Arun Kumar, MD

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

Study Overview

Objective: To assess whether ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing elective percutaneous coronary intervention (PCI).

Design: Multicenter, open-label, and prospective randomized control trial. Setting and participants: A total of 1910 patients with indication for PCI and at least 1 high risk characteristic were randomized to either ticagrelor or clopidogrel.

Main outcome measures: The primary outcome was the composite of PCI-related type 4a or 4b myocardial infarction or major myocardial injury. The primary safety outcome was major bleeding, evaluated within 48 hours of PCI.

Main results: At 48 hours, the primary outcome was observed in 334 of 941 patients (35%) in the ticagrelor group and 341 of 942 patients (36%) in the clopidogrel group (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.80-1.17; P = .75). The primary safety outcome did not differ between groups. Minor bleeding events at 30 days were more frequently observed with ticagrelor (11%) than clopidogrel (8%) (1.54; 95% CI 1.12-2.11; P = .007).

Conclusion: Among patients undergoing elective PCI, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis. Ticagrelor did not cause increase in major bleeding compared to clopidogrel but did increase the rate of minor bleeding at 30 days.

Commentary

Standard treatment after PCI includes dual antiplatelet therapy combining adenosine diphosphate (ADP) receptor antagonist and aspirin. The newer generation thienopyridine prasugrel and the reversible direct acting oral antagonist of the ADP receptor ticagrelor, provides consistent and greater antiplatelet effect compared to clopidogrel, and are superior in reducing ischemic events when compared to clopidogrel in patients presenting with acute coronary syndrome (ACS).^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel in patients presenting with ACS.^3,4 However, whether these findings of improved outcomes with newer agents compared to clopidogrel extends to patients with stable ischemic heart disease presenting for elective PCI is unknown.

In this context, Silvain et al investigated this clinical question and compared ticagrelor and clopidogrel by performing a well-designed multicenter randomized control trial in patients presenting with elective PCI. At 48 hours and at 30 days the composite of PCI-related type 4 myocardial infarction or major myocardial injury defined by the third universal definition⁵ was similar between the ticagrelor and clopidogrel groups. Although the incidence of major bleeding was not significantly different between the 2 groups, minor bleeding at 30 days was higher in the ticagrelor group (11%) than clopidogrel (8%) (1.54; 95% CI, 1.12-2.11, P = .007).

The strengths of this current study include the randomized design and the large number of patients enrolled with adequate power to evaluate for superiority of ticagrelor compared to clopidogrel. This was a multicenter trial in Europe with 49 participating centers from France and Czech, and the interventional technique used by the operators reflects contemporary technique with 95% use of radial or ulnar access.

There are a few important points to consider in this study. First, the primary outcome was biomarker assessed myocardial necrosis and myocardial injury, and the study was not powered to assess the hard outcomes such as death and myocardial infarction. Although there have been previous reports describing the relationship between the postprocedural myocardial necrosis with worse outcomes, the definition of myocardial necrosis post-PCI and its relationship with hard outcomes remains controversial. Second, half of the patients enrolled were on chronic clopidogrel therapy which suggests that patients with inadequate platelet inhibition with clopidogrel may be under-represented in this cohort. Third, this was an open-label study and the knowledge of agent used could have affected the study results. Finally, whether the population included represents a true high-risk population is questionable. Some of the prespecified high-risk features necessary to enter the study was relatively light, such as presence of diabetes mellitus or body mass index > 30 kg/m² compared to other criteria such as bifurcation stenting or left main stenting.

Currently, when treating patients with stable ischemic heart disease with higher risk anatomy, some operators may use ticagrelor over clopidogrel by extrapolating the study results from the ACS population. However, the results from the current study do not support the uniform use of ticagrelor in stable patients and suggests that the use of clopidogrel continues to be the standard of care. This is especially relevant considering the cost difference for the 2 agents studied. Whether there is a subgroup that benefits from ticagrelor use, such as patients with unprotected left main stenting or bifurcation stenting with 2 stent strategies, requires further investigation.

Applications for Clinical Practice

In patients presenting with stable ischemic heart disease undergoing elective PCI, ticagrelor did not lower composite of periprocedural myocardial infarction and myocardial injury at 48 hours. Clopidogrel continues to be a first line treatment after elective PCI.

Study Overview

Objective. To assess the relative merits of ticagrelor compared to prasugrel in patients with acute coronary syndromes who will undergo invasive evaluation.

Design. Multicenter, open-label, prospective randomized controlled trial.

Setting and participants. A total of 4018 patients who presented with ACS with or without ST-segment elevation.

Intervention. Patients were randomly assigned to receive either ticagrelor or prasugrel.

Main outcome measures. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. The secondary end point was bleeding.

Main results. At 1 year, a primary end point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.09-1.70; P = 0.006). In the comparison between ticagrelor and prasugrel, the individual components of the primary end point were as follows: death, 4.5% versus 3.7%; myocardial infarction, 4.8% versus 3.0%; and stroke, 1.1% versus 1.0%, respectively. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% in patients assigned to prasugrel. Major bleeding was observed in 5.4% of the patients in the ticagrelor group and 4.8% in the prasugrel group (HR, 1.12; 95% CI, 0.83-1.51, P = 0.46).

Conclusion. In patients who presented with ACS with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel as compared to those who received ticagrelor, and incidence of major bleeding was not significantly different.

Dual antiplatelet therapy combining an adenosine disphosphate (ADP) receptor antagonist and aspirin is standard treatment for patients presenting with ACS. The limitation of clopidogrel has been its modest antiplatelet effect, with substantial interpatient variability. The newer generation thienopyridine prasugrel and the reversible direct-acting oral antagonist of the ADP receptor ticagrelor provide consistent and greater antiplatelet effect compared to clopidogrel. It has been previously reported that these agents are superior in reducing ischemic events when compared to clopidogrel.^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel.^3,4 However, there has been no large randomized controlled study comparing the effect of ticagrelor and prasugrel. In this context, Shupke et al investigated this clinical question by performing a well-designed multicenter randomized controlled trial in patients presenting with ACS. At 12-month follow-up, the composite of death, myocardial infarction, and stroke occurred more frequently in the ticagrelor group compared to the prasugrel group (9.3% versus 6.9%; HR, 1.36; 95% CI, 1.09-1.70; P < 0.01). The incidence of major bleeding was not significantly different between the 2 groups (5.4% versus 4.8%; P = 0.46).

The strengths of this current study include the randomized design and the large number of patients enrolled, with adequate power to evaluate for superiority. This was a multicenter trial in Europe with 23 participating centers (21 from Germany). Furthermore, the interventional technique used by the operators reflects more contemporary technique compared to the previous studies comparing each agent to clopidogrel,^1,2 with more frequent use of radial access (37%) and drug-eluting stents (90%) and reduced use of GPIIb/IIIa inhibitors (12%).

There are a few important points to consider due to the differences between the 2 agents compared in this study. First, the loading dose of ticagrelor and prasugrel was administered differently in patients presenting with ACS without ST elevation. Ticagrelor was administered as soon as possible prior to the coronary angiogram, but prasugrel was administered after the coronary anatomy was defined prior to the intervention, which is how this agent is administered in current clinical practice. Therefore, this trial was an open-label study that compared not only different medications, but different administration strategies. Second, ticagrelor and prasugrel have different side-effect profiles. The side effects unique to ticagrelor are dyspnea and bradycardia. On the other hand, a contraindication unique to prasugrel is patients with a history of transient ischemic attack or stroke due to increased risk of thrombotic and hemorrhagic stroke.¹ In addition, prasugrel has increased bleeding risk in patients older than 75 years of age and those with low body weight (< 60 kg). In this study, the overall medication discontinuation rate was higher in the ticagrelor group specifically due to dyspnea, and the reduced dose of 5 mg of prasugrel was used in patients older than 75 years or with low body weight.

Since the timing of administration of ticagrelor (preloading prior to coronary angiography is recommended) is similar to that of clopidogrel, and given the theoretical benefit of reversible inhibition of the ADP receptor, ticagrelor has been used more commonly in clinical practice than prasugrel, and it has been implemented in the ACS protocol in many hospitals. In light of the results from this first head-to-head comparison utilizing more contemporary interventional techniques, these protocols may need to be adjusted in favor of prasugrel for patients presenting with ACS. However, given the difference in timing of administration and the difference in side-effect profile, operators must also tailor these agents depending on the patient profile.

Applications for Clinical Practice

In patients presenting with ACS, prasugrel was superior to ticagrelor, with a lower composite of death, myocardial infarction, and stroke at 12 months. Prasugrel should be considered as a first-line treatment for ACS.

– Taishi Hirai, MD, and Arun Kumar, MD, University of Missouri, Columbia, MO

Study Overview

Objective. To assess the relative merits of ticagrelor compared to prasugrel in patients with acute coronary syndromes who will undergo invasive evaluation.

Design. Multicenter, open-label, prospective randomized controlled trial.

Setting and participants. A total of 4018 patients who presented with ACS with or without ST-segment elevation.

Intervention. Patients were randomly assigned to receive either ticagrelor or prasugrel.

Main outcome measures. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. The secondary end point was bleeding.

Main results. At 1 year, a primary end point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.09-1.70; P = 0.006). In the comparison between ticagrelor and prasugrel, the individual components of the primary end point were as follows: death, 4.5% versus 3.7%; myocardial infarction, 4.8% versus 3.0%; and stroke, 1.1% versus 1.0%, respectively. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% in patients assigned to prasugrel. Major bleeding was observed in 5.4% of the patients in the ticagrelor group and 4.8% in the prasugrel group (HR, 1.12; 95% CI, 0.83-1.51, P = 0.46).

Conclusion. In patients who presented with ACS with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel as compared to those who received ticagrelor, and incidence of major bleeding was not significantly different.

Dual antiplatelet therapy combining an adenosine disphosphate (ADP) receptor antagonist and aspirin is standard treatment for patients presenting with ACS. The limitation of clopidogrel has been its modest antiplatelet effect, with substantial interpatient variability. The newer generation thienopyridine prasugrel and the reversible direct-acting oral antagonist of the ADP receptor ticagrelor provide consistent and greater antiplatelet effect compared to clopidogrel. It has been previously reported that these agents are superior in reducing ischemic events when compared to clopidogrel.^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel.^3,4 However, there has been no large randomized controlled study comparing the effect of ticagrelor and prasugrel. In this context, Shupke et al investigated this clinical question by performing a well-designed multicenter randomized controlled trial in patients presenting with ACS. At 12-month follow-up, the composite of death, myocardial infarction, and stroke occurred more frequently in the ticagrelor group compared to the prasugrel group (9.3% versus 6.9%; HR, 1.36; 95% CI, 1.09-1.70; P < 0.01). The incidence of major bleeding was not significantly different between the 2 groups (5.4% versus 4.8%; P = 0.46).

The strengths of this current study include the randomized design and the large number of patients enrolled, with adequate power to evaluate for superiority. This was a multicenter trial in Europe with 23 participating centers (21 from Germany). Furthermore, the interventional technique used by the operators reflects more contemporary technique compared to the previous studies comparing each agent to clopidogrel,^1,2 with more frequent use of radial access (37%) and drug-eluting stents (90%) and reduced use of GPIIb/IIIa inhibitors (12%).

There are a few important points to consider due to the differences between the 2 agents compared in this study. First, the loading dose of ticagrelor and prasugrel was administered differently in patients presenting with ACS without ST elevation. Ticagrelor was administered as soon as possible prior to the coronary angiogram, but prasugrel was administered after the coronary anatomy was defined prior to the intervention, which is how this agent is administered in current clinical practice. Therefore, this trial was an open-label study that compared not only different medications, but different administration strategies. Second, ticagrelor and prasugrel have different side-effect profiles. The side effects unique to ticagrelor are dyspnea and bradycardia. On the other hand, a contraindication unique to prasugrel is patients with a history of transient ischemic attack or stroke due to increased risk of thrombotic and hemorrhagic stroke.¹ In addition, prasugrel has increased bleeding risk in patients older than 75 years of age and those with low body weight (< 60 kg). In this study, the overall medication discontinuation rate was higher in the ticagrelor group specifically due to dyspnea, and the reduced dose of 5 mg of prasugrel was used in patients older than 75 years or with low body weight.

Since the timing of administration of ticagrelor (preloading prior to coronary angiography is recommended) is similar to that of clopidogrel, and given the theoretical benefit of reversible inhibition of the ADP receptor, ticagrelor has been used more commonly in clinical practice than prasugrel, and it has been implemented in the ACS protocol in many hospitals. In light of the results from this first head-to-head comparison utilizing more contemporary interventional techniques, these protocols may need to be adjusted in favor of prasugrel for patients presenting with ACS. However, given the difference in timing of administration and the difference in side-effect profile, operators must also tailor these agents depending on the patient profile.

Applications for Clinical Practice

In patients presenting with ACS, prasugrel was superior to ticagrelor, with a lower composite of death, myocardial infarction, and stroke at 12 months. Prasugrel should be considered as a first-line treatment for ACS.

– Taishi Hirai, MD, and Arun Kumar, MD, University of Missouri, Columbia, MO

Study Overview

Objective. To assess the relative merits of ticagrelor compared to prasugrel in patients with acute coronary syndromes who will undergo invasive evaluation.

Design. Multicenter, open-label, prospective randomized controlled trial.

Setting and participants. A total of 4018 patients who presented with ACS with or without ST-segment elevation.

Intervention. Patients were randomly assigned to receive either ticagrelor or prasugrel.

Main outcome measures. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. The secondary end point was bleeding.

Main results. At 1 year, a primary end point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.09-1.70; P = 0.006). In the comparison between ticagrelor and prasugrel, the individual components of the primary end point were as follows: death, 4.5% versus 3.7%; myocardial infarction, 4.8% versus 3.0%; and stroke, 1.1% versus 1.0%, respectively. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% in patients assigned to prasugrel. Major bleeding was observed in 5.4% of the patients in the ticagrelor group and 4.8% in the prasugrel group (HR, 1.12; 95% CI, 0.83-1.51, P = 0.46).

Conclusion. In patients who presented with ACS with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel as compared to those who received ticagrelor, and incidence of major bleeding was not significantly different.

Dual antiplatelet therapy combining an adenosine disphosphate (ADP) receptor antagonist and aspirin is standard treatment for patients presenting with ACS. The limitation of clopidogrel has been its modest antiplatelet effect, with substantial interpatient variability. The newer generation thienopyridine prasugrel and the reversible direct-acting oral antagonist of the ADP receptor ticagrelor provide consistent and greater antiplatelet effect compared to clopidogrel. It has been previously reported that these agents are superior in reducing ischemic events when compared to clopidogrel.^1,2 Therefore, current guidelines recommend ticagrelor and prasugrel in preference to clopidogrel.^3,4 However, there has been no large randomized controlled study comparing the effect of ticagrelor and prasugrel. In this context, Shupke et al investigated this clinical question by performing a well-designed multicenter randomized controlled trial in patients presenting with ACS. At 12-month follow-up, the composite of death, myocardial infarction, and stroke occurred more frequently in the ticagrelor group compared to the prasugrel group (9.3% versus 6.9%; HR, 1.36; 95% CI, 1.09-1.70; P < 0.01). The incidence of major bleeding was not significantly different between the 2 groups (5.4% versus 4.8%; P = 0.46).

The strengths of this current study include the randomized design and the large number of patients enrolled, with adequate power to evaluate for superiority. This was a multicenter trial in Europe with 23 participating centers (21 from Germany). Furthermore, the interventional technique used by the operators reflects more contemporary technique compared to the previous studies comparing each agent to clopidogrel,^1,2 with more frequent use of radial access (37%) and drug-eluting stents (90%) and reduced use of GPIIb/IIIa inhibitors (12%).

There are a few important points to consider due to the differences between the 2 agents compared in this study. First, the loading dose of ticagrelor and prasugrel was administered differently in patients presenting with ACS without ST elevation. Ticagrelor was administered as soon as possible prior to the coronary angiogram, but prasugrel was administered after the coronary anatomy was defined prior to the intervention, which is how this agent is administered in current clinical practice. Therefore, this trial was an open-label study that compared not only different medications, but different administration strategies. Second, ticagrelor and prasugrel have different side-effect profiles. The side effects unique to ticagrelor are dyspnea and bradycardia. On the other hand, a contraindication unique to prasugrel is patients with a history of transient ischemic attack or stroke due to increased risk of thrombotic and hemorrhagic stroke.¹ In addition, prasugrel has increased bleeding risk in patients older than 75 years of age and those with low body weight (< 60 kg). In this study, the overall medication discontinuation rate was higher in the ticagrelor group specifically due to dyspnea, and the reduced dose of 5 mg of prasugrel was used in patients older than 75 years or with low body weight.

Since the timing of administration of ticagrelor (preloading prior to coronary angiography is recommended) is similar to that of clopidogrel, and given the theoretical benefit of reversible inhibition of the ADP receptor, ticagrelor has been used more commonly in clinical practice than prasugrel, and it has been implemented in the ACS protocol in many hospitals. In light of the results from this first head-to-head comparison utilizing more contemporary interventional techniques, these protocols may need to be adjusted in favor of prasugrel for patients presenting with ACS. However, given the difference in timing of administration and the difference in side-effect profile, operators must also tailor these agents depending on the patient profile.

Applications for Clinical Practice

In patients presenting with ACS, prasugrel was superior to ticagrelor, with a lower composite of death, myocardial infarction, and stroke at 12 months. Prasugrel should be considered as a first-line treatment for ACS.

– Taishi Hirai, MD, and Arun Kumar, MD, University of Missouri, Columbia, MO