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Study supports use of rivaroxaban to prevent VTE recurrence
WASHINGTON, DC—Results of the EINSTEIN CHOICE study suggest rivaroxaban is more effective than, and just as safe as, aspirin for long-term anticoagulation in patients with venous thromboembolism (VTE).
In this phase 3 study, patients who had completed 6 to 12 months of anticoagulant therapy were randomized to receive rivaroxaban or aspirin.
Those who received rivaroxaban had a significantly lower risk of recurrent VTE, and the rates of major bleeding were similar between the treatment arms.
“How best to extend anticoagulant use beyond the initial treatment window has been a constant source of debate, with physicians carefully balancing patients’ risk of another VTE with the risk of anticoagulant-related bleeding,” said study investigator Philip S. Wells, MD, of The Ottawa Hospital in Ontario, Canada.
“With EINSTEIN CHOICE, for the first time, we have clinical evidence confirming rivaroxaban is superior to aspirin in reducing recurrent VTE, with no significant impact on safety. These important results have the potential to trigger a paradigm shift in how physicians manage their patients and protect them from VTE recurrence over the long term.”
These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and published in NEJM. The research was funded by Bayer Pharmaceuticals.
The study enrolled 3365 patients with confirmed deep vein thrombosis or pulmonary embolism who were initially treated with anticoagulant therapy for 6 to 12 months.
Patients who required extended anticoagulation at therapeutic doses were not included in this trial, as the objective was to investigate those patients for whom the treating physician was uncertain about the need for continuing anticoagulant therapy.
Patients were randomized in a 1:1:1 ratio to receive a prophylactic dose of rivaroxaban (10 mg once daily), a treatment dose of rivaroxaban (20 mg once daily), or aspirin (100 mg once daily) for up to 12 months. Sixty percent of patients completed the full 12 months of treatment.
Efficacy
Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.
The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2%, respectively.
For the primary endpoint, the HR for the comparison between the 20 mg and 10 mg rivaroxaban arms was 1.34 (95% CI, 0.65 to 2.75, P=0.42). However, the researchers noted that the comparison of these 2 arms was not powered for significance.
The researchers also found that rivaroxaban reduced patients’ risk of experiencing one of the following events: recurrent VTE, heart attack, ischemic stroke, systemic embolism, or venous thrombosis in another location.
This endpoint occurred in 1.9% of patients in the 10 mg rivaroxaban group (HR=0.33; 95% CI, 0.20 to 0.54; P<0.001), 2.0% of patients in the 20 mg rivaroxaban group (HR=0.35; 95% CI, 0.22 to 0.57; P<0.001), and 5.6% of patients in the aspirin group.
Recurrent VTE or all-cause mortality occurred in 1.3% of patients in the 10 mg rivaroxaban group (HR=0.27; 95% CI, 0.15 to 0.47; P<0.001), 2.1% of patients in the 20 mg rivaroxaban group (HR=0.42; 95% CI, 0.26 to 0.68; P<0.001), and 4.9% of patients in the aspirin group.
Safety
The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.
The rate of major bleeding was 0.4% for the 10 mg rivaroxaban group (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban group (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin group.
Rates of clinically relevant non-major bleeding were 2.0%, 2.7%, and 1.8%, respectively (no significant difference).
“We know from previous studies that only about 40% of venous thromboembolism patients are actually on long-term blood thinners,” Dr Wells said.
“We hope that this study, which shows the blood thinner rivaroxaban is as safe as aspirin but much more effective at preventing future clots, will convince patients and their physicians to continue life-long medication that can prevent potentially dangerous blood clots.” 
WASHINGTON, DC—Results of the EINSTEIN CHOICE study suggest rivaroxaban is more effective than, and just as safe as, aspirin for long-term anticoagulation in patients with venous thromboembolism (VTE).
In this phase 3 study, patients who had completed 6 to 12 months of anticoagulant therapy were randomized to receive rivaroxaban or aspirin.
Those who received rivaroxaban had a significantly lower risk of recurrent VTE, and the rates of major bleeding were similar between the treatment arms.
“How best to extend anticoagulant use beyond the initial treatment window has been a constant source of debate, with physicians carefully balancing patients’ risk of another VTE with the risk of anticoagulant-related bleeding,” said study investigator Philip S. Wells, MD, of The Ottawa Hospital in Ontario, Canada.
“With EINSTEIN CHOICE, for the first time, we have clinical evidence confirming rivaroxaban is superior to aspirin in reducing recurrent VTE, with no significant impact on safety. These important results have the potential to trigger a paradigm shift in how physicians manage their patients and protect them from VTE recurrence over the long term.”
These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and published in NEJM. The research was funded by Bayer Pharmaceuticals.
The study enrolled 3365 patients with confirmed deep vein thrombosis or pulmonary embolism who were initially treated with anticoagulant therapy for 6 to 12 months.
Patients who required extended anticoagulation at therapeutic doses were not included in this trial, as the objective was to investigate those patients for whom the treating physician was uncertain about the need for continuing anticoagulant therapy.
Patients were randomized in a 1:1:1 ratio to receive a prophylactic dose of rivaroxaban (10 mg once daily), a treatment dose of rivaroxaban (20 mg once daily), or aspirin (100 mg once daily) for up to 12 months. Sixty percent of patients completed the full 12 months of treatment.
Efficacy
Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.
The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2%, respectively.
For the primary endpoint, the HR for the comparison between the 20 mg and 10 mg rivaroxaban arms was 1.34 (95% CI, 0.65 to 2.75, P=0.42). However, the researchers noted that the comparison of these 2 arms was not powered for significance.
The researchers also found that rivaroxaban reduced patients’ risk of experiencing one of the following events: recurrent VTE, heart attack, ischemic stroke, systemic embolism, or venous thrombosis in another location.
This endpoint occurred in 1.9% of patients in the 10 mg rivaroxaban group (HR=0.33; 95% CI, 0.20 to 0.54; P<0.001), 2.0% of patients in the 20 mg rivaroxaban group (HR=0.35; 95% CI, 0.22 to 0.57; P<0.001), and 5.6% of patients in the aspirin group.
Recurrent VTE or all-cause mortality occurred in 1.3% of patients in the 10 mg rivaroxaban group (HR=0.27; 95% CI, 0.15 to 0.47; P<0.001), 2.1% of patients in the 20 mg rivaroxaban group (HR=0.42; 95% CI, 0.26 to 0.68; P<0.001), and 4.9% of patients in the aspirin group.
Safety
The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.
The rate of major bleeding was 0.4% for the 10 mg rivaroxaban group (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban group (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin group.
Rates of clinically relevant non-major bleeding were 2.0%, 2.7%, and 1.8%, respectively (no significant difference).
“We know from previous studies that only about 40% of venous thromboembolism patients are actually on long-term blood thinners,” Dr Wells said.
“We hope that this study, which shows the blood thinner rivaroxaban is as safe as aspirin but much more effective at preventing future clots, will convince patients and their physicians to continue life-long medication that can prevent potentially dangerous blood clots.”
WASHINGTON, DC—Results of the EINSTEIN CHOICE study suggest rivaroxaban is more effective than, and just as safe as, aspirin for long-term anticoagulation in patients with venous thromboembolism (VTE).
In this phase 3 study, patients who had completed 6 to 12 months of anticoagulant therapy were randomized to receive rivaroxaban or aspirin.
Those who received rivaroxaban had a significantly lower risk of recurrent VTE, and the rates of major bleeding were similar between the treatment arms.
“How best to extend anticoagulant use beyond the initial treatment window has been a constant source of debate, with physicians carefully balancing patients’ risk of another VTE with the risk of anticoagulant-related bleeding,” said study investigator Philip S. Wells, MD, of The Ottawa Hospital in Ontario, Canada.
“With EINSTEIN CHOICE, for the first time, we have clinical evidence confirming rivaroxaban is superior to aspirin in reducing recurrent VTE, with no significant impact on safety. These important results have the potential to trigger a paradigm shift in how physicians manage their patients and protect them from VTE recurrence over the long term.”
These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and published in NEJM. The research was funded by Bayer Pharmaceuticals.
The study enrolled 3365 patients with confirmed deep vein thrombosis or pulmonary embolism who were initially treated with anticoagulant therapy for 6 to 12 months.
Patients who required extended anticoagulation at therapeutic doses were not included in this trial, as the objective was to investigate those patients for whom the treating physician was uncertain about the need for continuing anticoagulant therapy.
Patients were randomized in a 1:1:1 ratio to receive a prophylactic dose of rivaroxaban (10 mg once daily), a treatment dose of rivaroxaban (20 mg once daily), or aspirin (100 mg once daily) for up to 12 months. Sixty percent of patients completed the full 12 months of treatment.
Efficacy
Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.
The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2%, respectively.
For the primary endpoint, the HR for the comparison between the 20 mg and 10 mg rivaroxaban arms was 1.34 (95% CI, 0.65 to 2.75, P=0.42). However, the researchers noted that the comparison of these 2 arms was not powered for significance.
The researchers also found that rivaroxaban reduced patients’ risk of experiencing one of the following events: recurrent VTE, heart attack, ischemic stroke, systemic embolism, or venous thrombosis in another location.
This endpoint occurred in 1.9% of patients in the 10 mg rivaroxaban group (HR=0.33; 95% CI, 0.20 to 0.54; P<0.001), 2.0% of patients in the 20 mg rivaroxaban group (HR=0.35; 95% CI, 0.22 to 0.57; P<0.001), and 5.6% of patients in the aspirin group.
Recurrent VTE or all-cause mortality occurred in 1.3% of patients in the 10 mg rivaroxaban group (HR=0.27; 95% CI, 0.15 to 0.47; P<0.001), 2.1% of patients in the 20 mg rivaroxaban group (HR=0.42; 95% CI, 0.26 to 0.68; P<0.001), and 4.9% of patients in the aspirin group.
Safety
The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.
The rate of major bleeding was 0.4% for the 10 mg rivaroxaban group (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban group (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin group.
Rates of clinically relevant non-major bleeding were 2.0%, 2.7%, and 1.8%, respectively (no significant difference).
“We know from previous studies that only about 40% of venous thromboembolism patients are actually on long-term blood thinners,” Dr Wells said.
“We hope that this study, which shows the blood thinner rivaroxaban is as safe as aspirin but much more effective at preventing future clots, will convince patients and their physicians to continue life-long medication that can prevent potentially dangerous blood clots.”
Apixaban bests warfarin in real-world analysis
WASHINGTON, DC—An analysis of real-world data suggests elderly patients with non-valvular atrial fibrillation (NVAF) have a lower risk of stroke or systemic embolism and a lower risk of major bleeding if they receive apixaban rather than warfarin.
The study also indicates that elderly NVAF patients who receive dabigatran have a similar risk of stroke/systemic embolism as those on warfarin, but the risk of major bleeding is lower with dabigatran.
And rivaroxaban poses a lower risk of stroke/systemic embolism than warfarin but a higher risk of major bleeding.
However, the researchers who conducted this analysis stressed that it cannot be used as stand-alone evidence to validate the efficacy and/or safety of any of the drugs studied.
The results of the analysis were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 1134M-13).
The researchers also presented data on the financial costs of major bleeding associated with apixaban, dabigatran, rivaroxaban, and warfarin (abstract 1189-085/085).
The research was conducted by employees from Bristol-Myers Squibb Company and Pfizer Inc., the companies marketing apixaban, as well as other researchers who have relationships with the companies.
The team evaluated medical and pharmacy claims from the US Medicare fee-for-service database. They looked at NVAF patients age 65 and older who were newly prescribed apixaban, dabigatran, rivaroxaban, or warfarin between January 1, 2013, and December 31, 2014.
The researchers compared each of the direct oral anticoagulants to warfarin using 1:1 propensity score matching methodology to balance select demographic and clinical characteristics between the groups.
The team used Cox proportional hazards models to estimate the hazard ratio (HR) of stroke/systemic embolism and major bleeding.
Results
In a comparison of apixaban and warfarin (20,803 patients in each treatment group), apixaban was associated with a significantly lower risk of stroke or systemic embolism than warfarin (HR: 0.40, 95% CI: 0.31-0.53; P<0.0001).
Apixaban was also associated with a significantly lower risk of major bleeding than warfarin (HR: 0.51, 95% CI: 0.44-0.58; P<0.0001). The cost of major bleeding per patient per month was $286 with apixaban and $537 with warfarin (P<0.0001).
In a comparison of dabigatran and warfarin (16,731 patients in each treatment group), the risk of stroke or systemic embolism was similar between the cohorts (HR: 0.94, 95% CI: 0.74-1.21; P=0.647).
However, the risk of major bleeding was significantly lower with dabigatran than with warfarin (HR: 0.79, 95% CI: 0.69-0.91; P=0.001). The cost of major bleeding per patient per month was $367 with dabigatran and $452 with warfarin (P=0.032).
In a comparison of rivaroxaban and warfarin (52,476 patients in each group), rivaroxaban was associated with a significantly lower risk of stroke or systemic embolism than warfarin (HR: 0.72, 95% CI: 0.63-0.83; P<0.0001).
However, the risk of major bleeding was significantly higher with rivaroxaban than with warfarin (HR: 1.17, 95% CI: 1.10-1.26; P<0.0001). The cost of major bleeding per patient per month was $524 with rivaroxaban and $500 with warfarin (P=0.154).
Limitations
The researchers noted that this analysis has several limitations. For instance, information on laboratory results and time in therapeutic range were not available. Diagnoses were identified through ICD-9 codes, and drug prescriptions were identified through prescription claims.
Propensity score matching was used to mimic randomization by balancing pre-defined demographic and clinical characteristics at baseline for both treatment cohorts. However, unobserved confounders (such as laboratory values and patient preferences) may exist.
As with any real-world data analysis, missing values, coding errors, and a lack of clinical accuracy may have introduced bias.
The researchers stressed that, due to such limitations, real-world data analyses cannot be used as stand-alone evidence to validate the efficacy and/or safety of a treatment. However, these analyses add to information provided by randomized clinical trials.
“Studies such as this large US Medicare database analysis supplement pivotal trials by broadening and deepening our scientific knowledge of how patients respond to direct oral anticoagulants in everyday clinical practice,” said Alpesh Amin, MD, principal investigator and professor of medicine at the University of California, Irvine.
“Given the diversity of patients with non-valvular atrial fibrillation, analyses of real-world data provide further information that adds to data generated in randomized clinical trials.”
WASHINGTON, DC—An analysis of real-world data suggests elderly patients with non-valvular atrial fibrillation (NVAF) have a lower risk of stroke or systemic embolism and a lower risk of major bleeding if they receive apixaban rather than warfarin.
The study also indicates that elderly NVAF patients who receive dabigatran have a similar risk of stroke/systemic embolism as those on warfarin, but the risk of major bleeding is lower with dabigatran.
And rivaroxaban poses a lower risk of stroke/systemic embolism than warfarin but a higher risk of major bleeding.
However, the researchers who conducted this analysis stressed that it cannot be used as stand-alone evidence to validate the efficacy and/or safety of any of the drugs studied.
The results of the analysis were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 1134M-13).
The researchers also presented data on the financial costs of major bleeding associated with apixaban, dabigatran, rivaroxaban, and warfarin (abstract 1189-085/085).
The research was conducted by employees from Bristol-Myers Squibb Company and Pfizer Inc., the companies marketing apixaban, as well as other researchers who have relationships with the companies.
The team evaluated medical and pharmacy claims from the US Medicare fee-for-service database. They looked at NVAF patients age 65 and older who were newly prescribed apixaban, dabigatran, rivaroxaban, or warfarin between January 1, 2013, and December 31, 2014.
The researchers compared each of the direct oral anticoagulants to warfarin using 1:1 propensity score matching methodology to balance select demographic and clinical characteristics between the groups.
The team used Cox proportional hazards models to estimate the hazard ratio (HR) of stroke/systemic embolism and major bleeding.
Results
In a comparison of apixaban and warfarin (20,803 patients in each treatment group), apixaban was associated with a significantly lower risk of stroke or systemic embolism than warfarin (HR: 0.40, 95% CI: 0.31-0.53; P<0.0001).
Apixaban was also associated with a significantly lower risk of major bleeding than warfarin (HR: 0.51, 95% CI: 0.44-0.58; P<0.0001). The cost of major bleeding per patient per month was $286 with apixaban and $537 with warfarin (P<0.0001).
In a comparison of dabigatran and warfarin (16,731 patients in each treatment group), the risk of stroke or systemic embolism was similar between the cohorts (HR: 0.94, 95% CI: 0.74-1.21; P=0.647).
However, the risk of major bleeding was significantly lower with dabigatran than with warfarin (HR: 0.79, 95% CI: 0.69-0.91; P=0.001). The cost of major bleeding per patient per month was $367 with dabigatran and $452 with warfarin (P=0.032).
In a comparison of rivaroxaban and warfarin (52,476 patients in each group), rivaroxaban was associated with a significantly lower risk of stroke or systemic embolism than warfarin (HR: 0.72, 95% CI: 0.63-0.83; P<0.0001).
However, the risk of major bleeding was significantly higher with rivaroxaban than with warfarin (HR: 1.17, 95% CI: 1.10-1.26; P<0.0001). The cost of major bleeding per patient per month was $524 with rivaroxaban and $500 with warfarin (P=0.154).
Limitations
The researchers noted that this analysis has several limitations. For instance, information on laboratory results and time in therapeutic range were not available. Diagnoses were identified through ICD-9 codes, and drug prescriptions were identified through prescription claims.
Propensity score matching was used to mimic randomization by balancing pre-defined demographic and clinical characteristics at baseline for both treatment cohorts. However, unobserved confounders (such as laboratory values and patient preferences) may exist.
As with any real-world data analysis, missing values, coding errors, and a lack of clinical accuracy may have introduced bias.
The researchers stressed that, due to such limitations, real-world data analyses cannot be used as stand-alone evidence to validate the efficacy and/or safety of a treatment. However, these analyses add to information provided by randomized clinical trials.
“Studies such as this large US Medicare database analysis supplement pivotal trials by broadening and deepening our scientific knowledge of how patients respond to direct oral anticoagulants in everyday clinical practice,” said Alpesh Amin, MD, principal investigator and professor of medicine at the University of California, Irvine.
“Given the diversity of patients with non-valvular atrial fibrillation, analyses of real-world data provide further information that adds to data generated in randomized clinical trials.”
WASHINGTON, DC—An analysis of real-world data suggests elderly patients with non-valvular atrial fibrillation (NVAF) have a lower risk of stroke or systemic embolism and a lower risk of major bleeding if they receive apixaban rather than warfarin.
The study also indicates that elderly NVAF patients who receive dabigatran have a similar risk of stroke/systemic embolism as those on warfarin, but the risk of major bleeding is lower with dabigatran.
And rivaroxaban poses a lower risk of stroke/systemic embolism than warfarin but a higher risk of major bleeding.
However, the researchers who conducted this analysis stressed that it cannot be used as stand-alone evidence to validate the efficacy and/or safety of any of the drugs studied.
The results of the analysis were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 1134M-13).
The researchers also presented data on the financial costs of major bleeding associated with apixaban, dabigatran, rivaroxaban, and warfarin (abstract 1189-085/085).
The research was conducted by employees from Bristol-Myers Squibb Company and Pfizer Inc., the companies marketing apixaban, as well as other researchers who have relationships with the companies.
The team evaluated medical and pharmacy claims from the US Medicare fee-for-service database. They looked at NVAF patients age 65 and older who were newly prescribed apixaban, dabigatran, rivaroxaban, or warfarin between January 1, 2013, and December 31, 2014.
The researchers compared each of the direct oral anticoagulants to warfarin using 1:1 propensity score matching methodology to balance select demographic and clinical characteristics between the groups.
The team used Cox proportional hazards models to estimate the hazard ratio (HR) of stroke/systemic embolism and major bleeding.
Results
In a comparison of apixaban and warfarin (20,803 patients in each treatment group), apixaban was associated with a significantly lower risk of stroke or systemic embolism than warfarin (HR: 0.40, 95% CI: 0.31-0.53; P<0.0001).
Apixaban was also associated with a significantly lower risk of major bleeding than warfarin (HR: 0.51, 95% CI: 0.44-0.58; P<0.0001). The cost of major bleeding per patient per month was $286 with apixaban and $537 with warfarin (P<0.0001).
In a comparison of dabigatran and warfarin (16,731 patients in each treatment group), the risk of stroke or systemic embolism was similar between the cohorts (HR: 0.94, 95% CI: 0.74-1.21; P=0.647).
However, the risk of major bleeding was significantly lower with dabigatran than with warfarin (HR: 0.79, 95% CI: 0.69-0.91; P=0.001). The cost of major bleeding per patient per month was $367 with dabigatran and $452 with warfarin (P=0.032).
In a comparison of rivaroxaban and warfarin (52,476 patients in each group), rivaroxaban was associated with a significantly lower risk of stroke or systemic embolism than warfarin (HR: 0.72, 95% CI: 0.63-0.83; P<0.0001).
However, the risk of major bleeding was significantly higher with rivaroxaban than with warfarin (HR: 1.17, 95% CI: 1.10-1.26; P<0.0001). The cost of major bleeding per patient per month was $524 with rivaroxaban and $500 with warfarin (P=0.154).
Limitations
The researchers noted that this analysis has several limitations. For instance, information on laboratory results and time in therapeutic range were not available. Diagnoses were identified through ICD-9 codes, and drug prescriptions were identified through prescription claims.
Propensity score matching was used to mimic randomization by balancing pre-defined demographic and clinical characteristics at baseline for both treatment cohorts. However, unobserved confounders (such as laboratory values and patient preferences) may exist.
As with any real-world data analysis, missing values, coding errors, and a lack of clinical accuracy may have introduced bias.
The researchers stressed that, due to such limitations, real-world data analyses cannot be used as stand-alone evidence to validate the efficacy and/or safety of a treatment. However, these analyses add to information provided by randomized clinical trials.
“Studies such as this large US Medicare database analysis supplement pivotal trials by broadening and deepening our scientific knowledge of how patients respond to direct oral anticoagulants in everyday clinical practice,” said Alpesh Amin, MD, principal investigator and professor of medicine at the University of California, Irvine.
“Given the diversity of patients with non-valvular atrial fibrillation, analyses of real-world data provide further information that adds to data generated in randomized clinical trials.”
Major bleeding lower with dabigatran than warfarin
WASHINGTON, DC—Results from the RE-CIRCUIT trial suggest that uninterrupted dabigatran poses a lower risk of major bleeding than uninterrupted warfarin in patients with non-valvular atrial fibrillation (NVAF) who are undergoing catheter ablation.
Patients who received dabigatran also had fewer serious and severe adverse events (AEs).
The incidence of minor bleeding was similar between the treatment groups, and the incidence of AEs leading to treatment discontinuation was higher with dabigatran.
These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and simultaneously published in NEJM.
This study was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc.
The RE-CIRCUIT trial enrolled 704 patients with paroxysmal or persistent NVAF, and 635 of them ultimately underwent catheter ablation with uninterrupted anticoagulation.
The patients were randomized to receive dabigatran at 150 mg twice daily or warfarin (with a target international normalized ratio [INR] of 2.0–3.0) in a 1:1 ratio and remained on this treatment for the duration of the trial.
The mean adherence to dabigatran was 97.6%, and patients receiving warfarin were within the guideline-defined target INR range 66% of the time. The majority of patients in both groups (86.1% in the dabigatran group and 84.3% in the warfarin group) received study treatment for at least 8 weeks after ablation.
Results
The study’s primary endpoint was the incidence of major bleeding events, as defined by the International Society on Thrombosis and Hemostasis, during the ablation procedure and up to 2 months after.
There was a significantly lower incidence of major bleeding with uninterrupted dabigatran than with uninterrupted warfarin—1.6% (n=5) and 6.9% (n=22), respectively (P<0.001).
Major bleeding events (in the dabigatran and warfarin groups, respectively) included pericardial tamponade (1 and 6), pericardial effusion (1 and 0), groin bleeds (2 in both), groin hematomas (0 and 8), gastrointestinal bleeds (1 and 2), intracranial bleeds (0 and 2), pseudoaneurysm (0 and 1), and hematomas (0 and 2).
The incidence of minor bleeding was similar between the treatment groups—18.6% (n=59) in the dabigatran group and 17.0% (n=54) in the warfarin group.
The incidence of serious AEs was 18.6% in the dabigatran group and 22.2% in the warfarin group. The most frequent serious AEs were atrial flutter (5.9% and 5.6%, respectively), atrial fibrillation (1.8% and 3.8%, respectively), and cardiac tamponade (0.3% and 1.2%, respectively).
The incidence of severe AEs was 3.3% in the dabigatran group and 6.2% in the warfarin group. The incidence of AEs leading to treatment discontinuation was 5.6% and 2.4%, respectively.
There were no cases of stroke, systemic embolism, or transient ischemic attack in the dabigatran group. However, there was a transient ischemic attack in the warfarin group.
“These results are exciting news for the medical community,” said study investigator Hugh Calkins, MD, of Johns Hopkins Hospital in Baltimore, Maryland.
“During an ablation procedure, patients are at risk of potential major complications, including stroke and bleeding. Therefore, anticoagulation management at the time of AFib ablation is critically important. In RE-CIRCUIT, we have seen that uninterrupted anticoagulation with dabigatran showed significantly lower major bleeding complications than warfarin in atrial fibrillation patients undergoing cardiac ablation.”
WASHINGTON, DC—Results from the RE-CIRCUIT trial suggest that uninterrupted dabigatran poses a lower risk of major bleeding than uninterrupted warfarin in patients with non-valvular atrial fibrillation (NVAF) who are undergoing catheter ablation.
Patients who received dabigatran also had fewer serious and severe adverse events (AEs).
The incidence of minor bleeding was similar between the treatment groups, and the incidence of AEs leading to treatment discontinuation was higher with dabigatran.
These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and simultaneously published in NEJM.
This study was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc.
The RE-CIRCUIT trial enrolled 704 patients with paroxysmal or persistent NVAF, and 635 of them ultimately underwent catheter ablation with uninterrupted anticoagulation.
The patients were randomized to receive dabigatran at 150 mg twice daily or warfarin (with a target international normalized ratio [INR] of 2.0–3.0) in a 1:1 ratio and remained on this treatment for the duration of the trial.
The mean adherence to dabigatran was 97.6%, and patients receiving warfarin were within the guideline-defined target INR range 66% of the time. The majority of patients in both groups (86.1% in the dabigatran group and 84.3% in the warfarin group) received study treatment for at least 8 weeks after ablation.
Results
The study’s primary endpoint was the incidence of major bleeding events, as defined by the International Society on Thrombosis and Hemostasis, during the ablation procedure and up to 2 months after.
There was a significantly lower incidence of major bleeding with uninterrupted dabigatran than with uninterrupted warfarin—1.6% (n=5) and 6.9% (n=22), respectively (P<0.001).
Major bleeding events (in the dabigatran and warfarin groups, respectively) included pericardial tamponade (1 and 6), pericardial effusion (1 and 0), groin bleeds (2 in both), groin hematomas (0 and 8), gastrointestinal bleeds (1 and 2), intracranial bleeds (0 and 2), pseudoaneurysm (0 and 1), and hematomas (0 and 2).
The incidence of minor bleeding was similar between the treatment groups—18.6% (n=59) in the dabigatran group and 17.0% (n=54) in the warfarin group.
The incidence of serious AEs was 18.6% in the dabigatran group and 22.2% in the warfarin group. The most frequent serious AEs were atrial flutter (5.9% and 5.6%, respectively), atrial fibrillation (1.8% and 3.8%, respectively), and cardiac tamponade (0.3% and 1.2%, respectively).
The incidence of severe AEs was 3.3% in the dabigatran group and 6.2% in the warfarin group. The incidence of AEs leading to treatment discontinuation was 5.6% and 2.4%, respectively.
There were no cases of stroke, systemic embolism, or transient ischemic attack in the dabigatran group. However, there was a transient ischemic attack in the warfarin group.
“These results are exciting news for the medical community,” said study investigator Hugh Calkins, MD, of Johns Hopkins Hospital in Baltimore, Maryland.
“During an ablation procedure, patients are at risk of potential major complications, including stroke and bleeding. Therefore, anticoagulation management at the time of AFib ablation is critically important. In RE-CIRCUIT, we have seen that uninterrupted anticoagulation with dabigatran showed significantly lower major bleeding complications than warfarin in atrial fibrillation patients undergoing cardiac ablation.”
WASHINGTON, DC—Results from the RE-CIRCUIT trial suggest that uninterrupted dabigatran poses a lower risk of major bleeding than uninterrupted warfarin in patients with non-valvular atrial fibrillation (NVAF) who are undergoing catheter ablation.
Patients who received dabigatran also had fewer serious and severe adverse events (AEs).
The incidence of minor bleeding was similar between the treatment groups, and the incidence of AEs leading to treatment discontinuation was higher with dabigatran.
These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and simultaneously published in NEJM.
This study was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc.
The RE-CIRCUIT trial enrolled 704 patients with paroxysmal or persistent NVAF, and 635 of them ultimately underwent catheter ablation with uninterrupted anticoagulation.
The patients were randomized to receive dabigatran at 150 mg twice daily or warfarin (with a target international normalized ratio [INR] of 2.0–3.0) in a 1:1 ratio and remained on this treatment for the duration of the trial.
The mean adherence to dabigatran was 97.6%, and patients receiving warfarin were within the guideline-defined target INR range 66% of the time. The majority of patients in both groups (86.1% in the dabigatran group and 84.3% in the warfarin group) received study treatment for at least 8 weeks after ablation.
Results
The study’s primary endpoint was the incidence of major bleeding events, as defined by the International Society on Thrombosis and Hemostasis, during the ablation procedure and up to 2 months after.
There was a significantly lower incidence of major bleeding with uninterrupted dabigatran than with uninterrupted warfarin—1.6% (n=5) and 6.9% (n=22), respectively (P<0.001).
Major bleeding events (in the dabigatran and warfarin groups, respectively) included pericardial tamponade (1 and 6), pericardial effusion (1 and 0), groin bleeds (2 in both), groin hematomas (0 and 8), gastrointestinal bleeds (1 and 2), intracranial bleeds (0 and 2), pseudoaneurysm (0 and 1), and hematomas (0 and 2).
The incidence of minor bleeding was similar between the treatment groups—18.6% (n=59) in the dabigatran group and 17.0% (n=54) in the warfarin group.
The incidence of serious AEs was 18.6% in the dabigatran group and 22.2% in the warfarin group. The most frequent serious AEs were atrial flutter (5.9% and 5.6%, respectively), atrial fibrillation (1.8% and 3.8%, respectively), and cardiac tamponade (0.3% and 1.2%, respectively).
The incidence of severe AEs was 3.3% in the dabigatran group and 6.2% in the warfarin group. The incidence of AEs leading to treatment discontinuation was 5.6% and 2.4%, respectively.
There were no cases of stroke, systemic embolism, or transient ischemic attack in the dabigatran group. However, there was a transient ischemic attack in the warfarin group.
“These results are exciting news for the medical community,” said study investigator Hugh Calkins, MD, of Johns Hopkins Hospital in Baltimore, Maryland.
“During an ablation procedure, patients are at risk of potential major complications, including stroke and bleeding. Therefore, anticoagulation management at the time of AFib ablation is critically important. In RE-CIRCUIT, we have seen that uninterrupted anticoagulation with dabigatran showed significantly lower major bleeding complications than warfarin in atrial fibrillation patients undergoing cardiac ablation.”
VIDEO: Subclinical leaflet thrombosis frequent after TAVR, SAVR
WASHINGTON – Subclinical leaflet thrombosis, as evidenced by reduced leaflet motion and corresponding hypoattenuating lesions on high-resolution CT, occurs frequently in bioprosthetic aortic valves implanted either by the transcatheter route or surgically, according to a report presented at the annual meeting of the American College of Cardiology and simultaneously published March 19 in the Lancet.
In an observational cohort study involving 890 patients enrolled in two single-center registries, reduced leaflet motion signaling the presence of thrombosis was detected in 106 patients (12%) by four-dimensional, volume-rendered CT. The thrombosis was hemodynamically silent and undetected by transthoracic echocardiograms done in a large subgroup of the study participants. Mean aortic valve gradients were numerically higher in affected patients, but still fell within the normal range in most of them, said Raj R. Makkar, MD, of Cedars-Sinai Heart Institute, Los Angeles.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Makkar and his associates studied this issue by analyzing data in the RESOLVE (Assessment of Transcatheter and Surgical Aortic Bioprosthetic Valve Thrombosis and its Treatment with Anticoagulation) registry at Cedars-Sinai and the SAVORY (Subclinical Aortic Valve Biosprosthesis Thrombosis Assessed with Four-Dimensional CT) registry at the Rigshospitalet Heart Center in Copenhagen. Their study focused on enrolled patients who underwent either TAVR (626 patients) or SAVR (264 patients) and then had high-resolution CT scans done at various times after implantation. All the CT scans were analyzed in blinded fashion, and the study participants were followed for a mean of 540 days.
The prevalence of subclinical leaflet thrombosis was significantly higher in TAVR valves (13%) than in SAVR valves (4%). The severity of the thrombosis also was significantly higher in TAVR valves, when measured by the extent of leaflet motion restriction (71.0% vs. 56.9%).
One possible reason for this discrepancy is that traumatic injury to the pericardial leaflets, which theoretically could predispose to thrombus formation, may be more likely to occur during crimping and deployment of balloon-expandable and self-expanding stent valves in TAVR. Another possibility is that resection of the calcified native aortic valves during SAVR might improve flow dynamics after valve replacement, compared with leaving native aortic valve cusps in situ during TAVR. A third possibility is that inadvertent incomplete expansion or overexpansion of transcatheter valves might alter mechanical stress on the leaflets, predisposing them to thrombus formation, compared with the uniform expansion of valves placed surgically, the investigator said.
“Nevertheless, these findings should be interpreted in the context of findings from multiple randomized controlled trials showing similar mortality and stroke rates, better hemodynamics, and equivalent durability of transcatheter aortic valves at 5 years, compared with surgical valves,” he noted.
Patients taking novel oral anticoagulants (NOACs) or warfarin for anticoagulation before valve replacement were less likely to develop subclinical leaflet thrombosis than patients not taking those anticoagulants. And the thrombosis appeared to resolve in all patients treated with NOACs or warfarin for 30 days after it was found on CT, but it persisted or progressed in those not treated with anticoagulation. Thus, “anticoagulation with NOACs or warfarin was effective in prevention and treatment of reduced leaflet motion, but dual-antiplatelet therapy, which is the standard of care, was not,” the investigators said (Lancet 2017 Mar 19. doi: 10.1016/S0140-6736(17)30757-2.
“Our study challenges the American College of Cardiology and American Heart Association and European Society of Cardiology and European Association for Cardio-Thoracic Surgery guidelines, which recommend dual-antiplatelet therapy after TAVR and do not recommend routine anticoagulation after TAVR,” he noted.
However, routine anticoagulation for all TAVR and SAVR patients, or even for all who develop leaflet thrombosis, cannot be recommended on the basis of results from a single observational study. The benefit of anticoagulation may not offset the risk of bleeding in this predominantly elderly population with multiple comorbidities, he said.
There were no significant differences between patients who developed subclinical leaflet thrombosis and those who did not regarding rates of death, MI, or stroke. However, “reduced leaflet wall motion was significantly associated with increased rates of all TIAs [transient ischemic attacks], nonprocedural TIAs, and post-CT TIAs.” Dr. Makkar said.
Based on his new findings, Dr. Makkar suggested that clinicians keep possible leaflet thrombosis on a replaced aortic valve in mind if they see clinical evidence for it, such as an increase in the valve’s pressure gradient or development of a TIA or stroke.* These events should trigger further investigation of the valve with CT angiography, and if thrombosis is then confirmed, the patient should receive treatment with an anticoagulant, although the appropriate duration of anticoagulant treatment remains unclear, he said in a video interview. Dr. Makkar also said that trials are needed to determine whether routine CT angiography assessment or routine prophylactic treatment with an anticoagulant is warranted because the antiplatelet therapy that patients currently receive after aortic valve replacement seems unable to prevent leaflet thrombosis.
Since this was an observational study based on data from nonrandomized registries, the findings cannot prove causality but only an association between leaflet thrombosis and TIA. They must be substantiated in further studies, including “the current Food and Drug Administration–mandated imaging substudies in randomized clinical trials.”
Dr. Makkar has received consultant fees and/or honoraria from Abbott Vascular, Medtronic, Cordis, and Entourage Medical, and research grants from Edwards Lifesciences and St. Jude Medical.
Mitchel L. Zoler contributed to this report.
Correction, 3/20/17: An earlier version of this article misstated the clinical evidence for possible leaflet thrombosis on a replaced aortic valve.
The study by Dr. Makkar and his coinvestigators provides important new information to guide future research, but changing clinical practice or guidelines on the basis of this information would be premature.
In particular, whether to recommend anticoagulation therapy to TAVR and SAVR patients is unknown, given the risks of chronic anticoagulation. We do not yet know whether such a recommendation should be guided by CT or echocardiographic imaging, and, if so, at what intervals? We don’t yet know the optimal duration of anticoagulation treatment, or whether NOAC’s are as good as or better than warfarin in this setting. And we don’t yet know whether the risk of bleeding is offset by a reduction in stroke or any other meaningful clinical sequelae.
Jeroen J. Bax, MD, is in the department of cardiology at Leiden (the Netherlands) University Medical Center. Gregg W. Stone, MD, is at Columbia University Medical Center and the Cardiovascular Research Foundation, both in New York. Dr. Bax’s institution has received unrestricted research grants from Biotronik, Medtronic, Boston Scientific, and Edwards LifeScience; Dr. Stone reported ties to numerous industry sources. Dr. Bax and Dr. Stone made these remarks in an editorial accompanying the Lancet report (Lancet 2017 Mar 19. doi: 10.1016/S0140-6736(17)30757-2).
The study by Dr. Makkar and his coinvestigators provides important new information to guide future research, but changing clinical practice or guidelines on the basis of this information would be premature.
In particular, whether to recommend anticoagulation therapy to TAVR and SAVR patients is unknown, given the risks of chronic anticoagulation. We do not yet know whether such a recommendation should be guided by CT or echocardiographic imaging, and, if so, at what intervals? We don’t yet know the optimal duration of anticoagulation treatment, or whether NOAC’s are as good as or better than warfarin in this setting. And we don’t yet know whether the risk of bleeding is offset by a reduction in stroke or any other meaningful clinical sequelae.
Jeroen J. Bax, MD, is in the department of cardiology at Leiden (the Netherlands) University Medical Center. Gregg W. Stone, MD, is at Columbia University Medical Center and the Cardiovascular Research Foundation, both in New York. Dr. Bax’s institution has received unrestricted research grants from Biotronik, Medtronic, Boston Scientific, and Edwards LifeScience; Dr. Stone reported ties to numerous industry sources. Dr. Bax and Dr. Stone made these remarks in an editorial accompanying the Lancet report (Lancet 2017 Mar 19. doi: 10.1016/S0140-6736(17)30757-2).
The study by Dr. Makkar and his coinvestigators provides important new information to guide future research, but changing clinical practice or guidelines on the basis of this information would be premature.
In particular, whether to recommend anticoagulation therapy to TAVR and SAVR patients is unknown, given the risks of chronic anticoagulation. We do not yet know whether such a recommendation should be guided by CT or echocardiographic imaging, and, if so, at what intervals? We don’t yet know the optimal duration of anticoagulation treatment, or whether NOAC’s are as good as or better than warfarin in this setting. And we don’t yet know whether the risk of bleeding is offset by a reduction in stroke or any other meaningful clinical sequelae.
Jeroen J. Bax, MD, is in the department of cardiology at Leiden (the Netherlands) University Medical Center. Gregg W. Stone, MD, is at Columbia University Medical Center and the Cardiovascular Research Foundation, both in New York. Dr. Bax’s institution has received unrestricted research grants from Biotronik, Medtronic, Boston Scientific, and Edwards LifeScience; Dr. Stone reported ties to numerous industry sources. Dr. Bax and Dr. Stone made these remarks in an editorial accompanying the Lancet report (Lancet 2017 Mar 19. doi: 10.1016/S0140-6736(17)30757-2).
WASHINGTON – Subclinical leaflet thrombosis, as evidenced by reduced leaflet motion and corresponding hypoattenuating lesions on high-resolution CT, occurs frequently in bioprosthetic aortic valves implanted either by the transcatheter route or surgically, according to a report presented at the annual meeting of the American College of Cardiology and simultaneously published March 19 in the Lancet.
In an observational cohort study involving 890 patients enrolled in two single-center registries, reduced leaflet motion signaling the presence of thrombosis was detected in 106 patients (12%) by four-dimensional, volume-rendered CT. The thrombosis was hemodynamically silent and undetected by transthoracic echocardiograms done in a large subgroup of the study participants. Mean aortic valve gradients were numerically higher in affected patients, but still fell within the normal range in most of them, said Raj R. Makkar, MD, of Cedars-Sinai Heart Institute, Los Angeles.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Makkar and his associates studied this issue by analyzing data in the RESOLVE (Assessment of Transcatheter and Surgical Aortic Bioprosthetic Valve Thrombosis and its Treatment with Anticoagulation) registry at Cedars-Sinai and the SAVORY (Subclinical Aortic Valve Biosprosthesis Thrombosis Assessed with Four-Dimensional CT) registry at the Rigshospitalet Heart Center in Copenhagen. Their study focused on enrolled patients who underwent either TAVR (626 patients) or SAVR (264 patients) and then had high-resolution CT scans done at various times after implantation. All the CT scans were analyzed in blinded fashion, and the study participants were followed for a mean of 540 days.
The prevalence of subclinical leaflet thrombosis was significantly higher in TAVR valves (13%) than in SAVR valves (4%). The severity of the thrombosis also was significantly higher in TAVR valves, when measured by the extent of leaflet motion restriction (71.0% vs. 56.9%).
One possible reason for this discrepancy is that traumatic injury to the pericardial leaflets, which theoretically could predispose to thrombus formation, may be more likely to occur during crimping and deployment of balloon-expandable and self-expanding stent valves in TAVR. Another possibility is that resection of the calcified native aortic valves during SAVR might improve flow dynamics after valve replacement, compared with leaving native aortic valve cusps in situ during TAVR. A third possibility is that inadvertent incomplete expansion or overexpansion of transcatheter valves might alter mechanical stress on the leaflets, predisposing them to thrombus formation, compared with the uniform expansion of valves placed surgically, the investigator said.
“Nevertheless, these findings should be interpreted in the context of findings from multiple randomized controlled trials showing similar mortality and stroke rates, better hemodynamics, and equivalent durability of transcatheter aortic valves at 5 years, compared with surgical valves,” he noted.
Patients taking novel oral anticoagulants (NOACs) or warfarin for anticoagulation before valve replacement were less likely to develop subclinical leaflet thrombosis than patients not taking those anticoagulants. And the thrombosis appeared to resolve in all patients treated with NOACs or warfarin for 30 days after it was found on CT, but it persisted or progressed in those not treated with anticoagulation. Thus, “anticoagulation with NOACs or warfarin was effective in prevention and treatment of reduced leaflet motion, but dual-antiplatelet therapy, which is the standard of care, was not,” the investigators said (Lancet 2017 Mar 19. doi: 10.1016/S0140-6736(17)30757-2.
“Our study challenges the American College of Cardiology and American Heart Association and European Society of Cardiology and European Association for Cardio-Thoracic Surgery guidelines, which recommend dual-antiplatelet therapy after TAVR and do not recommend routine anticoagulation after TAVR,” he noted.
However, routine anticoagulation for all TAVR and SAVR patients, or even for all who develop leaflet thrombosis, cannot be recommended on the basis of results from a single observational study. The benefit of anticoagulation may not offset the risk of bleeding in this predominantly elderly population with multiple comorbidities, he said.
There were no significant differences between patients who developed subclinical leaflet thrombosis and those who did not regarding rates of death, MI, or stroke. However, “reduced leaflet wall motion was significantly associated with increased rates of all TIAs [transient ischemic attacks], nonprocedural TIAs, and post-CT TIAs.” Dr. Makkar said.
Based on his new findings, Dr. Makkar suggested that clinicians keep possible leaflet thrombosis on a replaced aortic valve in mind if they see clinical evidence for it, such as an increase in the valve’s pressure gradient or development of a TIA or stroke.* These events should trigger further investigation of the valve with CT angiography, and if thrombosis is then confirmed, the patient should receive treatment with an anticoagulant, although the appropriate duration of anticoagulant treatment remains unclear, he said in a video interview. Dr. Makkar also said that trials are needed to determine whether routine CT angiography assessment or routine prophylactic treatment with an anticoagulant is warranted because the antiplatelet therapy that patients currently receive after aortic valve replacement seems unable to prevent leaflet thrombosis.
Since this was an observational study based on data from nonrandomized registries, the findings cannot prove causality but only an association between leaflet thrombosis and TIA. They must be substantiated in further studies, including “the current Food and Drug Administration–mandated imaging substudies in randomized clinical trials.”
Dr. Makkar has received consultant fees and/or honoraria from Abbott Vascular, Medtronic, Cordis, and Entourage Medical, and research grants from Edwards Lifesciences and St. Jude Medical.
Mitchel L. Zoler contributed to this report.
Correction, 3/20/17: An earlier version of this article misstated the clinical evidence for possible leaflet thrombosis on a replaced aortic valve.
WASHINGTON – Subclinical leaflet thrombosis, as evidenced by reduced leaflet motion and corresponding hypoattenuating lesions on high-resolution CT, occurs frequently in bioprosthetic aortic valves implanted either by the transcatheter route or surgically, according to a report presented at the annual meeting of the American College of Cardiology and simultaneously published March 19 in the Lancet.
In an observational cohort study involving 890 patients enrolled in two single-center registries, reduced leaflet motion signaling the presence of thrombosis was detected in 106 patients (12%) by four-dimensional, volume-rendered CT. The thrombosis was hemodynamically silent and undetected by transthoracic echocardiograms done in a large subgroup of the study participants. Mean aortic valve gradients were numerically higher in affected patients, but still fell within the normal range in most of them, said Raj R. Makkar, MD, of Cedars-Sinai Heart Institute, Los Angeles.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Makkar and his associates studied this issue by analyzing data in the RESOLVE (Assessment of Transcatheter and Surgical Aortic Bioprosthetic Valve Thrombosis and its Treatment with Anticoagulation) registry at Cedars-Sinai and the SAVORY (Subclinical Aortic Valve Biosprosthesis Thrombosis Assessed with Four-Dimensional CT) registry at the Rigshospitalet Heart Center in Copenhagen. Their study focused on enrolled patients who underwent either TAVR (626 patients) or SAVR (264 patients) and then had high-resolution CT scans done at various times after implantation. All the CT scans were analyzed in blinded fashion, and the study participants were followed for a mean of 540 days.
The prevalence of subclinical leaflet thrombosis was significantly higher in TAVR valves (13%) than in SAVR valves (4%). The severity of the thrombosis also was significantly higher in TAVR valves, when measured by the extent of leaflet motion restriction (71.0% vs. 56.9%).
One possible reason for this discrepancy is that traumatic injury to the pericardial leaflets, which theoretically could predispose to thrombus formation, may be more likely to occur during crimping and deployment of balloon-expandable and self-expanding stent valves in TAVR. Another possibility is that resection of the calcified native aortic valves during SAVR might improve flow dynamics after valve replacement, compared with leaving native aortic valve cusps in situ during TAVR. A third possibility is that inadvertent incomplete expansion or overexpansion of transcatheter valves might alter mechanical stress on the leaflets, predisposing them to thrombus formation, compared with the uniform expansion of valves placed surgically, the investigator said.
“Nevertheless, these findings should be interpreted in the context of findings from multiple randomized controlled trials showing similar mortality and stroke rates, better hemodynamics, and equivalent durability of transcatheter aortic valves at 5 years, compared with surgical valves,” he noted.
Patients taking novel oral anticoagulants (NOACs) or warfarin for anticoagulation before valve replacement were less likely to develop subclinical leaflet thrombosis than patients not taking those anticoagulants. And the thrombosis appeared to resolve in all patients treated with NOACs or warfarin for 30 days after it was found on CT, but it persisted or progressed in those not treated with anticoagulation. Thus, “anticoagulation with NOACs or warfarin was effective in prevention and treatment of reduced leaflet motion, but dual-antiplatelet therapy, which is the standard of care, was not,” the investigators said (Lancet 2017 Mar 19. doi: 10.1016/S0140-6736(17)30757-2.
“Our study challenges the American College of Cardiology and American Heart Association and European Society of Cardiology and European Association for Cardio-Thoracic Surgery guidelines, which recommend dual-antiplatelet therapy after TAVR and do not recommend routine anticoagulation after TAVR,” he noted.
However, routine anticoagulation for all TAVR and SAVR patients, or even for all who develop leaflet thrombosis, cannot be recommended on the basis of results from a single observational study. The benefit of anticoagulation may not offset the risk of bleeding in this predominantly elderly population with multiple comorbidities, he said.
There were no significant differences between patients who developed subclinical leaflet thrombosis and those who did not regarding rates of death, MI, or stroke. However, “reduced leaflet wall motion was significantly associated with increased rates of all TIAs [transient ischemic attacks], nonprocedural TIAs, and post-CT TIAs.” Dr. Makkar said.
Based on his new findings, Dr. Makkar suggested that clinicians keep possible leaflet thrombosis on a replaced aortic valve in mind if they see clinical evidence for it, such as an increase in the valve’s pressure gradient or development of a TIA or stroke.* These events should trigger further investigation of the valve with CT angiography, and if thrombosis is then confirmed, the patient should receive treatment with an anticoagulant, although the appropriate duration of anticoagulant treatment remains unclear, he said in a video interview. Dr. Makkar also said that trials are needed to determine whether routine CT angiography assessment or routine prophylactic treatment with an anticoagulant is warranted because the antiplatelet therapy that patients currently receive after aortic valve replacement seems unable to prevent leaflet thrombosis.
Since this was an observational study based on data from nonrandomized registries, the findings cannot prove causality but only an association between leaflet thrombosis and TIA. They must be substantiated in further studies, including “the current Food and Drug Administration–mandated imaging substudies in randomized clinical trials.”
Dr. Makkar has received consultant fees and/or honoraria from Abbott Vascular, Medtronic, Cordis, and Entourage Medical, and research grants from Edwards Lifesciences and St. Jude Medical.
Mitchel L. Zoler contributed to this report.
Correction, 3/20/17: An earlier version of this article misstated the clinical evidence for possible leaflet thrombosis on a replaced aortic valve.
AT ACC 17
Key clinical point: Subclinical leaflet thrombosis occurs frequently in bioprosthetic aortic valves implanted either by the transcatheter route or surgically.
Major finding: Reduced leaflet motion signaling the presence of thrombosis was detected in 106 patients (12%).
Data source: An observational cohort study involving 890 patients enrolled in two registries who underwent high-resolution CT to detect leaflet thrombosis after either TAVR or SAVR.
Disclosures: The RESOLVE study was funded by Cedars-Sinai Heart Institute and the SAVORY study was funded by Rigshospitalet. Dr. Makkar has received consultant fees and/or honoraria from Abbott Vascular, Medtronic, Cordis, and Entourage Medical, and research grants from Edwards Lifesciences and St. Jude Medical.
Evolocumab doesn’t make patients dumb
WASHINGTON – Concerns about possible adverse cognitive effects from the new lipid-lowering drug evolocumab and from aggressive lowering of LDL cholesterol were largely put to rest with results from a nearly 2,000-patient study showing that a median 20 months of treatment with evolocumab caused no cognitive or memory decline, either compared with baseline measures or compared with similar patients randomized to placebo treatment.
A subgroup analysis in the study also showed that, even among patients who achieved and sustained LDL cholesterol below 25 mg/dL, no hint arose of an adverse effect on memory or cognition, said Dr. Giugliano, a cardiologist at Brigham and Women’s Hospital in Boston.
“Every day in my office, patients tell me that statins make you dumb. Now I can comfortably tell my patients that we studied whether this drug [evolocumab] makes you dumb, and it doesn’t; nor did having an LDL cholesterol level below 25 mg/dL,” commented Sandra J. Lewis, MD, chief of cardiology at Legacy Good Samaritan Hospital in Portland, Ore.
The primary assessment tool Dr. Giugliano and his associates used in EBBINGHAUS was the Cambridge Neuropsychological Test Automated Battery (CANTAB) Assessments, a computer-based test of spatial working memory strategy index of executive function, and 1,204 patients underwent CANTAB testing both before they received their first dose of their assigned agent and also at the end of treatment. The scores of the patients on evolocumab virtually superimposed on those of patients in the placebo group, both at baseline and at the end of treatment, easily meeting the study’s prespecified definition of noninferiority, Dr. Giugliano reported at the annual meeting of the American College of Cardiology.
The CANTAB scores also showed no change from baseline over time in the individual subgroups of both evolocumab-treated and placebo-treated patients. The total absence of a signal of mental deterioration in the placebo patients who remained on statin treatment throughout the study provided new evidence that medium-term treatment with a statin was not linked with any change in memory or cognition.
EBBINGHAUS also assessed participants using several other memory and cognition tests, had patients complete an end-of-study survey of their perceptions of their mental function, and questioned participating physicians about patients’ mental performance. None of these measures showed any signals of impairment. A full description of the range of assessments used in EBBINGHAUS appeared recently in a published article (Clin Cardiol. 2017 Feb;40[2]:59-65).
Dr. Giugliano conceded that what remains unknown at this point is the possible impact of further prolonged treatment with a PCSK9 drug or from extended maintenance of LDL cholesterol levels at very low levels, effects that could continue for decades in the routine treatment of selected patients. He noted that patients who participated in FOURIER and in EBBINGHAUS are undergoing continued follow-up to gain better insight into the longer-term effects of their treatment.
EBBINGHAUS was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has been a consultant to and received research support from Amgen and from several other drug companies. Dr. Bhatt has received research support from Amgen, from Sanofi Regeneron associated with research on another PCSK9 inhibitor, and from several other drug companies, Dr. Lewis had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
WASHINGTON – Concerns about possible adverse cognitive effects from the new lipid-lowering drug evolocumab and from aggressive lowering of LDL cholesterol were largely put to rest with results from a nearly 2,000-patient study showing that a median 20 months of treatment with evolocumab caused no cognitive or memory decline, either compared with baseline measures or compared with similar patients randomized to placebo treatment.
A subgroup analysis in the study also showed that, even among patients who achieved and sustained LDL cholesterol below 25 mg/dL, no hint arose of an adverse effect on memory or cognition, said Dr. Giugliano, a cardiologist at Brigham and Women’s Hospital in Boston.
“Every day in my office, patients tell me that statins make you dumb. Now I can comfortably tell my patients that we studied whether this drug [evolocumab] makes you dumb, and it doesn’t; nor did having an LDL cholesterol level below 25 mg/dL,” commented Sandra J. Lewis, MD, chief of cardiology at Legacy Good Samaritan Hospital in Portland, Ore.
The primary assessment tool Dr. Giugliano and his associates used in EBBINGHAUS was the Cambridge Neuropsychological Test Automated Battery (CANTAB) Assessments, a computer-based test of spatial working memory strategy index of executive function, and 1,204 patients underwent CANTAB testing both before they received their first dose of their assigned agent and also at the end of treatment. The scores of the patients on evolocumab virtually superimposed on those of patients in the placebo group, both at baseline and at the end of treatment, easily meeting the study’s prespecified definition of noninferiority, Dr. Giugliano reported at the annual meeting of the American College of Cardiology.
The CANTAB scores also showed no change from baseline over time in the individual subgroups of both evolocumab-treated and placebo-treated patients. The total absence of a signal of mental deterioration in the placebo patients who remained on statin treatment throughout the study provided new evidence that medium-term treatment with a statin was not linked with any change in memory or cognition.
EBBINGHAUS also assessed participants using several other memory and cognition tests, had patients complete an end-of-study survey of their perceptions of their mental function, and questioned participating physicians about patients’ mental performance. None of these measures showed any signals of impairment. A full description of the range of assessments used in EBBINGHAUS appeared recently in a published article (Clin Cardiol. 2017 Feb;40[2]:59-65).
Dr. Giugliano conceded that what remains unknown at this point is the possible impact of further prolonged treatment with a PCSK9 drug or from extended maintenance of LDL cholesterol levels at very low levels, effects that could continue for decades in the routine treatment of selected patients. He noted that patients who participated in FOURIER and in EBBINGHAUS are undergoing continued follow-up to gain better insight into the longer-term effects of their treatment.
EBBINGHAUS was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has been a consultant to and received research support from Amgen and from several other drug companies. Dr. Bhatt has received research support from Amgen, from Sanofi Regeneron associated with research on another PCSK9 inhibitor, and from several other drug companies, Dr. Lewis had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
WASHINGTON – Concerns about possible adverse cognitive effects from the new lipid-lowering drug evolocumab and from aggressive lowering of LDL cholesterol were largely put to rest with results from a nearly 2,000-patient study showing that a median 20 months of treatment with evolocumab caused no cognitive or memory decline, either compared with baseline measures or compared with similar patients randomized to placebo treatment.
A subgroup analysis in the study also showed that, even among patients who achieved and sustained LDL cholesterol below 25 mg/dL, no hint arose of an adverse effect on memory or cognition, said Dr. Giugliano, a cardiologist at Brigham and Women’s Hospital in Boston.
“Every day in my office, patients tell me that statins make you dumb. Now I can comfortably tell my patients that we studied whether this drug [evolocumab] makes you dumb, and it doesn’t; nor did having an LDL cholesterol level below 25 mg/dL,” commented Sandra J. Lewis, MD, chief of cardiology at Legacy Good Samaritan Hospital in Portland, Ore.
The primary assessment tool Dr. Giugliano and his associates used in EBBINGHAUS was the Cambridge Neuropsychological Test Automated Battery (CANTAB) Assessments, a computer-based test of spatial working memory strategy index of executive function, and 1,204 patients underwent CANTAB testing both before they received their first dose of their assigned agent and also at the end of treatment. The scores of the patients on evolocumab virtually superimposed on those of patients in the placebo group, both at baseline and at the end of treatment, easily meeting the study’s prespecified definition of noninferiority, Dr. Giugliano reported at the annual meeting of the American College of Cardiology.
The CANTAB scores also showed no change from baseline over time in the individual subgroups of both evolocumab-treated and placebo-treated patients. The total absence of a signal of mental deterioration in the placebo patients who remained on statin treatment throughout the study provided new evidence that medium-term treatment with a statin was not linked with any change in memory or cognition.
EBBINGHAUS also assessed participants using several other memory and cognition tests, had patients complete an end-of-study survey of their perceptions of their mental function, and questioned participating physicians about patients’ mental performance. None of these measures showed any signals of impairment. A full description of the range of assessments used in EBBINGHAUS appeared recently in a published article (Clin Cardiol. 2017 Feb;40[2]:59-65).
Dr. Giugliano conceded that what remains unknown at this point is the possible impact of further prolonged treatment with a PCSK9 drug or from extended maintenance of LDL cholesterol levels at very low levels, effects that could continue for decades in the routine treatment of selected patients. He noted that patients who participated in FOURIER and in EBBINGHAUS are undergoing continued follow-up to gain better insight into the longer-term effects of their treatment.
EBBINGHAUS was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has been a consultant to and received research support from Amgen and from several other drug companies. Dr. Bhatt has received research support from Amgen, from Sanofi Regeneron associated with research on another PCSK9 inhibitor, and from several other drug companies, Dr. Lewis had no disclosures.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT ACC 17
Key clinical point:
Major finding: Patients on evolocumab for 20 months had noninferior memory and executive function test scores, compared with patients on placebo.
Data source: EBBINGHAUS, a multicenter randomized trial with 1,974 patients.
Disclosures: EBBINGHAUS was sponsored by Amgen, the company that markets evolocumab (Repatha). Dr. Giugliano has been a consultant to and received research support from Amgen and from several other drug companies.
VIDEO: iFR outperforms FFR in two major trials
WASHINGTON – Instantaneous wave-free ratio (iFR) is the new evidence-based standard of care for invasive physiologic assessment of stable coronary lesions of intermediate angiographic severity, supplanting the older fractional flow reserve (FFR) technology, Matthias Gotberg, MD, said at the annual meeting of the American College of Cardiology.
The virtually identical results of these two trials should encourage more interventional cardiologists to incorporate physiologic assessment of stable coronary lesions into their clinical practice instead of relying solely on anatomic assessment by angiography, which abundant evidence shows is insufficiently accurate in identifying hemodynamically significant lesions warranting revascularization.
FFR never really caught on because of its limitations. DEFINE-FLAIR and iFR-SWEDEHEART show that iFR overcomes those limitations, said Dr. Gotberg, director of the cardiac catheterization laboratory at Skane University Hospital in Lund, Sweden.
The two studies showed that iFR was noninferior to FFR in the 1-year composite endpoint of all-cause mortality, nonfatal MI, or unplanned revascularization. And iFR was associated with significantly shorter procedure times, less stent utilization, and markedly less patient discomfort because, unlike FFR, it doesn’t require administration of adenosine to induce hyperemia.
Indeed, in iFR-SWEDEHEART, which included more than 2,000 randomized patients in three Scandinavian countries, only 3% of the iFR group reported experiencing chest pain, dyspnea, or other forms of discomfort during their procedure, compared with 68% of the FFR group, Dr. Gotberg explains in this video interview.[[{"fid":"192539","view_mode":"medstat_image_full_text","attributes":{"height":"390","width":"100%","class":"media-element file-medstat-image-full-text","data-delta":"1"},"fields":{"format":"medstat_image_full_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_full_text"}}}]]
WASHINGTON – Instantaneous wave-free ratio (iFR) is the new evidence-based standard of care for invasive physiologic assessment of stable coronary lesions of intermediate angiographic severity, supplanting the older fractional flow reserve (FFR) technology, Matthias Gotberg, MD, said at the annual meeting of the American College of Cardiology.
The virtually identical results of these two trials should encourage more interventional cardiologists to incorporate physiologic assessment of stable coronary lesions into their clinical practice instead of relying solely on anatomic assessment by angiography, which abundant evidence shows is insufficiently accurate in identifying hemodynamically significant lesions warranting revascularization.
FFR never really caught on because of its limitations. DEFINE-FLAIR and iFR-SWEDEHEART show that iFR overcomes those limitations, said Dr. Gotberg, director of the cardiac catheterization laboratory at Skane University Hospital in Lund, Sweden.
The two studies showed that iFR was noninferior to FFR in the 1-year composite endpoint of all-cause mortality, nonfatal MI, or unplanned revascularization. And iFR was associated with significantly shorter procedure times, less stent utilization, and markedly less patient discomfort because, unlike FFR, it doesn’t require administration of adenosine to induce hyperemia.
Indeed, in iFR-SWEDEHEART, which included more than 2,000 randomized patients in three Scandinavian countries, only 3% of the iFR group reported experiencing chest pain, dyspnea, or other forms of discomfort during their procedure, compared with 68% of the FFR group, Dr. Gotberg explains in this video interview.[[{"fid":"192539","view_mode":"medstat_image_full_text","attributes":{"height":"390","width":"100%","class":"media-element file-medstat-image-full-text","data-delta":"1"},"fields":{"format":"medstat_image_full_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_full_text"}}}]]
WASHINGTON – Instantaneous wave-free ratio (iFR) is the new evidence-based standard of care for invasive physiologic assessment of stable coronary lesions of intermediate angiographic severity, supplanting the older fractional flow reserve (FFR) technology, Matthias Gotberg, MD, said at the annual meeting of the American College of Cardiology.
The virtually identical results of these two trials should encourage more interventional cardiologists to incorporate physiologic assessment of stable coronary lesions into their clinical practice instead of relying solely on anatomic assessment by angiography, which abundant evidence shows is insufficiently accurate in identifying hemodynamically significant lesions warranting revascularization.
FFR never really caught on because of its limitations. DEFINE-FLAIR and iFR-SWEDEHEART show that iFR overcomes those limitations, said Dr. Gotberg, director of the cardiac catheterization laboratory at Skane University Hospital in Lund, Sweden.
The two studies showed that iFR was noninferior to FFR in the 1-year composite endpoint of all-cause mortality, nonfatal MI, or unplanned revascularization. And iFR was associated with significantly shorter procedure times, less stent utilization, and markedly less patient discomfort because, unlike FFR, it doesn’t require administration of adenosine to induce hyperemia.
Indeed, in iFR-SWEDEHEART, which included more than 2,000 randomized patients in three Scandinavian countries, only 3% of the iFR group reported experiencing chest pain, dyspnea, or other forms of discomfort during their procedure, compared with 68% of the FFR group, Dr. Gotberg explains in this video interview.[[{"fid":"192539","view_mode":"medstat_image_full_text","attributes":{"height":"390","width":"100%","class":"media-element file-medstat-image-full-text","data-delta":"1"},"fields":{"format":"medstat_image_full_text"},"type":"media","field_deltas":{"1":{"format":"medstat_image_full_text"}}}]]
AT ACC 17
Drugs demonstrate similar safety profile in ACS trial
WASHINGTON, DC—Results of a phase 2 trial suggest rivaroxaban and aspirin have similar safety profiles in patients with acute coronary syndrome (ACS) who are also taking a P2Y12 inhibitor.
Researchers found that, overall, the risk of bleeding was similar whether patients received aspirin or rivaroxaban.
There was no significant difference between the groups when the researchers used TIMI, GUSTO, or BARC bleeding definitions.
However, patients who received rivaroxaban did have a significantly increased risk of bleeding according to the ISTH major bleeding definition.
There was no significant difference between the treatment groups when it came to the study’s efficacy endpoints, although the researchers said the study was not adequately powered to assess efficacy.
These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and published simultaneously in The Lancet.
The study, known as GEMINI-ACS-1, was funded by Janssen Research & Development and Bayer AG.
In this trial, researchers compared rivaroxaban (given at 2.5 mg twice daily) and aspirin (at 100 mg once daily) in patients with ACS who were also receiving clopidogrel or ticagrelor for the secondary prevention of cardiovascular events.
The trial included 3037 adults with unstable angina, non-ST segment elevation myocardial infarction, or ST segment elevation myocardial infarction. Patients had positive cardiac biomarkers and either ischemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography.
Within 10 days of hospital admission for ACS, the patients were randomized to receive aspirin (n=1518) or rivaroxaban (n=1519). Patients also received clopidogrel (n=1333) or ticagrelor (n=1704) based on investigator preference.
Patients received a minimum of 180 days of study treatment. The median treatment duration was 291 days.
Safety
The study’s primary endpoint was TIMI clinically significant bleeding not related to coronary artery bypass grafting (CABG) up to day 390.
This type of bleeding occurred in 5.3% of patients in the rivaroxaban group and 4.9% of patients in the aspirin group. The hazard ratio (HR) was 1.09 (P=0.5840).
The researchers also assessed other types of bleeding and used other bleeding definitions. The HRs for these endpoints (with aspirin as the reference) were as follows.
- TIMI major bleeding, HR=1.25 (P=0.6341)
- TIMI non-CABG major bleeding, HR=1.25 (P=0.6341)
- TIMI minor bleeding, HR=2.25 (P=0.1664)
- TIMI bleeding requiring medical attention, HR=1.01 (P=0.9581)
- TIMI insignificant bleeding, HR=0.84 (P=0.5504)
- GUSTO life-threatening or severe bleeding, HR=1.50 (P=0.6571)
- GUSTO life-threatening, severe, or moderate bleeding, HR=1.58 (P=0.3395)
- GUSTO life-threatening, severe, moderate, or mild bleeding, HR=1.04 (P=0.7869)
- BARC 3a and higher bleeding, HR=1.70 (P=0.1263)
- BARC 3b and higher bleeding, HR=1.38 (P=0.4882)
- ISTH major bleeding, HR=1.83 (P=0.0420)
Efficacy
Researchers also examined several exploratory efficacy endpoints. For the composite efficacy endpoint (which included cardiovascular death, myocardial infarction, stroke, and stent thrombosis), the 2 treatment groups had similar rates.
Five percent of patients in the rivaroxaban group and 4.7% of patients in the aspirin group experienced one of these cardiovascular events. The HR was 1.06 (P=0.7316).
There was no significant difference between the treatment arms for the individual components of the efficacy endpoint or for all-cause death.
The HRs were 1.12 (P=0.7401) for cardiovascular death, 1.15 (P=0.4872) for myocardial infarction, 0.58 (P=0.2506) for stroke, 1.37 (P=0.4917) for definite stent thrombosis, and 0.95 (P=0.8771) for all-cause death.
WASHINGTON, DC—Results of a phase 2 trial suggest rivaroxaban and aspirin have similar safety profiles in patients with acute coronary syndrome (ACS) who are also taking a P2Y12 inhibitor.
Researchers found that, overall, the risk of bleeding was similar whether patients received aspirin or rivaroxaban.
There was no significant difference between the groups when the researchers used TIMI, GUSTO, or BARC bleeding definitions.
However, patients who received rivaroxaban did have a significantly increased risk of bleeding according to the ISTH major bleeding definition.
There was no significant difference between the treatment groups when it came to the study’s efficacy endpoints, although the researchers said the study was not adequately powered to assess efficacy.
These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and published simultaneously in The Lancet.
The study, known as GEMINI-ACS-1, was funded by Janssen Research & Development and Bayer AG.
In this trial, researchers compared rivaroxaban (given at 2.5 mg twice daily) and aspirin (at 100 mg once daily) in patients with ACS who were also receiving clopidogrel or ticagrelor for the secondary prevention of cardiovascular events.
The trial included 3037 adults with unstable angina, non-ST segment elevation myocardial infarction, or ST segment elevation myocardial infarction. Patients had positive cardiac biomarkers and either ischemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography.
Within 10 days of hospital admission for ACS, the patients were randomized to receive aspirin (n=1518) or rivaroxaban (n=1519). Patients also received clopidogrel (n=1333) or ticagrelor (n=1704) based on investigator preference.
Patients received a minimum of 180 days of study treatment. The median treatment duration was 291 days.
Safety
The study’s primary endpoint was TIMI clinically significant bleeding not related to coronary artery bypass grafting (CABG) up to day 390.
This type of bleeding occurred in 5.3% of patients in the rivaroxaban group and 4.9% of patients in the aspirin group. The hazard ratio (HR) was 1.09 (P=0.5840).
The researchers also assessed other types of bleeding and used other bleeding definitions. The HRs for these endpoints (with aspirin as the reference) were as follows.
- TIMI major bleeding, HR=1.25 (P=0.6341)
- TIMI non-CABG major bleeding, HR=1.25 (P=0.6341)
- TIMI minor bleeding, HR=2.25 (P=0.1664)
- TIMI bleeding requiring medical attention, HR=1.01 (P=0.9581)
- TIMI insignificant bleeding, HR=0.84 (P=0.5504)
- GUSTO life-threatening or severe bleeding, HR=1.50 (P=0.6571)
- GUSTO life-threatening, severe, or moderate bleeding, HR=1.58 (P=0.3395)
- GUSTO life-threatening, severe, moderate, or mild bleeding, HR=1.04 (P=0.7869)
- BARC 3a and higher bleeding, HR=1.70 (P=0.1263)
- BARC 3b and higher bleeding, HR=1.38 (P=0.4882)
- ISTH major bleeding, HR=1.83 (P=0.0420)
Efficacy
Researchers also examined several exploratory efficacy endpoints. For the composite efficacy endpoint (which included cardiovascular death, myocardial infarction, stroke, and stent thrombosis), the 2 treatment groups had similar rates.
Five percent of patients in the rivaroxaban group and 4.7% of patients in the aspirin group experienced one of these cardiovascular events. The HR was 1.06 (P=0.7316).
There was no significant difference between the treatment arms for the individual components of the efficacy endpoint or for all-cause death.
The HRs were 1.12 (P=0.7401) for cardiovascular death, 1.15 (P=0.4872) for myocardial infarction, 0.58 (P=0.2506) for stroke, 1.37 (P=0.4917) for definite stent thrombosis, and 0.95 (P=0.8771) for all-cause death.
WASHINGTON, DC—Results of a phase 2 trial suggest rivaroxaban and aspirin have similar safety profiles in patients with acute coronary syndrome (ACS) who are also taking a P2Y12 inhibitor.
Researchers found that, overall, the risk of bleeding was similar whether patients received aspirin or rivaroxaban.
There was no significant difference between the groups when the researchers used TIMI, GUSTO, or BARC bleeding definitions.
However, patients who received rivaroxaban did have a significantly increased risk of bleeding according to the ISTH major bleeding definition.
There was no significant difference between the treatment groups when it came to the study’s efficacy endpoints, although the researchers said the study was not adequately powered to assess efficacy.
These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and published simultaneously in The Lancet.
The study, known as GEMINI-ACS-1, was funded by Janssen Research & Development and Bayer AG.
In this trial, researchers compared rivaroxaban (given at 2.5 mg twice daily) and aspirin (at 100 mg once daily) in patients with ACS who were also receiving clopidogrel or ticagrelor for the secondary prevention of cardiovascular events.
The trial included 3037 adults with unstable angina, non-ST segment elevation myocardial infarction, or ST segment elevation myocardial infarction. Patients had positive cardiac biomarkers and either ischemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography.
Within 10 days of hospital admission for ACS, the patients were randomized to receive aspirin (n=1518) or rivaroxaban (n=1519). Patients also received clopidogrel (n=1333) or ticagrelor (n=1704) based on investigator preference.
Patients received a minimum of 180 days of study treatment. The median treatment duration was 291 days.
Safety
The study’s primary endpoint was TIMI clinically significant bleeding not related to coronary artery bypass grafting (CABG) up to day 390.
This type of bleeding occurred in 5.3% of patients in the rivaroxaban group and 4.9% of patients in the aspirin group. The hazard ratio (HR) was 1.09 (P=0.5840).
The researchers also assessed other types of bleeding and used other bleeding definitions. The HRs for these endpoints (with aspirin as the reference) were as follows.
- TIMI major bleeding, HR=1.25 (P=0.6341)
- TIMI non-CABG major bleeding, HR=1.25 (P=0.6341)
- TIMI minor bleeding, HR=2.25 (P=0.1664)
- TIMI bleeding requiring medical attention, HR=1.01 (P=0.9581)
- TIMI insignificant bleeding, HR=0.84 (P=0.5504)
- GUSTO life-threatening or severe bleeding, HR=1.50 (P=0.6571)
- GUSTO life-threatening, severe, or moderate bleeding, HR=1.58 (P=0.3395)
- GUSTO life-threatening, severe, moderate, or mild bleeding, HR=1.04 (P=0.7869)
- BARC 3a and higher bleeding, HR=1.70 (P=0.1263)
- BARC 3b and higher bleeding, HR=1.38 (P=0.4882)
- ISTH major bleeding, HR=1.83 (P=0.0420)
Efficacy
Researchers also examined several exploratory efficacy endpoints. For the composite efficacy endpoint (which included cardiovascular death, myocardial infarction, stroke, and stent thrombosis), the 2 treatment groups had similar rates.
Five percent of patients in the rivaroxaban group and 4.7% of patients in the aspirin group experienced one of these cardiovascular events. The HR was 1.06 (P=0.7316).
There was no significant difference between the treatment arms for the individual components of the efficacy endpoint or for all-cause death.
The HRs were 1.12 (P=0.7401) for cardiovascular death, 1.15 (P=0.4872) for myocardial infarction, 0.58 (P=0.2506) for stroke, 1.37 (P=0.4917) for definite stent thrombosis, and 0.95 (P=0.8771) for all-cause death.
PE patients rarely receive CDT or ST, study shows
WASHINGTON, DC—New research suggests US patients with pulmonary embolism (PE) rarely receive catheter-directed thrombolysis (CDT) or systemic thrombolysis (ST).
Investigators analyzed data from more than 100,000 patients who were hospitalized for PE and found that roughly 2% received CDT or ST.
These findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 904-12).
“For years, ST and CDT have been available for use in patients with PE,” said study investigator Srinath Adusumalli, MD, of the University of Pennsylvania in Philadelphia.
“However, there has been little research done to understand how these therapies are being utilized in the real world. Our initial data suggest that, in fact, both ST and CDT are used infrequently to treat PE, including in young, critically ill patients who may experience the highest clinical benefit from those therapies.”
Dr Adusumalli and his colleagues performed a retrospective study in which they collected data from the OptumInsight national commercial insurance claims database.
The team identified 100,744 patients who had been hospitalized with PE during a 10-year period (2004-2014). About 2% of these patients (2.2%, n=2175) received either CDT (n=761) or ST (n=1414).
During the period studied, the number of PE hospitalizations increased by 306% (P<0.001), while the number of patients treated with CDT increased by 197% (P=0.001) and the number treated with ST increased by 514% (P<0.001).
The investigators said these findings are clinically useful and could impact decisions about patient care, but more research is needed.
“This study is the first in a 2-step research plan,” noted Bram Geller, MD, of the University of Pennsylvania.
“[O]ur next phase will be to actually evaluate the safety and clinical effectiveness of CDT versus ST by exploring patient outcomes in the OptumInsight commercial insurance claims database.”
WASHINGTON, DC—New research suggests US patients with pulmonary embolism (PE) rarely receive catheter-directed thrombolysis (CDT) or systemic thrombolysis (ST).
Investigators analyzed data from more than 100,000 patients who were hospitalized for PE and found that roughly 2% received CDT or ST.
These findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 904-12).
“For years, ST and CDT have been available for use in patients with PE,” said study investigator Srinath Adusumalli, MD, of the University of Pennsylvania in Philadelphia.
“However, there has been little research done to understand how these therapies are being utilized in the real world. Our initial data suggest that, in fact, both ST and CDT are used infrequently to treat PE, including in young, critically ill patients who may experience the highest clinical benefit from those therapies.”
Dr Adusumalli and his colleagues performed a retrospective study in which they collected data from the OptumInsight national commercial insurance claims database.
The team identified 100,744 patients who had been hospitalized with PE during a 10-year period (2004-2014). About 2% of these patients (2.2%, n=2175) received either CDT (n=761) or ST (n=1414).
During the period studied, the number of PE hospitalizations increased by 306% (P<0.001), while the number of patients treated with CDT increased by 197% (P=0.001) and the number treated with ST increased by 514% (P<0.001).
The investigators said these findings are clinically useful and could impact decisions about patient care, but more research is needed.
“This study is the first in a 2-step research plan,” noted Bram Geller, MD, of the University of Pennsylvania.
“[O]ur next phase will be to actually evaluate the safety and clinical effectiveness of CDT versus ST by exploring patient outcomes in the OptumInsight commercial insurance claims database.”
WASHINGTON, DC—New research suggests US patients with pulmonary embolism (PE) rarely receive catheter-directed thrombolysis (CDT) or systemic thrombolysis (ST).
Investigators analyzed data from more than 100,000 patients who were hospitalized for PE and found that roughly 2% received CDT or ST.
These findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 904-12).
“For years, ST and CDT have been available for use in patients with PE,” said study investigator Srinath Adusumalli, MD, of the University of Pennsylvania in Philadelphia.
“However, there has been little research done to understand how these therapies are being utilized in the real world. Our initial data suggest that, in fact, both ST and CDT are used infrequently to treat PE, including in young, critically ill patients who may experience the highest clinical benefit from those therapies.”
Dr Adusumalli and his colleagues performed a retrospective study in which they collected data from the OptumInsight national commercial insurance claims database.
The team identified 100,744 patients who had been hospitalized with PE during a 10-year period (2004-2014). About 2% of these patients (2.2%, n=2175) received either CDT (n=761) or ST (n=1414).
During the period studied, the number of PE hospitalizations increased by 306% (P<0.001), while the number of patients treated with CDT increased by 197% (P=0.001) and the number treated with ST increased by 514% (P<0.001).
The investigators said these findings are clinically useful and could impact decisions about patient care, but more research is needed.
“This study is the first in a 2-step research plan,” noted Bram Geller, MD, of the University of Pennsylvania.
“[O]ur next phase will be to actually evaluate the safety and clinical effectiveness of CDT versus ST by exploring patient outcomes in the OptumInsight commercial insurance claims database.”
VIDEO: Evolocumab caused no cognitive issues in FOURIER substudy
WASHINGTON – Don’t give the cognitive effects of evolocumab a second thought, results from a preplanned substudy of the landmark FOURIER study that assessed the impact of this PCSK9 inhibitor on memory or other measures of cognition in a random subgroup of 1,973 patients enrolled in the main study suggest.
Based on these results “I wouldn’t be concerned about adverse cognitive effects” in patients treated with evolocumab (Repatha) or, for the time being, any other PCSK9 inhibitor, said Robert P. Giugliano, MD, in a video interview at the annual meeting of the American College of Cardiology”
Concerns about the cognitive effects of the drugs in this class of lipid-lowering drugs have lingered following suggestions of a possible problem that arose during earlier, much smaller studies of these agents as well as similar concerns that arose about statins that have been perpetuated through misleading posts on the Internet.
The battery of memory and cognition assessments used in EBBINGHAUS, the FOURIER substudy, should lay concerns about brain effects of evolocumab to rest, at least within the context of the median 26 months of treatment that patients in FOURIER received, said Dr. Giugliano, a cardiologist at Brigham and Women’s Hospital in Boston and lead investigator of the EBBINGHAUS substudy. Further analysis also showed that, even among patients who achieved LDL cholesterol levels of less than 25 mg/dL, treatment with evolocumab appeared to cause no deterioration of the measured mental functions.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
WASHINGTON – Don’t give the cognitive effects of evolocumab a second thought, results from a preplanned substudy of the landmark FOURIER study that assessed the impact of this PCSK9 inhibitor on memory or other measures of cognition in a random subgroup of 1,973 patients enrolled in the main study suggest.
Based on these results “I wouldn’t be concerned about adverse cognitive effects” in patients treated with evolocumab (Repatha) or, for the time being, any other PCSK9 inhibitor, said Robert P. Giugliano, MD, in a video interview at the annual meeting of the American College of Cardiology”
Concerns about the cognitive effects of the drugs in this class of lipid-lowering drugs have lingered following suggestions of a possible problem that arose during earlier, much smaller studies of these agents as well as similar concerns that arose about statins that have been perpetuated through misleading posts on the Internet.
The battery of memory and cognition assessments used in EBBINGHAUS, the FOURIER substudy, should lay concerns about brain effects of evolocumab to rest, at least within the context of the median 26 months of treatment that patients in FOURIER received, said Dr. Giugliano, a cardiologist at Brigham and Women’s Hospital in Boston and lead investigator of the EBBINGHAUS substudy. Further analysis also showed that, even among patients who achieved LDL cholesterol levels of less than 25 mg/dL, treatment with evolocumab appeared to cause no deterioration of the measured mental functions.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
WASHINGTON – Don’t give the cognitive effects of evolocumab a second thought, results from a preplanned substudy of the landmark FOURIER study that assessed the impact of this PCSK9 inhibitor on memory or other measures of cognition in a random subgroup of 1,973 patients enrolled in the main study suggest.
Based on these results “I wouldn’t be concerned about adverse cognitive effects” in patients treated with evolocumab (Repatha) or, for the time being, any other PCSK9 inhibitor, said Robert P. Giugliano, MD, in a video interview at the annual meeting of the American College of Cardiology”
Concerns about the cognitive effects of the drugs in this class of lipid-lowering drugs have lingered following suggestions of a possible problem that arose during earlier, much smaller studies of these agents as well as similar concerns that arose about statins that have been perpetuated through misleading posts on the Internet.
The battery of memory and cognition assessments used in EBBINGHAUS, the FOURIER substudy, should lay concerns about brain effects of evolocumab to rest, at least within the context of the median 26 months of treatment that patients in FOURIER received, said Dr. Giugliano, a cardiologist at Brigham and Women’s Hospital in Boston and lead investigator of the EBBINGHAUS substudy. Further analysis also showed that, even among patients who achieved LDL cholesterol levels of less than 25 mg/dL, treatment with evolocumab appeared to cause no deterioration of the measured mental functions.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT ACC 2017
Evolocumab strikes gold in FOURIER trial
WASHINGTON – The PCSK9 inhibitor evolocumab reduced the incidence of the composite endpoint of cardiovascular death, MI, or stroke by an additional 20% in patients with established cardiovascular disease who were already on background maximum-tolerated statin therapy in the landmark FOURIER trial, Marc S. Sabatine, MD, reported at the annual meeting of the American College of Cardiology.
FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was eagerly anticipated as the first dedicated cardiovascular outcomes trial to report results for a proprotein convertase subtilisin/kexin type 9 inhibitor, the novel drug class that achieves previously unattainable LDL lowering.
FOURIER randomized 27,564 patients with preexisting high-risk cardiovascular disease in 49 countries to double-blind therapy with subcutaneous evolocumab (Repatha) at either 140 mg every 2 weeks or 420 mg once monthly or to placebo injections. Participants had a baseline LDL-cholesterol level of 70 mg/dL or above while on statin therapy, which continued throughout the study. Sixty-nine percent of subjects were on high-intensity statin therapy, and the rest were on a moderate-intensity statin.
The median LDL level plunged from 92 mg/dL at baseline to 30 mg/dL in the evolocumab group, a 59% reduction. Moreover, one-quarter of patients on evolocumab achieved an LDL below 20 mg/dL. And this effect remained durable over the median 26 months of study follow-up.
“The LDL reduction achieved with evolocumab was rock steady over time,” observed Dr. Sabatine, professor of medicine at Harvard Medical School, Boston, and chair of the Thrombolysis in Myocardial Infarction Study Group.
The primary study endpoint – a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization – occurred in 11.3% of controls and 9.8% of the evolocumab group, for a significant 15% relative risk reduction. But Dr. Sabatine drew attention to the prespecified and fully powered secondary endpoint of cardiovascular death, MI, or stroke, which he considers more clinically relevant: 7.4% in controls, compared with 5.9% in the evolocumab group, for a 20% reduction in risk.
The cardiovascular benefits of greater lipid lowering grew over time. The evolocumab group’s relative risk reduction in the secondary composite endpoint was 16% in the first 12 months of follow-up and 25% beyond 12 months.
Even more impressively, the relative risk reduction in the stripped-down secondary endpoint of fatal or nonfatal MI or stroke was 19% in the first 12 months and 33%, compared with placebo, beyond 12 months.
The benefit in terms of cardiovascular risk reduction was consistent across baseline LDL subgroups, including those in the lowest baseline quartile, whose average baseline LDL was 74 mg/dL. Thus, the former LDL goal of a target below 70 mg/dL as representing maximum benefit has flown out the window.
“Even lower LDL appears to be even better, now down in this trial to 22 mg/dL,” the cardiologist declared.
There was no significant difference between the two study arms in the cardiovascular mortality rate, although Dr. Sabatine didn’t consider that surprising.
“Over the past decade, none of the trials of more intensive LDL lowering when compared with patients on moderate-intensity LDL-lowering therapy showed a significant reduction in cardiovascular mortality, which thankfully is now less common after acute MI and acute stroke than it had been in the past,” he said.
The number needed to treat (NNT) in order to prevent one additional cardiovascular death, MI, or stroke, based upon the current 3-year follow-up data, is roughly 50, according to Dr. Sabatine. Projecting out to 5 years, based upon the close fit between FOURIER and the data from the Cholesterol Treatment Trialists Collaboration, the NNT at 5 years for evolocumab is about 30, although the true NNT may actually prove to be smaller than that, given the steadily increasing benefit seen through 3 years. The projected 5-year NNT for the composite of coronary revascularization, cardiovascular death, MI, or stroke drops to about 20, he added.
The treatment was safe and well tolerated. The rate of study discontinuation attributable to treatment-related adverse events was low, at about 1.5% in both treatment arms. The rates of neurocognitive adverse events, new-onset diabetes, cataracts, and muscle-related complaints didn’t differ between the evolocumab and placebo groups, either. Of note, no one developed neutralizing antibodies to evolocumab. Long-term follow-up will continue in roughly 6,000 FOURIER participants.
Discussant Pamela B. Morris, MD, said FOURIER contains an important secondary message that mustn’t get lost in the enthusiasm for a safe and effective new drug.
“I’m very struck by the high event rate in this population, even with LDL levels down to 30 mg/dL. I think what that says is that although LDL cholesterol is etiologic and incredibly important, there were multiple other risk factors in this population, and given a 4.2% event rate per year despite achieving a very low LDL, we can’t take our foot off the gas in terms of other risk factors,” said Dr. Morris of the Medical University of South Carolina, Charleston.
Discussant Sidney C. Smith Jr., MD, a member of the 2013 ACC/AHA cholesterol treatment guidelines committee, which did away with LDL lowering to a target level in favor of a risk-based approach which embraced percent reduction in LDL as a therapeutic goal, asked Dr. Sabatine if it’s time for the committee to revisit and perhaps restore the concept of shooting for an LDL target range.
“We labored with that in the 2013 guidelines, as to whether there’s some optimal range for LDL or one can look at percent reduction as an indicator,” noted Dr. Smith, professor of medicine at the University of North Carolina in Chapel Hill.
Dr. Sabatine replied, “Dr. [Eugene] Braunwald has made the analogy that if this was smoking, we wouldn’t want people to just reduce their amount of smoking by 50%, we’d want them to reduce it to zero cigarettes.”
The investigator added, “My own feeling is that the benefit is more closely related to the absolute reduction than the percent reduction in LDL, and like any other risk factor, you want to get it down as low as you can go.”
In a later video interview, Dr. Smith said that the FOURIER data make a strong case – at least in these first years of what will be much-longer-term drug therapy – that a target LDL in the range of 25-35 mg/dL may be optimal in a very-high-risk patient population.
Dr. Sabatine reported receiving grant support and consultant fees from Amgen, which funded the FOURIER trial.
Simultaneous with his presentation at the ACC meeting, the FOURIER results were published online at NEJM.org (doi: 10.1056/NEJMoa1615664).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
WASHINGTON – The PCSK9 inhibitor evolocumab reduced the incidence of the composite endpoint of cardiovascular death, MI, or stroke by an additional 20% in patients with established cardiovascular disease who were already on background maximum-tolerated statin therapy in the landmark FOURIER trial, Marc S. Sabatine, MD, reported at the annual meeting of the American College of Cardiology.
FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was eagerly anticipated as the first dedicated cardiovascular outcomes trial to report results for a proprotein convertase subtilisin/kexin type 9 inhibitor, the novel drug class that achieves previously unattainable LDL lowering.
FOURIER randomized 27,564 patients with preexisting high-risk cardiovascular disease in 49 countries to double-blind therapy with subcutaneous evolocumab (Repatha) at either 140 mg every 2 weeks or 420 mg once monthly or to placebo injections. Participants had a baseline LDL-cholesterol level of 70 mg/dL or above while on statin therapy, which continued throughout the study. Sixty-nine percent of subjects were on high-intensity statin therapy, and the rest were on a moderate-intensity statin.
The median LDL level plunged from 92 mg/dL at baseline to 30 mg/dL in the evolocumab group, a 59% reduction. Moreover, one-quarter of patients on evolocumab achieved an LDL below 20 mg/dL. And this effect remained durable over the median 26 months of study follow-up.
“The LDL reduction achieved with evolocumab was rock steady over time,” observed Dr. Sabatine, professor of medicine at Harvard Medical School, Boston, and chair of the Thrombolysis in Myocardial Infarction Study Group.
The primary study endpoint – a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization – occurred in 11.3% of controls and 9.8% of the evolocumab group, for a significant 15% relative risk reduction. But Dr. Sabatine drew attention to the prespecified and fully powered secondary endpoint of cardiovascular death, MI, or stroke, which he considers more clinically relevant: 7.4% in controls, compared with 5.9% in the evolocumab group, for a 20% reduction in risk.
The cardiovascular benefits of greater lipid lowering grew over time. The evolocumab group’s relative risk reduction in the secondary composite endpoint was 16% in the first 12 months of follow-up and 25% beyond 12 months.
Even more impressively, the relative risk reduction in the stripped-down secondary endpoint of fatal or nonfatal MI or stroke was 19% in the first 12 months and 33%, compared with placebo, beyond 12 months.
The benefit in terms of cardiovascular risk reduction was consistent across baseline LDL subgroups, including those in the lowest baseline quartile, whose average baseline LDL was 74 mg/dL. Thus, the former LDL goal of a target below 70 mg/dL as representing maximum benefit has flown out the window.
“Even lower LDL appears to be even better, now down in this trial to 22 mg/dL,” the cardiologist declared.
There was no significant difference between the two study arms in the cardiovascular mortality rate, although Dr. Sabatine didn’t consider that surprising.
“Over the past decade, none of the trials of more intensive LDL lowering when compared with patients on moderate-intensity LDL-lowering therapy showed a significant reduction in cardiovascular mortality, which thankfully is now less common after acute MI and acute stroke than it had been in the past,” he said.
The number needed to treat (NNT) in order to prevent one additional cardiovascular death, MI, or stroke, based upon the current 3-year follow-up data, is roughly 50, according to Dr. Sabatine. Projecting out to 5 years, based upon the close fit between FOURIER and the data from the Cholesterol Treatment Trialists Collaboration, the NNT at 5 years for evolocumab is about 30, although the true NNT may actually prove to be smaller than that, given the steadily increasing benefit seen through 3 years. The projected 5-year NNT for the composite of coronary revascularization, cardiovascular death, MI, or stroke drops to about 20, he added.
The treatment was safe and well tolerated. The rate of study discontinuation attributable to treatment-related adverse events was low, at about 1.5% in both treatment arms. The rates of neurocognitive adverse events, new-onset diabetes, cataracts, and muscle-related complaints didn’t differ between the evolocumab and placebo groups, either. Of note, no one developed neutralizing antibodies to evolocumab. Long-term follow-up will continue in roughly 6,000 FOURIER participants.
Discussant Pamela B. Morris, MD, said FOURIER contains an important secondary message that mustn’t get lost in the enthusiasm for a safe and effective new drug.
“I’m very struck by the high event rate in this population, even with LDL levels down to 30 mg/dL. I think what that says is that although LDL cholesterol is etiologic and incredibly important, there were multiple other risk factors in this population, and given a 4.2% event rate per year despite achieving a very low LDL, we can’t take our foot off the gas in terms of other risk factors,” said Dr. Morris of the Medical University of South Carolina, Charleston.
Discussant Sidney C. Smith Jr., MD, a member of the 2013 ACC/AHA cholesterol treatment guidelines committee, which did away with LDL lowering to a target level in favor of a risk-based approach which embraced percent reduction in LDL as a therapeutic goal, asked Dr. Sabatine if it’s time for the committee to revisit and perhaps restore the concept of shooting for an LDL target range.
“We labored with that in the 2013 guidelines, as to whether there’s some optimal range for LDL or one can look at percent reduction as an indicator,” noted Dr. Smith, professor of medicine at the University of North Carolina in Chapel Hill.
Dr. Sabatine replied, “Dr. [Eugene] Braunwald has made the analogy that if this was smoking, we wouldn’t want people to just reduce their amount of smoking by 50%, we’d want them to reduce it to zero cigarettes.”
The investigator added, “My own feeling is that the benefit is more closely related to the absolute reduction than the percent reduction in LDL, and like any other risk factor, you want to get it down as low as you can go.”
In a later video interview, Dr. Smith said that the FOURIER data make a strong case – at least in these first years of what will be much-longer-term drug therapy – that a target LDL in the range of 25-35 mg/dL may be optimal in a very-high-risk patient population.
Dr. Sabatine reported receiving grant support and consultant fees from Amgen, which funded the FOURIER trial.
Simultaneous with his presentation at the ACC meeting, the FOURIER results were published online at NEJM.org (doi: 10.1056/NEJMoa1615664).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
WASHINGTON – The PCSK9 inhibitor evolocumab reduced the incidence of the composite endpoint of cardiovascular death, MI, or stroke by an additional 20% in patients with established cardiovascular disease who were already on background maximum-tolerated statin therapy in the landmark FOURIER trial, Marc S. Sabatine, MD, reported at the annual meeting of the American College of Cardiology.
FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was eagerly anticipated as the first dedicated cardiovascular outcomes trial to report results for a proprotein convertase subtilisin/kexin type 9 inhibitor, the novel drug class that achieves previously unattainable LDL lowering.
FOURIER randomized 27,564 patients with preexisting high-risk cardiovascular disease in 49 countries to double-blind therapy with subcutaneous evolocumab (Repatha) at either 140 mg every 2 weeks or 420 mg once monthly or to placebo injections. Participants had a baseline LDL-cholesterol level of 70 mg/dL or above while on statin therapy, which continued throughout the study. Sixty-nine percent of subjects were on high-intensity statin therapy, and the rest were on a moderate-intensity statin.
The median LDL level plunged from 92 mg/dL at baseline to 30 mg/dL in the evolocumab group, a 59% reduction. Moreover, one-quarter of patients on evolocumab achieved an LDL below 20 mg/dL. And this effect remained durable over the median 26 months of study follow-up.
“The LDL reduction achieved with evolocumab was rock steady over time,” observed Dr. Sabatine, professor of medicine at Harvard Medical School, Boston, and chair of the Thrombolysis in Myocardial Infarction Study Group.
The primary study endpoint – a composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization – occurred in 11.3% of controls and 9.8% of the evolocumab group, for a significant 15% relative risk reduction. But Dr. Sabatine drew attention to the prespecified and fully powered secondary endpoint of cardiovascular death, MI, or stroke, which he considers more clinically relevant: 7.4% in controls, compared with 5.9% in the evolocumab group, for a 20% reduction in risk.
The cardiovascular benefits of greater lipid lowering grew over time. The evolocumab group’s relative risk reduction in the secondary composite endpoint was 16% in the first 12 months of follow-up and 25% beyond 12 months.
Even more impressively, the relative risk reduction in the stripped-down secondary endpoint of fatal or nonfatal MI or stroke was 19% in the first 12 months and 33%, compared with placebo, beyond 12 months.
The benefit in terms of cardiovascular risk reduction was consistent across baseline LDL subgroups, including those in the lowest baseline quartile, whose average baseline LDL was 74 mg/dL. Thus, the former LDL goal of a target below 70 mg/dL as representing maximum benefit has flown out the window.
“Even lower LDL appears to be even better, now down in this trial to 22 mg/dL,” the cardiologist declared.
There was no significant difference between the two study arms in the cardiovascular mortality rate, although Dr. Sabatine didn’t consider that surprising.
“Over the past decade, none of the trials of more intensive LDL lowering when compared with patients on moderate-intensity LDL-lowering therapy showed a significant reduction in cardiovascular mortality, which thankfully is now less common after acute MI and acute stroke than it had been in the past,” he said.
The number needed to treat (NNT) in order to prevent one additional cardiovascular death, MI, or stroke, based upon the current 3-year follow-up data, is roughly 50, according to Dr. Sabatine. Projecting out to 5 years, based upon the close fit between FOURIER and the data from the Cholesterol Treatment Trialists Collaboration, the NNT at 5 years for evolocumab is about 30, although the true NNT may actually prove to be smaller than that, given the steadily increasing benefit seen through 3 years. The projected 5-year NNT for the composite of coronary revascularization, cardiovascular death, MI, or stroke drops to about 20, he added.
The treatment was safe and well tolerated. The rate of study discontinuation attributable to treatment-related adverse events was low, at about 1.5% in both treatment arms. The rates of neurocognitive adverse events, new-onset diabetes, cataracts, and muscle-related complaints didn’t differ between the evolocumab and placebo groups, either. Of note, no one developed neutralizing antibodies to evolocumab. Long-term follow-up will continue in roughly 6,000 FOURIER participants.
Discussant Pamela B. Morris, MD, said FOURIER contains an important secondary message that mustn’t get lost in the enthusiasm for a safe and effective new drug.
“I’m very struck by the high event rate in this population, even with LDL levels down to 30 mg/dL. I think what that says is that although LDL cholesterol is etiologic and incredibly important, there were multiple other risk factors in this population, and given a 4.2% event rate per year despite achieving a very low LDL, we can’t take our foot off the gas in terms of other risk factors,” said Dr. Morris of the Medical University of South Carolina, Charleston.
Discussant Sidney C. Smith Jr., MD, a member of the 2013 ACC/AHA cholesterol treatment guidelines committee, which did away with LDL lowering to a target level in favor of a risk-based approach which embraced percent reduction in LDL as a therapeutic goal, asked Dr. Sabatine if it’s time for the committee to revisit and perhaps restore the concept of shooting for an LDL target range.
“We labored with that in the 2013 guidelines, as to whether there’s some optimal range for LDL or one can look at percent reduction as an indicator,” noted Dr. Smith, professor of medicine at the University of North Carolina in Chapel Hill.
Dr. Sabatine replied, “Dr. [Eugene] Braunwald has made the analogy that if this was smoking, we wouldn’t want people to just reduce their amount of smoking by 50%, we’d want them to reduce it to zero cigarettes.”
The investigator added, “My own feeling is that the benefit is more closely related to the absolute reduction than the percent reduction in LDL, and like any other risk factor, you want to get it down as low as you can go.”
In a later video interview, Dr. Smith said that the FOURIER data make a strong case – at least in these first years of what will be much-longer-term drug therapy – that a target LDL in the range of 25-35 mg/dL may be optimal in a very-high-risk patient population.
Dr. Sabatine reported receiving grant support and consultant fees from Amgen, which funded the FOURIER trial.
Simultaneous with his presentation at the ACC meeting, the FOURIER results were published online at NEJM.org (doi: 10.1056/NEJMoa1615664).
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Key clinical point:
Major finding: The projected NNT with evolocumab for 5 years in order to prevent one additional cardiovascular death, MI, or stroke is roughly 30 patients.
Data source: The FOURIER trial was a randomized, double-blind, placebo-controlled trial including more than 27,000 patients with high-risk cardiovascular disease on background statin therapy.
Disclosures: The presenter reported receiving grant support and consultant fees from Amgen, which funded the study.