of all strokes.^39–41

The degree of carotid stenosis and whether it is producing symptoms influence how it should be managed. For patients with symptomatic carotid stenosis of more than 70%, multicenter randomized trials have shown that surgery (ie, carotid endarterectomy) added to medical therapy decreases the rate of recurrent stroke by up to 17% and the rate of combined stroke and death by 10% to 12% over a 2- to 3-year follow-up period (level of evidence A).^42–44 No study has proven the efficacy of surgery in patients with symptomatic stenosis of less than 50%.^43,44

Similarly, in asymptomatic carotid disease, preventive surgery is a beneficial adjunct to medical therapy in certain patients. An approximate 6% reduction in the rate of stroke or death over 5 years has been shown in patients with moderate stenosis (> 60%), with men younger than age 75 and with greater than 70% stenosis deriving the most benefit.^45–47

However, these robust, positive results with surgical intervention should not overshadow the importance of intensive and guided medical therapy, which has been shown to mitigate the risk of stroke.^48,49

Is stenting as good as surgery? In the multicenter randomized Carotid Revascularization Endarterectomy vs Stenting Trial (CREST), stenting resulted in similar rates of stroke and MI in patients with symptomatic and asymptomatic disease.⁵⁰ However, stenting carried a greater risk of perioperative stroke, and endarterectomy carried a greater risk of MI. Those under age 70 benefited more from stenting, and those over age 70 benefited more from endarterectomy.

But another fact to keep in mind is that the relationship between carotid narrowing and an ipsilateral stroke is not necessarily direct. Two follow-up studies in patients from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) found that up to 45% of strokes that occurred after intervention in the distribution of the asymptomatic stenosed carotid artery were unrelated to the stenosis.^51,52 Moreover, up to 20% of subsequent strokes in the distribution of the symptomatic artery were not of large-artery origin, increasing up to 35% for those with stenosis of less than 70%.⁵¹ Clearly, thorough screening of those with presumed symptomatic stenosis is needed to eliminate other possible causes.