ESC Congress 2013

Treatment with the renin inhibitor aliskiren did not improve or slow the progression of coronary atherosclerosis in patients with prehypertension and coronary artery disease, according to the prospective, randomized, placebo-controlled Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS).

The change in the primary efficacy measure – percent atheroma volume (PAV) from baseline to completion – did not differ significantly in 225 subjects who were randomized to receive 300 mg of aliskiren for 104 weeks and 233 subjects who were randomized to receive a placebo (–0.33% vs. 0.11%, respectively), Dr. Stephen J. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, Australia and his colleagues reported.

A secondary efficacy parameter – the change from baseline in normalized total atheroma volume (TAV) – also did not differ between the aliskiren and placebo groups (–4.1 mm³ vs. –2.1 mm³), and no significant differences were seen between the groups in the proportion of participants who experienced regression of PAV (56.9% vs. 48.9%) and TAV (64.4% vs. 57.5%), the investigators reported at the annual congress of the European Society of Cardiology.

The findings were simultaneously published online Sept. 3 in JAMA.

Patients included in AQUARIUS were adults over age 35 years with coronary artery disease and prehypertension, with systolic blood pressure of 125-139 mm Hg, and diastolic blood pressure less than 90 mm Hg, and with two additional cardiovascular risk factors. They were enrolled during March 2009–February 2011 at 103 participating academic and community hospitals in Europe, Australia, North America, and South America. At baseline, after coronary angiography, they underwent coronary intravascular ultrasound (IVUS) imaging.

A total of 613 participants were enrolled and treated with 150 mg of aliskiren for a 1-week run-in period before randomization. After 104 weeks, three-quarters of the patients, or 458, had a second IVUS on the same vessel (JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169]).

Patients with diabetes were withdrawn during the study period after a product label change warned that concomitant use of aliskiren in patients with diabetes who were treated with an ACE inhibitor or angiotensin receptor blocker was contraindicated; this alteration in the trial represents "a factor potentially confounding interpretation," the investigators noted.

Nonetheless, the study is among the first to evaluate the effect of renin inhibition on atherosclerotic plaque in patients with coronary atherosclerosis whose blood pressure was considered optimally controlled, they said.

"The benefit of additional blood pressure lowering agents in patients who have reached treatment goals has not been established. However, few trials have examined the benefits and risks of further intensifying blood pressure treatment in patient with established coronary artery disease (CAD) who are in the prehypertension range," they said.

Since renin-angiotensin-aldosterone system (RAAS) activation is known to play an important role in atherosclerosis, and since RAAS inhibition may have a direct beneficial effect on the artery wall, the investigators sought to determine if aliskiren, a direct renin inhibitor, would slow progression of coronary atherosclerosis in these patients.

"Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration," they wrote.

However, the primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between those who received aliskiren and those who received placebo.

"During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group (26 vs. 50). Although these exploratory findings support the hypothesis of potential beneficial effects of renin inhibition in patients with preexisting CAD and blood pressure levels treated to goal, the current clinical findings are inconclusive. Definitive demonstration of a clinical outcome benefit will require a larger, adequately powered clinical trial with cardiovascular events prespecified as the primary end point," they said.

This study was sponsored by Novartis Pharmaceuticals. Dr. Nicholls reported receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix; and receiving honoraria from or serving as a consultant to AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Other authors also reported having disclosures. Details are available with the full text of the article at JAMA.com.

Treatment with the renin inhibitor aliskiren did not improve or slow the progression of coronary atherosclerosis in patients with prehypertension and coronary artery disease, according to the prospective, randomized, placebo-controlled Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS).

The change in the primary efficacy measure – percent atheroma volume (PAV) from baseline to completion – did not differ significantly in 225 subjects who were randomized to receive 300 mg of aliskiren for 104 weeks and 233 subjects who were randomized to receive a placebo (–0.33% vs. 0.11%, respectively), Dr. Stephen J. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, Australia and his colleagues reported.

A secondary efficacy parameter – the change from baseline in normalized total atheroma volume (TAV) – also did not differ between the aliskiren and placebo groups (–4.1 mm³ vs. –2.1 mm³), and no significant differences were seen between the groups in the proportion of participants who experienced regression of PAV (56.9% vs. 48.9%) and TAV (64.4% vs. 57.5%), the investigators reported at the annual congress of the European Society of Cardiology.

The findings were simultaneously published online Sept. 3 in JAMA.

Patients included in AQUARIUS were adults over age 35 years with coronary artery disease and prehypertension, with systolic blood pressure of 125-139 mm Hg, and diastolic blood pressure less than 90 mm Hg, and with two additional cardiovascular risk factors. They were enrolled during March 2009–February 2011 at 103 participating academic and community hospitals in Europe, Australia, North America, and South America. At baseline, after coronary angiography, they underwent coronary intravascular ultrasound (IVUS) imaging.

A total of 613 participants were enrolled and treated with 150 mg of aliskiren for a 1-week run-in period before randomization. After 104 weeks, three-quarters of the patients, or 458, had a second IVUS on the same vessel (JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169]).

Patients with diabetes were withdrawn during the study period after a product label change warned that concomitant use of aliskiren in patients with diabetes who were treated with an ACE inhibitor or angiotensin receptor blocker was contraindicated; this alteration in the trial represents "a factor potentially confounding interpretation," the investigators noted.

Nonetheless, the study is among the first to evaluate the effect of renin inhibition on atherosclerotic plaque in patients with coronary atherosclerosis whose blood pressure was considered optimally controlled, they said.

"The benefit of additional blood pressure lowering agents in patients who have reached treatment goals has not been established. However, few trials have examined the benefits and risks of further intensifying blood pressure treatment in patient with established coronary artery disease (CAD) who are in the prehypertension range," they said.

Since renin-angiotensin-aldosterone system (RAAS) activation is known to play an important role in atherosclerosis, and since RAAS inhibition may have a direct beneficial effect on the artery wall, the investigators sought to determine if aliskiren, a direct renin inhibitor, would slow progression of coronary atherosclerosis in these patients.

"Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration," they wrote.

However, the primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between those who received aliskiren and those who received placebo.

"During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group (26 vs. 50). Although these exploratory findings support the hypothesis of potential beneficial effects of renin inhibition in patients with preexisting CAD and blood pressure levels treated to goal, the current clinical findings are inconclusive. Definitive demonstration of a clinical outcome benefit will require a larger, adequately powered clinical trial with cardiovascular events prespecified as the primary end point," they said.

This study was sponsored by Novartis Pharmaceuticals. Dr. Nicholls reported receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix; and receiving honoraria from or serving as a consultant to AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Other authors also reported having disclosures. Details are available with the full text of the article at JAMA.com.

Treatment with the renin inhibitor aliskiren did not improve or slow the progression of coronary atherosclerosis in patients with prehypertension and coronary artery disease, according to the prospective, randomized, placebo-controlled Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS).

The change in the primary efficacy measure – percent atheroma volume (PAV) from baseline to completion – did not differ significantly in 225 subjects who were randomized to receive 300 mg of aliskiren for 104 weeks and 233 subjects who were randomized to receive a placebo (–0.33% vs. 0.11%, respectively), Dr. Stephen J. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, Australia and his colleagues reported.

A secondary efficacy parameter – the change from baseline in normalized total atheroma volume (TAV) – also did not differ between the aliskiren and placebo groups (–4.1 mm³ vs. –2.1 mm³), and no significant differences were seen between the groups in the proportion of participants who experienced regression of PAV (56.9% vs. 48.9%) and TAV (64.4% vs. 57.5%), the investigators reported at the annual congress of the European Society of Cardiology.

The findings were simultaneously published online Sept. 3 in JAMA.

Patients included in AQUARIUS were adults over age 35 years with coronary artery disease and prehypertension, with systolic blood pressure of 125-139 mm Hg, and diastolic blood pressure less than 90 mm Hg, and with two additional cardiovascular risk factors. They were enrolled during March 2009–February 2011 at 103 participating academic and community hospitals in Europe, Australia, North America, and South America. At baseline, after coronary angiography, they underwent coronary intravascular ultrasound (IVUS) imaging.

A total of 613 participants were enrolled and treated with 150 mg of aliskiren for a 1-week run-in period before randomization. After 104 weeks, three-quarters of the patients, or 458, had a second IVUS on the same vessel (JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169]).

Patients with diabetes were withdrawn during the study period after a product label change warned that concomitant use of aliskiren in patients with diabetes who were treated with an ACE inhibitor or angiotensin receptor blocker was contraindicated; this alteration in the trial represents "a factor potentially confounding interpretation," the investigators noted.

Nonetheless, the study is among the first to evaluate the effect of renin inhibition on atherosclerotic plaque in patients with coronary atherosclerosis whose blood pressure was considered optimally controlled, they said.

"The benefit of additional blood pressure lowering agents in patients who have reached treatment goals has not been established. However, few trials have examined the benefits and risks of further intensifying blood pressure treatment in patient with established coronary artery disease (CAD) who are in the prehypertension range," they said.

Since renin-angiotensin-aldosterone system (RAAS) activation is known to play an important role in atherosclerosis, and since RAAS inhibition may have a direct beneficial effect on the artery wall, the investigators sought to determine if aliskiren, a direct renin inhibitor, would slow progression of coronary atherosclerosis in these patients.

"Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration," they wrote.

However, the primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between those who received aliskiren and those who received placebo.

"During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group (26 vs. 50). Although these exploratory findings support the hypothesis of potential beneficial effects of renin inhibition in patients with preexisting CAD and blood pressure levels treated to goal, the current clinical findings are inconclusive. Definitive demonstration of a clinical outcome benefit will require a larger, adequately powered clinical trial with cardiovascular events prespecified as the primary end point," they said.

This study was sponsored by Novartis Pharmaceuticals. Dr. Nicholls reported receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix; and receiving honoraria from or serving as a consultant to AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Other authors also reported having disclosures. Details are available with the full text of the article at JAMA.com.

AMSTERDAM – The growing role for the new factor Xa inhibitors in treating acute venous thromboembolism received another boost with the performance of a new drug from the class, edoxaban, in a pivotal, randomized, international trial with more than 8,000 patients.

Edoxaban showed noninferior efficacy and superior safety compared with the standard treatment, warfarin, during 12 months of follow-up, performance that closely matched prior results for the first two direct factor Xa inhibitors that were tested for treating venous thromboembolism (VTE), rivaroxaban (Xarelto) and apixaban (Eliquis). The edoxaban trial also showed an important new feature for drugs in this class, a statistically significant benefit compared with warfarin in the roughly one-third of enrolled patients with a severe pulmonary embolism causing right ventricular dysfunction.

"The most interesting observation is that the third of patients [with pulmonary embolism and] with right ventricular dysfunction were better off with edoxaban," Dr. Harry R. Büller said at the European Society of Cardiology Congress 2013.

"A criticism raised with [the pivotal rivaroxaban and apixaban trials treating acute VTE] was that the investigators were reluctant not to use low molecular weight heparin in the patients with large clots. In that group we’ve made a novel observation" in this prespecified subgroup analysis, said Dr. Büller, professor and chairman of vascular medicine at the Academic Medical Center in Amsterdam.

Investigators in the edoxaban trial may have been more willing to enroll their severely ill VTE patients because the treatment regimens compared began all patients with at least 5 days of treatment with either enoxaparin or unfractionated heparin. Intravenous treatment stopped after about a week and then continued with either oral warfarin or edoxaban. This treatment strategy contrasted with the prior rivaroxaban (EINSTEIN, N. Engl. J. Med. 2012;366:1287-97 and apixaban (AMPLIFY, N. Engl. J. Med. 2013;369:799-808) pivotal studies that began acute VTE patients on the oral drugs from the start of treatment. In the edoxaban study, participating physicians enrolled "the full spectrum of VTE patients," Dr. Büller said.

Physicians "feel comfortable intervening with heparin in these patients because you have quick, intravenous treatment with an anticoagulant," commented Dr. William A. Zoghbi, professor of medicine and director of the Cardiovascular Imaging Institute at the Debakey Heart and Vascular Center at Methodist Hospital in Houston. The results showing superior efficacy of edoxaban over warfarin in the most severely affected pulmonary embolism patients "makes you more confident that in the higher-risk patients edoxaban was not only not inferior but may even have an advantage," Dr. Zoghbi said in an interview.

The Hokusai-VTE trial randomized 4,921 patients with deep-vein thrombosis and 3,319 patients with pulmonary embolism at 439 centers in 37 countries during January 2010–October 2012. Patients averaged 56 years of age, a bit more than half were men, and they received heparin for a median of 7 days.

After 1 year, the primary efficacy endpoint of recurrent VTE in all patients occurred in 3.2% of the 4,118 patients randomized to received edoxaban and in 3.5% of the 4,122 randomized to receive warfarin, results that meet the study’s criterion for noninferiority.

Among the prespecified subgroup of pulmonary embolism patients with a larger clot and inferred right-ventricular dysfunction – based on both the anatomic size of their clot and on their blood level of N-terminal pro-brain natriuretic peptide – the rate of recurrent VTE during follow-up was 3.3% in the edoxaban group and 6.2% in the warfarin group, a statistically significant difference.

The study’s primary safety outcome was the rate of clinically relevant major or nonmajor bleeds, which occurred in 8.5% of the edoxaban patients and in 10.3% of the warfarin patients, for a relative hazard reduction of 19% by edoxaban that was statistically significant for superiority, reported Dr. Büller. Concurrent with his talk at the meeting a report of the trial results was published online (N. Engl. J. Med. 2013;doi:10.1056NEJMoa1306638).

The safety data also showed that the edoxaban-treated patients had a total of 5 intracranial or retroperitoneal bleeds, compared with 22 in the patients treated with warfarin, a difference that Dr. Büller said he believed was real and due to the effect of warfarin on clotting factor VII, and is something that has also been seen in the trials testing the other new factor Xa inhibitors.

The Hokusai-VTE study is unique among the trials of oral factor Xa inhibitors by being the only study that allowed for a flexible duration of anticoagulation treatment, followed all patients for 12 months, and used imaging and biomarkers to risk-stratify patients to prove efficacy in patients with severe pulmonary embolism, commented Dr. Stavros V. Konstantinides, professor and deputy scientific director of the Center for Thrombosis and Haemostasis of Johannes Gutenberg University in Mainz, Germany.

The data collected on all three oral factor X inhibitors so far suggest that they all are "noninferior to standard treatment and are also not inferior and most likely superior for safety, with apixaban showing the best safety profile so far," said Dr. Konstantinides, who was the designated discussant for Dr. Büller’s report. But Dr. Konstantinides also warned that these new drugs will need to "justify their high cost" by showing improvements in patient satisfaction with their treatment and quality of life, and by lowering overall health-care costs by lowering the number of rehospitalizations in VTE patients.

Hokusai-VTE was sponsored by Daiichi-Sankyo, the company developing endoxaban. Dr. Büller said that he has received honoraria from Daiichi Sankyo, as well as from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, Isis, and Thrombogenics. Dr. Büller also served as a principal investigator for the VTE pivotal trials of rivaroxaban and apixaban. Dr. Zoghbi said that he had no relevant disclosures. Dr. Konstantinides has been a speaker for and an advisor to Boehringer Ingelheim, Bayer, and Pfizer/Bristol-Myers Squibb.

[email protected]

Twitter:@mitchelzoler

AMSTERDAM – The growing role for the new factor Xa inhibitors in treating acute venous thromboembolism received another boost with the performance of a new drug from the class, edoxaban, in a pivotal, randomized, international trial with more than 8,000 patients.

Edoxaban showed noninferior efficacy and superior safety compared with the standard treatment, warfarin, during 12 months of follow-up, performance that closely matched prior results for the first two direct factor Xa inhibitors that were tested for treating venous thromboembolism (VTE), rivaroxaban (Xarelto) and apixaban (Eliquis). The edoxaban trial also showed an important new feature for drugs in this class, a statistically significant benefit compared with warfarin in the roughly one-third of enrolled patients with a severe pulmonary embolism causing right ventricular dysfunction.

"The most interesting observation is that the third of patients [with pulmonary embolism and] with right ventricular dysfunction were better off with edoxaban," Dr. Harry R. Büller said at the European Society of Cardiology Congress 2013.

"A criticism raised with [the pivotal rivaroxaban and apixaban trials treating acute VTE] was that the investigators were reluctant not to use low molecular weight heparin in the patients with large clots. In that group we’ve made a novel observation" in this prespecified subgroup analysis, said Dr. Büller, professor and chairman of vascular medicine at the Academic Medical Center in Amsterdam.

Investigators in the edoxaban trial may have been more willing to enroll their severely ill VTE patients because the treatment regimens compared began all patients with at least 5 days of treatment with either enoxaparin or unfractionated heparin. Intravenous treatment stopped after about a week and then continued with either oral warfarin or edoxaban. This treatment strategy contrasted with the prior rivaroxaban (EINSTEIN, N. Engl. J. Med. 2012;366:1287-97 and apixaban (AMPLIFY, N. Engl. J. Med. 2013;369:799-808) pivotal studies that began acute VTE patients on the oral drugs from the start of treatment. In the edoxaban study, participating physicians enrolled "the full spectrum of VTE patients," Dr. Büller said.

Physicians "feel comfortable intervening with heparin in these patients because you have quick, intravenous treatment with an anticoagulant," commented Dr. William A. Zoghbi, professor of medicine and director of the Cardiovascular Imaging Institute at the Debakey Heart and Vascular Center at Methodist Hospital in Houston. The results showing superior efficacy of edoxaban over warfarin in the most severely affected pulmonary embolism patients "makes you more confident that in the higher-risk patients edoxaban was not only not inferior but may even have an advantage," Dr. Zoghbi said in an interview.

The Hokusai-VTE trial randomized 4,921 patients with deep-vein thrombosis and 3,319 patients with pulmonary embolism at 439 centers in 37 countries during January 2010–October 2012. Patients averaged 56 years of age, a bit more than half were men, and they received heparin for a median of 7 days.

After 1 year, the primary efficacy endpoint of recurrent VTE in all patients occurred in 3.2% of the 4,118 patients randomized to received edoxaban and in 3.5% of the 4,122 randomized to receive warfarin, results that meet the study’s criterion for noninferiority.

Among the prespecified subgroup of pulmonary embolism patients with a larger clot and inferred right-ventricular dysfunction – based on both the anatomic size of their clot and on their blood level of N-terminal pro-brain natriuretic peptide – the rate of recurrent VTE during follow-up was 3.3% in the edoxaban group and 6.2% in the warfarin group, a statistically significant difference.

The study’s primary safety outcome was the rate of clinically relevant major or nonmajor bleeds, which occurred in 8.5% of the edoxaban patients and in 10.3% of the warfarin patients, for a relative hazard reduction of 19% by edoxaban that was statistically significant for superiority, reported Dr. Büller. Concurrent with his talk at the meeting a report of the trial results was published online (N. Engl. J. Med. 2013;doi:10.1056NEJMoa1306638).

The safety data also showed that the edoxaban-treated patients had a total of 5 intracranial or retroperitoneal bleeds, compared with 22 in the patients treated with warfarin, a difference that Dr. Büller said he believed was real and due to the effect of warfarin on clotting factor VII, and is something that has also been seen in the trials testing the other new factor Xa inhibitors.

The Hokusai-VTE study is unique among the trials of oral factor Xa inhibitors by being the only study that allowed for a flexible duration of anticoagulation treatment, followed all patients for 12 months, and used imaging and biomarkers to risk-stratify patients to prove efficacy in patients with severe pulmonary embolism, commented Dr. Stavros V. Konstantinides, professor and deputy scientific director of the Center for Thrombosis and Haemostasis of Johannes Gutenberg University in Mainz, Germany.

The data collected on all three oral factor X inhibitors so far suggest that they all are "noninferior to standard treatment and are also not inferior and most likely superior for safety, with apixaban showing the best safety profile so far," said Dr. Konstantinides, who was the designated discussant for Dr. Büller’s report. But Dr. Konstantinides also warned that these new drugs will need to "justify their high cost" by showing improvements in patient satisfaction with their treatment and quality of life, and by lowering overall health-care costs by lowering the number of rehospitalizations in VTE patients.

Hokusai-VTE was sponsored by Daiichi-Sankyo, the company developing endoxaban. Dr. Büller said that he has received honoraria from Daiichi Sankyo, as well as from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, Isis, and Thrombogenics. Dr. Büller also served as a principal investigator for the VTE pivotal trials of rivaroxaban and apixaban. Dr. Zoghbi said that he had no relevant disclosures. Dr. Konstantinides has been a speaker for and an advisor to Boehringer Ingelheim, Bayer, and Pfizer/Bristol-Myers Squibb.

[email protected]

Twitter:@mitchelzoler

AMSTERDAM – The growing role for the new factor Xa inhibitors in treating acute venous thromboembolism received another boost with the performance of a new drug from the class, edoxaban, in a pivotal, randomized, international trial with more than 8,000 patients.

Edoxaban showed noninferior efficacy and superior safety compared with the standard treatment, warfarin, during 12 months of follow-up, performance that closely matched prior results for the first two direct factor Xa inhibitors that were tested for treating venous thromboembolism (VTE), rivaroxaban (Xarelto) and apixaban (Eliquis). The edoxaban trial also showed an important new feature for drugs in this class, a statistically significant benefit compared with warfarin in the roughly one-third of enrolled patients with a severe pulmonary embolism causing right ventricular dysfunction.

"The most interesting observation is that the third of patients [with pulmonary embolism and] with right ventricular dysfunction were better off with edoxaban," Dr. Harry R. Büller said at the European Society of Cardiology Congress 2013.

"A criticism raised with [the pivotal rivaroxaban and apixaban trials treating acute VTE] was that the investigators were reluctant not to use low molecular weight heparin in the patients with large clots. In that group we’ve made a novel observation" in this prespecified subgroup analysis, said Dr. Büller, professor and chairman of vascular medicine at the Academic Medical Center in Amsterdam.

Investigators in the edoxaban trial may have been more willing to enroll their severely ill VTE patients because the treatment regimens compared began all patients with at least 5 days of treatment with either enoxaparin or unfractionated heparin. Intravenous treatment stopped after about a week and then continued with either oral warfarin or edoxaban. This treatment strategy contrasted with the prior rivaroxaban (EINSTEIN, N. Engl. J. Med. 2012;366:1287-97 and apixaban (AMPLIFY, N. Engl. J. Med. 2013;369:799-808) pivotal studies that began acute VTE patients on the oral drugs from the start of treatment. In the edoxaban study, participating physicians enrolled "the full spectrum of VTE patients," Dr. Büller said.

Physicians "feel comfortable intervening with heparin in these patients because you have quick, intravenous treatment with an anticoagulant," commented Dr. William A. Zoghbi, professor of medicine and director of the Cardiovascular Imaging Institute at the Debakey Heart and Vascular Center at Methodist Hospital in Houston. The results showing superior efficacy of edoxaban over warfarin in the most severely affected pulmonary embolism patients "makes you more confident that in the higher-risk patients edoxaban was not only not inferior but may even have an advantage," Dr. Zoghbi said in an interview.

The Hokusai-VTE trial randomized 4,921 patients with deep-vein thrombosis and 3,319 patients with pulmonary embolism at 439 centers in 37 countries during January 2010–October 2012. Patients averaged 56 years of age, a bit more than half were men, and they received heparin for a median of 7 days.

After 1 year, the primary efficacy endpoint of recurrent VTE in all patients occurred in 3.2% of the 4,118 patients randomized to received edoxaban and in 3.5% of the 4,122 randomized to receive warfarin, results that meet the study’s criterion for noninferiority.

Among the prespecified subgroup of pulmonary embolism patients with a larger clot and inferred right-ventricular dysfunction – based on both the anatomic size of their clot and on their blood level of N-terminal pro-brain natriuretic peptide – the rate of recurrent VTE during follow-up was 3.3% in the edoxaban group and 6.2% in the warfarin group, a statistically significant difference.

The study’s primary safety outcome was the rate of clinically relevant major or nonmajor bleeds, which occurred in 8.5% of the edoxaban patients and in 10.3% of the warfarin patients, for a relative hazard reduction of 19% by edoxaban that was statistically significant for superiority, reported Dr. Büller. Concurrent with his talk at the meeting a report of the trial results was published online (N. Engl. J. Med. 2013;doi:10.1056NEJMoa1306638).

The safety data also showed that the edoxaban-treated patients had a total of 5 intracranial or retroperitoneal bleeds, compared with 22 in the patients treated with warfarin, a difference that Dr. Büller said he believed was real and due to the effect of warfarin on clotting factor VII, and is something that has also been seen in the trials testing the other new factor Xa inhibitors.

The Hokusai-VTE study is unique among the trials of oral factor Xa inhibitors by being the only study that allowed for a flexible duration of anticoagulation treatment, followed all patients for 12 months, and used imaging and biomarkers to risk-stratify patients to prove efficacy in patients with severe pulmonary embolism, commented Dr. Stavros V. Konstantinides, professor and deputy scientific director of the Center for Thrombosis and Haemostasis of Johannes Gutenberg University in Mainz, Germany.

The data collected on all three oral factor X inhibitors so far suggest that they all are "noninferior to standard treatment and are also not inferior and most likely superior for safety, with apixaban showing the best safety profile so far," said Dr. Konstantinides, who was the designated discussant for Dr. Büller’s report. But Dr. Konstantinides also warned that these new drugs will need to "justify their high cost" by showing improvements in patient satisfaction with their treatment and quality of life, and by lowering overall health-care costs by lowering the number of rehospitalizations in VTE patients.

Hokusai-VTE was sponsored by Daiichi-Sankyo, the company developing endoxaban. Dr. Büller said that he has received honoraria from Daiichi Sankyo, as well as from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, Isis, and Thrombogenics. Dr. Büller also served as a principal investigator for the VTE pivotal trials of rivaroxaban and apixaban. Dr. Zoghbi said that he had no relevant disclosures. Dr. Konstantinides has been a speaker for and an advisor to Boehringer Ingelheim, Bayer, and Pfizer/Bristol-Myers Squibb.

[email protected]

Twitter:@mitchelzoler

AMSTERDAM – The growing role for the new factor Xa inhibitors in treating acute venous thromboembolism received another boost with the performance of a new drug from the class, edoxaban, in a pivotal, randomized, international trial with more than 8,000 patients.

Edoxaban showed noninferior efficacy and superior safety compared with the standard treatment, warfarin, during 12 months of follow-up, performance that closely matched prior results for the first two direct factor Xa inhibitors that were tested for treating venous thromboembolism (VTE), rivaroxaban (Xarelto) and apixaban (Eliquis). The edoxaban trial also showed an important new feature for drugs in this class, a statistically significant benefit compared with warfarin in the roughly one-third of enrolled patients with a severe pulmonary embolism causing right ventricular dysfunction.

"The most interesting observation is that the third of patients [with pulmonary embolism and] with right ventricular dysfunction were better off with edoxaban," Dr. Harry R. Büller said at the European Society of Cardiology Congress 2013.

"A criticism raised with [the pivotal rivaroxaban and apixaban trials treating acute VTE] was that the investigators were reluctant not to use low molecular weight heparin in the patients with large clots. In that group we’ve made a novel observation" in this prespecified subgroup analysis, said Dr. Büller, professor and chairman of vascular medicine at the Academic Medical Center in Amsterdam.

Investigators in the edoxaban trial may have been more willing to enroll their severely ill VTE patients because the treatment regimens compared began all patients with at least 5 days of treatment with either enoxaparin or unfractionated heparin. Intravenous treatment stopped after about a week and then continued with either oral warfarin or edoxaban. This treatment strategy contrasted with the prior rivaroxaban (EINSTEIN, N. Engl. J. Med. 2012;366:1287-97 and apixaban (AMPLIFY, N. Engl. J. Med. 2013;369:799-808) pivotal studies that began acute VTE patients on the oral drugs from the start of treatment. In the edoxaban study, participating physicians enrolled "the full spectrum of VTE patients," Dr. Büller said.

Physicians "feel comfortable intervening with heparin in these patients because you have quick, intravenous treatment with an anticoagulant," commented Dr. William A. Zoghbi, professor of medicine and director of the Cardiovascular Imaging Institute at the Debakey Heart and Vascular Center at Methodist Hospital in Houston. The results showing superior efficacy of edoxaban over warfarin in the most severely affected pulmonary embolism patients "makes you more confident that in the higher-risk patients edoxaban was not only not inferior but may even have an advantage," Dr. Zoghbi said in an interview.

The Hokusai-VTE trial randomized 4,921 patients with deep-vein thrombosis and 3,319 patients with pulmonary embolism at 439 centers in 37 countries during January 2010–October 2012. Patients averaged 56 years of age, a bit more than half were men, and they received heparin for a median of 7 days.

After 1 year, the primary efficacy endpoint of recurrent VTE in all patients occurred in 3.2% of the 4,118 patients randomized to received edoxaban and in 3.5% of the 4,122 randomized to receive warfarin, results that meet the study’s criterion for noninferiority.

Among the prespecified subgroup of pulmonary embolism patients with a larger clot and inferred right-ventricular dysfunction – based on both the anatomic size of their clot and on their blood level of N-terminal pro-brain natriuretic peptide – the rate of recurrent VTE during follow-up was 3.3% in the edoxaban group and 6.2% in the warfarin group, a statistically significant difference.

The study’s primary safety outcome was the rate of clinically relevant major or nonmajor bleeds, which occurred in 8.5% of the edoxaban patients and in 10.3% of the warfarin patients, for a relative hazard reduction of 19% by edoxaban that was statistically significant for superiority, reported Dr. Büller. Concurrent with his talk at the meeting a report of the trial results was published online (N. Engl. J. Med. 2013;doi:10.1056NEJMoa1306638).

The safety data also showed that the edoxaban-treated patients had a total of 5 intracranial or retroperitoneal bleeds, compared with 22 in the patients treated with warfarin, a difference that Dr. Büller said he believed was real and due to the effect of warfarin on clotting factor VII, and is something that has also been seen in the trials testing the other new factor Xa inhibitors.

The Hokusai-VTE study is unique among the trials of oral factor Xa inhibitors by being the only study that allowed for a flexible duration of anticoagulation treatment, followed all patients for 12 months, and used imaging and biomarkers to risk-stratify patients to prove efficacy in patients with severe pulmonary embolism, commented Dr. Stavros V. Konstantinides, professor and deputy scientific director of the Center for Thrombosis and Haemostasis of Johannes Gutenberg University in Mainz, Germany.

The data collected on all three oral factor X inhibitors so far suggest that they all are "noninferior to standard treatment and are also not inferior and most likely superior for safety, with apixaban showing the best safety profile so far," said Dr. Konstantinides, who was the designated discussant for Dr. Büller’s report. But Dr. Konstantinides also warned that these new drugs will need to "justify their high cost" by showing improvements in patient satisfaction with their treatment and quality of life, and by lowering overall health-care costs by lowering the number of rehospitalizations in VTE patients.

Hokusai-VTE was sponsored by Daiichi-Sankyo, the company developing endoxaban. Dr. Büller said that he has received honoraria from Daiichi Sankyo, as well as from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, Isis, and Thrombogenics. Dr. Büller also served as a principal investigator for the VTE pivotal trials of rivaroxaban and apixaban. Dr. Zoghbi said that he had no relevant disclosures. Dr. Konstantinides has been a speaker for and an advisor to Boehringer Ingelheim, Bayer, and Pfizer/Bristol-Myers Squibb.

[email protected]

Twitter:@mitchelzoler

AMSTERDAM – The growing role for the new factor Xa inhibitors in treating acute venous thromboembolism received another boost with the performance of a new drug from the class, edoxaban, in a pivotal, randomized, international trial with more than 8,000 patients.

Edoxaban showed noninferior efficacy and superior safety compared with the standard treatment, warfarin, during 12 months of follow-up, performance that closely matched prior results for the first two direct factor Xa inhibitors that were tested for treating venous thromboembolism (VTE), rivaroxaban (Xarelto) and apixaban (Eliquis). The edoxaban trial also showed an important new feature for drugs in this class, a statistically significant benefit compared with warfarin in the roughly one-third of enrolled patients with a severe pulmonary embolism causing right ventricular dysfunction.

"The most interesting observation is that the third of patients [with pulmonary embolism and] with right ventricular dysfunction were better off with edoxaban," Dr. Harry R. Büller said at the European Society of Cardiology Congress 2013.

"A criticism raised with [the pivotal rivaroxaban and apixaban trials treating acute VTE] was that the investigators were reluctant not to use low molecular weight heparin in the patients with large clots. In that group we’ve made a novel observation" in this prespecified subgroup analysis, said Dr. Büller, professor and chairman of vascular medicine at the Academic Medical Center in Amsterdam.

Investigators in the edoxaban trial may have been more willing to enroll their severely ill VTE patients because the treatment regimens compared began all patients with at least 5 days of treatment with either enoxaparin or unfractionated heparin. Intravenous treatment stopped after about a week and then continued with either oral warfarin or edoxaban. This treatment strategy contrasted with the prior rivaroxaban (EINSTEIN, N. Engl. J. Med. 2012;366:1287-97 and apixaban (AMPLIFY, N. Engl. J. Med. 2013;369:799-808) pivotal studies that began acute VTE patients on the oral drugs from the start of treatment. In the edoxaban study, participating physicians enrolled "the full spectrum of VTE patients," Dr. Büller said.

Physicians "feel comfortable intervening with heparin in these patients because you have quick, intravenous treatment with an anticoagulant," commented Dr. William A. Zoghbi, professor of medicine and director of the Cardiovascular Imaging Institute at the Debakey Heart and Vascular Center at Methodist Hospital in Houston. The results showing superior efficacy of edoxaban over warfarin in the most severely affected pulmonary embolism patients "makes you more confident that in the higher-risk patients edoxaban was not only not inferior but may even have an advantage," Dr. Zoghbi said in an interview.

The Hokusai-VTE trial randomized 4,921 patients with deep-vein thrombosis and 3,319 patients with pulmonary embolism at 439 centers in 37 countries during January 2010–October 2012. Patients averaged 56 years of age, a bit more than half were men, and they received heparin for a median of 7 days.

After 1 year, the primary efficacy endpoint of recurrent VTE in all patients occurred in 3.2% of the 4,118 patients randomized to received edoxaban and in 3.5% of the 4,122 randomized to receive warfarin, results that meet the study’s criterion for noninferiority.

Among the prespecified subgroup of pulmonary embolism patients with a larger clot and inferred right-ventricular dysfunction – based on both the anatomic size of their clot and on their blood level of N-terminal pro-brain natriuretic peptide – the rate of recurrent VTE during follow-up was 3.3% in the edoxaban group and 6.2% in the warfarin group, a statistically significant difference.

The study’s primary safety outcome was the rate of clinically relevant major or nonmajor bleeds, which occurred in 8.5% of the edoxaban patients and in 10.3% of the warfarin patients, for a relative hazard reduction of 19% by edoxaban that was statistically significant for superiority, reported Dr. Büller. Concurrent with his talk at the meeting a report of the trial results was published online (N. Engl. J. Med. 2013;doi:10.1056NEJMoa1306638).

The safety data also showed that the edoxaban-treated patients had a total of 5 intracranial or retroperitoneal bleeds, compared with 22 in the patients treated with warfarin, a difference that Dr. Büller said he believed was real and due to the effect of warfarin on clotting factor VII, and is something that has also been seen in the trials testing the other new factor Xa inhibitors.

The Hokusai-VTE study is unique among the trials of oral factor Xa inhibitors by being the only study that allowed for a flexible duration of anticoagulation treatment, followed all patients for 12 months, and used imaging and biomarkers to risk-stratify patients to prove efficacy in patients with severe pulmonary embolism, commented Dr. Stavros V. Konstantinides, professor and deputy scientific director of the Center for Thrombosis and Haemostasis of Johannes Gutenberg University in Mainz, Germany.

The data collected on all three oral factor X inhibitors so far suggest that they all are "noninferior to standard treatment and are also not inferior and most likely superior for safety, with apixaban showing the best safety profile so far," said Dr. Konstantinides, who was the designated discussant for Dr. Büller’s report. But Dr. Konstantinides also warned that these new drugs will need to "justify their high cost" by showing improvements in patient satisfaction with their treatment and quality of life, and by lowering overall health-care costs by lowering the number of rehospitalizations in VTE patients.

Hokusai-VTE was sponsored by Daiichi-Sankyo, the company developing endoxaban. Dr. Büller said that he has received honoraria from Daiichi Sankyo, as well as from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, Isis, and Thrombogenics. Dr. Büller also served as a principal investigator for the VTE pivotal trials of rivaroxaban and apixaban. Dr. Zoghbi said that he had no relevant disclosures. Dr. Konstantinides has been a speaker for and an advisor to Boehringer Ingelheim, Bayer, and Pfizer/Bristol-Myers Squibb.

[email protected]

Twitter:@mitchelzoler

AMSTERDAM – The growing role for the new factor Xa inhibitors in treating acute venous thromboembolism received another boost with the performance of a new drug from the class, edoxaban, in a pivotal, randomized, international trial with more than 8,000 patients.

Edoxaban showed noninferior efficacy and superior safety compared with the standard treatment, warfarin, during 12 months of follow-up, performance that closely matched prior results for the first two direct factor Xa inhibitors that were tested for treating venous thromboembolism (VTE), rivaroxaban (Xarelto) and apixaban (Eliquis). The edoxaban trial also showed an important new feature for drugs in this class, a statistically significant benefit compared with warfarin in the roughly one-third of enrolled patients with a severe pulmonary embolism causing right ventricular dysfunction.

"The most interesting observation is that the third of patients [with pulmonary embolism and] with right ventricular dysfunction were better off with edoxaban," Dr. Harry R. Büller said at the European Society of Cardiology Congress 2013.

"A criticism raised with [the pivotal rivaroxaban and apixaban trials treating acute VTE] was that the investigators were reluctant not to use low molecular weight heparin in the patients with large clots. In that group we’ve made a novel observation" in this prespecified subgroup analysis, said Dr. Büller, professor and chairman of vascular medicine at the Academic Medical Center in Amsterdam.

Investigators in the edoxaban trial may have been more willing to enroll their severely ill VTE patients because the treatment regimens compared began all patients with at least 5 days of treatment with either enoxaparin or unfractionated heparin. Intravenous treatment stopped after about a week and then continued with either oral warfarin or edoxaban. This treatment strategy contrasted with the prior rivaroxaban (EINSTEIN, N. Engl. J. Med. 2012;366:1287-97 and apixaban (AMPLIFY, N. Engl. J. Med. 2013;369:799-808) pivotal studies that began acute VTE patients on the oral drugs from the start of treatment. In the edoxaban study, participating physicians enrolled "the full spectrum of VTE patients," Dr. Büller said.

Physicians "feel comfortable intervening with heparin in these patients because you have quick, intravenous treatment with an anticoagulant," commented Dr. William A. Zoghbi, professor of medicine and director of the Cardiovascular Imaging Institute at the Debakey Heart and Vascular Center at Methodist Hospital in Houston. The results showing superior efficacy of edoxaban over warfarin in the most severely affected pulmonary embolism patients "makes you more confident that in the higher-risk patients edoxaban was not only not inferior but may even have an advantage," Dr. Zoghbi said in an interview.

The Hokusai-VTE trial randomized 4,921 patients with deep-vein thrombosis and 3,319 patients with pulmonary embolism at 439 centers in 37 countries during January 2010–October 2012. Patients averaged 56 years of age, a bit more than half were men, and they received heparin for a median of 7 days.

After 1 year, the primary efficacy endpoint of recurrent VTE in all patients occurred in 3.2% of the 4,118 patients randomized to received edoxaban and in 3.5% of the 4,122 randomized to receive warfarin, results that meet the study’s criterion for noninferiority.

Among the prespecified subgroup of pulmonary embolism patients with a larger clot and inferred right-ventricular dysfunction – based on both the anatomic size of their clot and on their blood level of N-terminal pro-brain natriuretic peptide – the rate of recurrent VTE during follow-up was 3.3% in the edoxaban group and 6.2% in the warfarin group, a statistically significant difference.

The study’s primary safety outcome was the rate of clinically relevant major or nonmajor bleeds, which occurred in 8.5% of the edoxaban patients and in 10.3% of the warfarin patients, for a relative hazard reduction of 19% by edoxaban that was statistically significant for superiority, reported Dr. Büller. Concurrent with his talk at the meeting a report of the trial results was published online (N. Engl. J. Med. 2013;doi:10.1056NEJMoa1306638).

The safety data also showed that the edoxaban-treated patients had a total of 5 intracranial or retroperitoneal bleeds, compared with 22 in the patients treated with warfarin, a difference that Dr. Büller said he believed was real and due to the effect of warfarin on clotting factor VII, and is something that has also been seen in the trials testing the other new factor Xa inhibitors.

The Hokusai-VTE study is unique among the trials of oral factor Xa inhibitors by being the only study that allowed for a flexible duration of anticoagulation treatment, followed all patients for 12 months, and used imaging and biomarkers to risk-stratify patients to prove efficacy in patients with severe pulmonary embolism, commented Dr. Stavros V. Konstantinides, professor and deputy scientific director of the Center for Thrombosis and Haemostasis of Johannes Gutenberg University in Mainz, Germany.

The data collected on all three oral factor X inhibitors so far suggest that they all are "noninferior to standard treatment and are also not inferior and most likely superior for safety, with apixaban showing the best safety profile so far," said Dr. Konstantinides, who was the designated discussant for Dr. Büller’s report. But Dr. Konstantinides also warned that these new drugs will need to "justify their high cost" by showing improvements in patient satisfaction with their treatment and quality of life, and by lowering overall health-care costs by lowering the number of rehospitalizations in VTE patients.

Hokusai-VTE was sponsored by Daiichi-Sankyo, the company developing endoxaban. Dr. Büller said that he has received honoraria from Daiichi Sankyo, as well as from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, Isis, and Thrombogenics. Dr. Büller also served as a principal investigator for the VTE pivotal trials of rivaroxaban and apixaban. Dr. Zoghbi said that he had no relevant disclosures. Dr. Konstantinides has been a speaker for and an advisor to Boehringer Ingelheim, Bayer, and Pfizer/Bristol-Myers Squibb.

[email protected]

Twitter:@mitchelzoler

Neither saxagliptin nor alogliptin was associated with increased – or decreased – rates of major adverse cardiovascular events in high-risk patients with type 2 diabetes mellitus in separate randomized, double-blind, placebo-controlled trials.

The findings with respect to these recently approved antidiabetic therapies – members of the same class of selective dipeptidyl peptidase–4 (DDP-4) inhibitors – provide clinicians with important information to help guide treatment decision-making for patients with type 2 diabetes and cardiovascular risk, the authors concluded.

Both studies were mandated by the Food and Drug Administration, which in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction. The results were reported at the annual congress of the European Society of Cardiology, and were simultaneously published online Sept. 2 in the New England Journal of Medicine.

SAVOR-TIMI 53

SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) randomized 16,492 patients with type 2 diabetes and a history of established cardiovascular disease or multiple risk factors for vascular disease to either saxagliptin, doses ranging from 2.5 to 5 mg daily, or placebo.

The primary endpoint – a composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred at similar rates in 613 patients randomized to receive saxagliptin treatment and 609 patients randomized to receive placebo (7.3% and 7.2%, respectively) at a median follow-up of 2.1 years, Dr. Benjamin M. Scirica of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues reported on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators.

A major secondary endpoint – a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure – also occurred at similar rates in the treatment and placebo groups (12.8% and 12.4%, respectively), they reported (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1307684]).

However, more patients in the treatment group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%), they noted, adding that this was an unexpected finding that merits further study.

The findings demonstrate that DPP-4 inhibition with saxagliptin neither increases nor decreases the rate of ischemic events over a median 2-year period, although longer duration of treatment may have different effects.

"Together with ongoing trials of other DPP-4 inhibitors and novel antihyperglycemic agents, these data will provide a more rigorous and robust evidence base than is currently available to guide the future care of patients with diabetes," they concluded.

EXAMINE

Similarly, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial showed that the primary endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – did not occur significantly more often at a median follow-up of 18 months in 2,679 patients randomized to receive treatment, compared with 2,701 patients randomized to receive placebo (11.3% vs. 11.8%, respectively), Dr. William B. White of the University of Connecticut School of Medicine, Farmington, and his colleagues reported on behalf of the EXAMINE investigators.

Patients included in this noninferiority study had type 2 diabetes and a recent acute myocardial infarction or unstable angina requiring hospitalization, who received standard-of-care treatment for diabetes and cardiovascular risk factors throughout the study period. Alogliptin doses ranged from 6.25 to 25 mg daily on the basis of the patients’ estimated glomerular filtration rate at baseline.

"The alogliptin and placebo groups did not differ significantly with respect to the incidence of serious adverse events (33.6% and 35.5%, respectively)," the investigators wrote (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1305889]).

In this group of patients at very high cardiovascular event risk, alogliptin did not increase or decrease cardiovascular morbidity or mortality over a median 18-month period; the findings do not rule out longer-term risks with respect to cardiovascular endpoints, they noted.

"These data can be used to help guide clinicians in choosing among the many available antidiabetic agents when treating patients with type 2 diabetes and very high cardiovascular risk," they concluded.

The SAVOR-TIMI 53 trial was supported by AstraZeneca and Bristol-Myers Squibb. The EXAMINE trial was supported by Takeda Development Center Americas. Multiple authors for both studies reported disclosures. Details are provided with the full text of each article at NEJM.org.

Neither saxagliptin nor alogliptin was associated with increased – or decreased – rates of major adverse cardiovascular events in high-risk patients with type 2 diabetes mellitus in separate randomized, double-blind, placebo-controlled trials.

The findings with respect to these recently approved antidiabetic therapies – members of the same class of selective dipeptidyl peptidase–4 (DDP-4) inhibitors – provide clinicians with important information to help guide treatment decision-making for patients with type 2 diabetes and cardiovascular risk, the authors concluded.

Both studies were mandated by the Food and Drug Administration, which in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction. The results were reported at the annual congress of the European Society of Cardiology, and were simultaneously published online Sept. 2 in the New England Journal of Medicine.

SAVOR-TIMI 53

SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) randomized 16,492 patients with type 2 diabetes and a history of established cardiovascular disease or multiple risk factors for vascular disease to either saxagliptin, doses ranging from 2.5 to 5 mg daily, or placebo.

The primary endpoint – a composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred at similar rates in 613 patients randomized to receive saxagliptin treatment and 609 patients randomized to receive placebo (7.3% and 7.2%, respectively) at a median follow-up of 2.1 years, Dr. Benjamin M. Scirica of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues reported on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators.

A major secondary endpoint – a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure – also occurred at similar rates in the treatment and placebo groups (12.8% and 12.4%, respectively), they reported (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1307684]).

However, more patients in the treatment group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%), they noted, adding that this was an unexpected finding that merits further study.

The findings demonstrate that DPP-4 inhibition with saxagliptin neither increases nor decreases the rate of ischemic events over a median 2-year period, although longer duration of treatment may have different effects.

"Together with ongoing trials of other DPP-4 inhibitors and novel antihyperglycemic agents, these data will provide a more rigorous and robust evidence base than is currently available to guide the future care of patients with diabetes," they concluded.

EXAMINE

Similarly, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial showed that the primary endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – did not occur significantly more often at a median follow-up of 18 months in 2,679 patients randomized to receive treatment, compared with 2,701 patients randomized to receive placebo (11.3% vs. 11.8%, respectively), Dr. William B. White of the University of Connecticut School of Medicine, Farmington, and his colleagues reported on behalf of the EXAMINE investigators.

Patients included in this noninferiority study had type 2 diabetes and a recent acute myocardial infarction or unstable angina requiring hospitalization, who received standard-of-care treatment for diabetes and cardiovascular risk factors throughout the study period. Alogliptin doses ranged from 6.25 to 25 mg daily on the basis of the patients’ estimated glomerular filtration rate at baseline.

"The alogliptin and placebo groups did not differ significantly with respect to the incidence of serious adverse events (33.6% and 35.5%, respectively)," the investigators wrote (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1305889]).

In this group of patients at very high cardiovascular event risk, alogliptin did not increase or decrease cardiovascular morbidity or mortality over a median 18-month period; the findings do not rule out longer-term risks with respect to cardiovascular endpoints, they noted.

"These data can be used to help guide clinicians in choosing among the many available antidiabetic agents when treating patients with type 2 diabetes and very high cardiovascular risk," they concluded.

The SAVOR-TIMI 53 trial was supported by AstraZeneca and Bristol-Myers Squibb. The EXAMINE trial was supported by Takeda Development Center Americas. Multiple authors for both studies reported disclosures. Details are provided with the full text of each article at NEJM.org.

Neither saxagliptin nor alogliptin was associated with increased – or decreased – rates of major adverse cardiovascular events in high-risk patients with type 2 diabetes mellitus in separate randomized, double-blind, placebo-controlled trials.

The findings with respect to these recently approved antidiabetic therapies – members of the same class of selective dipeptidyl peptidase–4 (DDP-4) inhibitors – provide clinicians with important information to help guide treatment decision-making for patients with type 2 diabetes and cardiovascular risk, the authors concluded.

Both studies were mandated by the Food and Drug Administration, which in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction. The results were reported at the annual congress of the European Society of Cardiology, and were simultaneously published online Sept. 2 in the New England Journal of Medicine.

SAVOR-TIMI 53

SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) randomized 16,492 patients with type 2 diabetes and a history of established cardiovascular disease or multiple risk factors for vascular disease to either saxagliptin, doses ranging from 2.5 to 5 mg daily, or placebo.

The primary endpoint – a composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred at similar rates in 613 patients randomized to receive saxagliptin treatment and 609 patients randomized to receive placebo (7.3% and 7.2%, respectively) at a median follow-up of 2.1 years, Dr. Benjamin M. Scirica of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues reported on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators.

A major secondary endpoint – a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure – also occurred at similar rates in the treatment and placebo groups (12.8% and 12.4%, respectively), they reported (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1307684]).

However, more patients in the treatment group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%), they noted, adding that this was an unexpected finding that merits further study.

The findings demonstrate that DPP-4 inhibition with saxagliptin neither increases nor decreases the rate of ischemic events over a median 2-year period, although longer duration of treatment may have different effects.

"Together with ongoing trials of other DPP-4 inhibitors and novel antihyperglycemic agents, these data will provide a more rigorous and robust evidence base than is currently available to guide the future care of patients with diabetes," they concluded.

EXAMINE

Similarly, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial showed that the primary endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – did not occur significantly more often at a median follow-up of 18 months in 2,679 patients randomized to receive treatment, compared with 2,701 patients randomized to receive placebo (11.3% vs. 11.8%, respectively), Dr. William B. White of the University of Connecticut School of Medicine, Farmington, and his colleagues reported on behalf of the EXAMINE investigators.

Patients included in this noninferiority study had type 2 diabetes and a recent acute myocardial infarction or unstable angina requiring hospitalization, who received standard-of-care treatment for diabetes and cardiovascular risk factors throughout the study period. Alogliptin doses ranged from 6.25 to 25 mg daily on the basis of the patients’ estimated glomerular filtration rate at baseline.

"The alogliptin and placebo groups did not differ significantly with respect to the incidence of serious adverse events (33.6% and 35.5%, respectively)," the investigators wrote (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1305889]).

In this group of patients at very high cardiovascular event risk, alogliptin did not increase or decrease cardiovascular morbidity or mortality over a median 18-month period; the findings do not rule out longer-term risks with respect to cardiovascular endpoints, they noted.

"These data can be used to help guide clinicians in choosing among the many available antidiabetic agents when treating patients with type 2 diabetes and very high cardiovascular risk," they concluded.

The SAVOR-TIMI 53 trial was supported by AstraZeneca and Bristol-Myers Squibb. The EXAMINE trial was supported by Takeda Development Center Americas. Multiple authors for both studies reported disclosures. Details are provided with the full text of each article at NEJM.org.

Pretreatment with the P2Y₁₂ antagonist prasugrel in patients with non-ST–segment elevation acute coronary syndromes did not reduce the rate of major ischemic events, but did increase the rate of major bleeding complications within 30 days of coronary angiography in the randomized, controlled, phase III ACCOAST trial.

The incidence of the primary efficacy endpoint – a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy through day 7 – was similar in 2,037 patients who were randomized to receive prasugrel before and after angiography, and in 1,996 patients who were randomized to receive treatment only after angiography (10.0% and 9.8%; respectively; hazard ratio, 1.02), Dr. Gilles Montalescot of Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, and colleagues found.

The findings were similar, with no significant differences noted between the pretreatment and control groups with respect to the primary efficacy endpoint, among the 2,770 patients managed by percutaneous coronary intervention (PCI), compared with the entire cohort ultimately managed by PCI, coronary artery bypass grafting (CABG), or medical treatment alone.

However, the rate of a key safety endpoint – thrombolysis in myocardial infarction (TIMI) major bleeding episodes through day 7 – was increased in those in the pretreatment group, compared with the control group (2.6% vs. 1.4%; hazard ratio, 1.90), the investigators said, noting that the findings, which were reported at the annual congress of the European Society of Cardiology and simultaneously published online Sept. 1 in the New England Journal of Medicine, were confirmed at 30 days.

"There was an increase by a factor of 3 in all major bleeding not related to CABG and an increase by a factor of 6 in life-threatening bleeding not related to CABG. TIMI minor bleeding events were also increased with pretreatment compared with no pretreatment (hazard ratio, 2.50)," they wrote (N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJM1308075]).

Patients in the trial were adults with a mean age of 63 years who had non-ST–segment elevation (NSTE) acute coronary syndromes and a positive troponin level. They were enrolled between Dec. 6, 2009, and Nov. 16, 2012. All were scheduled to undergo coronary angiography within 2-48 hours following randomization.

Those randomized to the pretreatment group received a 30-mg loading dose with prasugrel before angiography, and an additional 30 mg at the time of PCI. Those randomized to the control group received a placebo before the angiography, and 60 mg of prasugrel at the time of PCI.

In a pharmacodynamic substudy involving 23 patients, the investigators noted that "at the time of arterial access, a median of 4.8 hours after the first loading dose, there was greater platelet inhibition in the pretreatment group than in the control group, which may have contributed to the increased rate of bleeding complications in the pretreatment group."

Of note, the lack of protection afforded by prasugrel against ischemic events was demonstrated consistently across all prespecified subgroups, including high-risk groups such as the elderly, those with diabetes, and those with a Global Registry of Acute Coronary Events (GRACE) risk score of 140 or higher.

"This suggests that stronger [than clopidogrel] antiplatelet therapy does not prevent the occurrence of a myocardial infarction before catheterization or after PCI," the investigators wrote. Nonetheless, the lack of P2Y₁₂ inhibition in the control group did notresult in an excess of ischemic events in patients who underwent CABG or medical therapy. In fact, other studies have shown that currently, the risk of ischemic events is "extremely low" because of the short time between admission to the hospital and catheterization.

The benefit of adding clopidogrel to aspirin in patients with NSTE acute coronary syndromes was demonstrated in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, in which a small subgroup of patients received the drug prior to undergoing PCI; the significant reduction in ischemic events set a precedent for clopidogrel treatment before catheterization, although subsequent studies have not supported the finding. The pretreatment use of clopidogrel and aspirin in patients with NSTE acute coronary syndrome to help reduce ischemic events following an invasive procedure is commonplace, and is included as a class I recommendation in guidelines from the American College of Cardiology Foundation–American Heart Association. This is despite a lack of rigorous studies supporting the practice, which has often been extended to new oral P2Y₁₂ antagonists like prasugrel as well, they explained.

However, prasugrel is more potent and has a more rapid onset of action than clopidogrel. "Our results support the administration of prasugrel when the coronary anatomy is known and after PCI is selected as the treatment strategy," they concluded.

This study was supported by Daiichi Sankyo and Eli Lilly. Multiple study authors, including Dr. Montalescot, reported having disclosures.

Pretreatment with the P2Y₁₂ antagonist prasugrel in patients with non-ST–segment elevation acute coronary syndromes did not reduce the rate of major ischemic events, but did increase the rate of major bleeding complications within 30 days of coronary angiography in the randomized, controlled, phase III ACCOAST trial.

The incidence of the primary efficacy endpoint – a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy through day 7 – was similar in 2,037 patients who were randomized to receive prasugrel before and after angiography, and in 1,996 patients who were randomized to receive treatment only after angiography (10.0% and 9.8%; respectively; hazard ratio, 1.02), Dr. Gilles Montalescot of Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, and colleagues found.

The findings were similar, with no significant differences noted between the pretreatment and control groups with respect to the primary efficacy endpoint, among the 2,770 patients managed by percutaneous coronary intervention (PCI), compared with the entire cohort ultimately managed by PCI, coronary artery bypass grafting (CABG), or medical treatment alone.

However, the rate of a key safety endpoint – thrombolysis in myocardial infarction (TIMI) major bleeding episodes through day 7 – was increased in those in the pretreatment group, compared with the control group (2.6% vs. 1.4%; hazard ratio, 1.90), the investigators said, noting that the findings, which were reported at the annual congress of the European Society of Cardiology and simultaneously published online Sept. 1 in the New England Journal of Medicine, were confirmed at 30 days.

"There was an increase by a factor of 3 in all major bleeding not related to CABG and an increase by a factor of 6 in life-threatening bleeding not related to CABG. TIMI minor bleeding events were also increased with pretreatment compared with no pretreatment (hazard ratio, 2.50)," they wrote (N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJM1308075]).

Patients in the trial were adults with a mean age of 63 years who had non-ST–segment elevation (NSTE) acute coronary syndromes and a positive troponin level. They were enrolled between Dec. 6, 2009, and Nov. 16, 2012. All were scheduled to undergo coronary angiography within 2-48 hours following randomization.

Those randomized to the pretreatment group received a 30-mg loading dose with prasugrel before angiography, and an additional 30 mg at the time of PCI. Those randomized to the control group received a placebo before the angiography, and 60 mg of prasugrel at the time of PCI.

In a pharmacodynamic substudy involving 23 patients, the investigators noted that "at the time of arterial access, a median of 4.8 hours after the first loading dose, there was greater platelet inhibition in the pretreatment group than in the control group, which may have contributed to the increased rate of bleeding complications in the pretreatment group."

Of note, the lack of protection afforded by prasugrel against ischemic events was demonstrated consistently across all prespecified subgroups, including high-risk groups such as the elderly, those with diabetes, and those with a Global Registry of Acute Coronary Events (GRACE) risk score of 140 or higher.

"This suggests that stronger [than clopidogrel] antiplatelet therapy does not prevent the occurrence of a myocardial infarction before catheterization or after PCI," the investigators wrote. Nonetheless, the lack of P2Y₁₂ inhibition in the control group did notresult in an excess of ischemic events in patients who underwent CABG or medical therapy. In fact, other studies have shown that currently, the risk of ischemic events is "extremely low" because of the short time between admission to the hospital and catheterization.

The benefit of adding clopidogrel to aspirin in patients with NSTE acute coronary syndromes was demonstrated in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, in which a small subgroup of patients received the drug prior to undergoing PCI; the significant reduction in ischemic events set a precedent for clopidogrel treatment before catheterization, although subsequent studies have not supported the finding. The pretreatment use of clopidogrel and aspirin in patients with NSTE acute coronary syndrome to help reduce ischemic events following an invasive procedure is commonplace, and is included as a class I recommendation in guidelines from the American College of Cardiology Foundation–American Heart Association. This is despite a lack of rigorous studies supporting the practice, which has often been extended to new oral P2Y₁₂ antagonists like prasugrel as well, they explained.

However, prasugrel is more potent and has a more rapid onset of action than clopidogrel. "Our results support the administration of prasugrel when the coronary anatomy is known and after PCI is selected as the treatment strategy," they concluded.

This study was supported by Daiichi Sankyo and Eli Lilly. Multiple study authors, including Dr. Montalescot, reported having disclosures.

Pretreatment with the P2Y₁₂ antagonist prasugrel in patients with non-ST–segment elevation acute coronary syndromes did not reduce the rate of major ischemic events, but did increase the rate of major bleeding complications within 30 days of coronary angiography in the randomized, controlled, phase III ACCOAST trial.

The incidence of the primary efficacy endpoint – a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy through day 7 – was similar in 2,037 patients who were randomized to receive prasugrel before and after angiography, and in 1,996 patients who were randomized to receive treatment only after angiography (10.0% and 9.8%; respectively; hazard ratio, 1.02), Dr. Gilles Montalescot of Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, and colleagues found.

The findings were similar, with no significant differences noted between the pretreatment and control groups with respect to the primary efficacy endpoint, among the 2,770 patients managed by percutaneous coronary intervention (PCI), compared with the entire cohort ultimately managed by PCI, coronary artery bypass grafting (CABG), or medical treatment alone.

However, the rate of a key safety endpoint – thrombolysis in myocardial infarction (TIMI) major bleeding episodes through day 7 – was increased in those in the pretreatment group, compared with the control group (2.6% vs. 1.4%; hazard ratio, 1.90), the investigators said, noting that the findings, which were reported at the annual congress of the European Society of Cardiology and simultaneously published online Sept. 1 in the New England Journal of Medicine, were confirmed at 30 days.

"There was an increase by a factor of 3 in all major bleeding not related to CABG and an increase by a factor of 6 in life-threatening bleeding not related to CABG. TIMI minor bleeding events were also increased with pretreatment compared with no pretreatment (hazard ratio, 2.50)," they wrote (N. Engl. J. Med. 2013 Sept. 1 [doi:10.1056/NEJM1308075]).

Patients in the trial were adults with a mean age of 63 years who had non-ST–segment elevation (NSTE) acute coronary syndromes and a positive troponin level. They were enrolled between Dec. 6, 2009, and Nov. 16, 2012. All were scheduled to undergo coronary angiography within 2-48 hours following randomization.

Those randomized to the pretreatment group received a 30-mg loading dose with prasugrel before angiography, and an additional 30 mg at the time of PCI. Those randomized to the control group received a placebo before the angiography, and 60 mg of prasugrel at the time of PCI.

In a pharmacodynamic substudy involving 23 patients, the investigators noted that "at the time of arterial access, a median of 4.8 hours after the first loading dose, there was greater platelet inhibition in the pretreatment group than in the control group, which may have contributed to the increased rate of bleeding complications in the pretreatment group."

Of note, the lack of protection afforded by prasugrel against ischemic events was demonstrated consistently across all prespecified subgroups, including high-risk groups such as the elderly, those with diabetes, and those with a Global Registry of Acute Coronary Events (GRACE) risk score of 140 or higher.

"This suggests that stronger [than clopidogrel] antiplatelet therapy does not prevent the occurrence of a myocardial infarction before catheterization or after PCI," the investigators wrote. Nonetheless, the lack of P2Y₁₂ inhibition in the control group did notresult in an excess of ischemic events in patients who underwent CABG or medical therapy. In fact, other studies have shown that currently, the risk of ischemic events is "extremely low" because of the short time between admission to the hospital and catheterization.

The benefit of adding clopidogrel to aspirin in patients with NSTE acute coronary syndromes was demonstrated in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, in which a small subgroup of patients received the drug prior to undergoing PCI; the significant reduction in ischemic events set a precedent for clopidogrel treatment before catheterization, although subsequent studies have not supported the finding. The pretreatment use of clopidogrel and aspirin in patients with NSTE acute coronary syndrome to help reduce ischemic events following an invasive procedure is commonplace, and is included as a class I recommendation in guidelines from the American College of Cardiology Foundation–American Heart Association. This is despite a lack of rigorous studies supporting the practice, which has often been extended to new oral P2Y₁₂ antagonists like prasugrel as well, they explained.

However, prasugrel is more potent and has a more rapid onset of action than clopidogrel. "Our results support the administration of prasugrel when the coronary anatomy is known and after PCI is selected as the treatment strategy," they concluded.

This study was supported by Daiichi Sankyo and Eli Lilly. Multiple study authors, including Dr. Montalescot, reported having disclosures.

AMSTERDAM – In patients with acute ST-segment elevation myocardial infarction, stenting of significant coronary stenoses not responsible for the infarction as well as the infarct-producing lesion led to substantially better outcomes than an intervention that only targeted the infarct-related stenosis in a randomized, multicenter trial with 465 patients.

The results appeared to refute the prevailing recommendation from cardiology societies to limit the percutaneous coronary intervention (PCI) done during acute treatment of ST-segment elevation myocardial infarction (STEMI) to the infarct-related lesion, especially when the secondary lesions are not clearly causing ongoing hemodynamic instability.

Mitchel L. Zoler/IMNG Medial Media

The new findings "make it clear that preventive PCI is a better strategy than restricting a further intervention to those patients with refractory angina or a subsequent myocardial infarction," Dr. David S. Wald reported on Sept. 1 at the annual congress of the European Society of Cardiology. Simultaneous with Dr. Wald’s report, the results appeared in an article published online (N. Engl. J. Med. 2013 [doi:10.156/NEJMoa1305520]).

Current guidelines on management of STEMI recommend PCI for the infarct-related artery only (Eur. Heart J. 2012;33:2569-619; Circulation 2013;127:529-55), primarily because, until now, scant evidence existed that a different strategy helped patients. "This uncertainty has led to variations in practice, with some cardiologists performing immediate preventive PCI in spite of the guidelines, some delaying preventive PCI until recovery from the acute episode, and others limiting the procedure to patients with recurrent symptoms or evidence of ischemia," noted Dr. Wald, an interventional cardiologist at the Wolfson Institute of Preventive Medicine of the Queen Mary University of London.

Dr. Wald acknowledged, however, that his study did not address whether patients would be better served by a staged approach that delayed preventive PCI of significant, noninfarct related stenoses in a second PCI procedure, whether the benefits extend to treating noninfarct stenoses that occlude less than half of a coronary artery, and whether a similar strategy would help patients with non-ST–elevation MI (NSTEMI).

The Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial enrolled consecutive patients of any age at five U.K. centers during April 2008 to January 2013. The study focused on STEMI patients because patients with a NSTEMI often do not have a clearly identifiable infarct-related artery. In addition, to qualify for entry, the patient’s infarct-related artery had to have been successfully treated by PCI and they had to have at least one other coronary artery with at least 50% stenosis judged treatable by PCI. Patients with coronary anatomy more appropriately treated with bypass surgery were excluded. The enrolled patients averaged 62 years of age, about three-quarters were men, and about 18% had diabetes. Roughly two-thirds had a second coronary artery with a greater than 50% stenosis, and the remaining patients had two coronary arteries with a significant lesion.

After successful treatment of the infarct-producing artery, patients with additional, significant lesions judged appropriate for PCI were randomized to either have their other significant lesions treated during the same procedure or to undergo no further intervention. This resulted in an average of 1.36 additional arteries undergoing PCI in the 234 patients randomized to the more aggressive protocol.

Following the PCI procedures, all patients received standard medical treatment: daily treatment with aspirin and a second antiplatelet drug, clopidogrel (Plavix), prasugrel (Effient), or ticagrelor (Brilinta). About 95% of patients in both study arms also received treatment with a statin, and about 90% received a beta-blocker and an angiotensin-converting enzyme inhibitor.

During an average follow-up of 23 months, the combined rate of death from cardiac causes, nonfatal MI, or refractory angina – the study’s primary endpoint – occurred in 9% of the patients randomized to immediate PCI of their noninfarct-related stenoses and in 23% of the 231 patients in the control arm, a statistically significant difference. The 14-percentage-point absolute reduction in endpoints translated into a 65% relative risk reduction. The rate of cardiac death or nonfatal MI was 5% in the patients who received added PCI while in the catheterization laboratory and 12% among those only treated in their infarct-related artery, also a statistically significant difference.

Additional analyses also showed statistically significantly lower rates of both nonfatal MI and refractory angina in the patients treated in multiple arteries when these endpoints were tallied individually and a strong trend toward fewer cardiac deaths in these patients as well. Kaplan-Meier analysis showed that the risk reduction in the preventive-PCI group was evident after 6 months of follow-up and then increased with continued follow-up.

These results were not materially affected by patient age, sex, diabetes status, infarct location, or the number of coronary arteries with significant stenoses. In addition, the complication rates, including procedure-related strokes, bleeding requiring transfusions or surgery, and contrast-induced nephropathy requiring dialysis, were similar in the two study arms.

The results were consistent with reports from two prior randomized trials that also assessed the value of preventive PCI in patients with acute STEMI, but in fewer patients. One of these prior studies involved a total of 69 patients (Int. J. Cardiovasc. Intervent. 2004;6:128-33), and the second enrolled a total of 214 patients (Heart 2010;96:662-7); both were limited by a lack of statistical power, and both relied on repeat revascularization as an endpoint, which may be subject to bias, Dr. Wald said.

Dr. Wald said that he a director for and shareholder in Polypill Ltd.

[email protected]

On Twitter @mitchelzoler

AMSTERDAM – In patients with acute ST-segment elevation myocardial infarction, stenting of significant coronary stenoses not responsible for the infarction as well as the infarct-producing lesion led to substantially better outcomes than an intervention that only targeted the infarct-related stenosis in a randomized, multicenter trial with 465 patients.

The results appeared to refute the prevailing recommendation from cardiology societies to limit the percutaneous coronary intervention (PCI) done during acute treatment of ST-segment elevation myocardial infarction (STEMI) to the infarct-related lesion, especially when the secondary lesions are not clearly causing ongoing hemodynamic instability.

Mitchel L. Zoler/IMNG Medial Media

The new findings "make it clear that preventive PCI is a better strategy than restricting a further intervention to those patients with refractory angina or a subsequent myocardial infarction," Dr. David S. Wald reported on Sept. 1 at the annual congress of the European Society of Cardiology. Simultaneous with Dr. Wald’s report, the results appeared in an article published online (N. Engl. J. Med. 2013 [doi:10.156/NEJMoa1305520]).

Current guidelines on management of STEMI recommend PCI for the infarct-related artery only (Eur. Heart J. 2012;33:2569-619; Circulation 2013;127:529-55), primarily because, until now, scant evidence existed that a different strategy helped patients. "This uncertainty has led to variations in practice, with some cardiologists performing immediate preventive PCI in spite of the guidelines, some delaying preventive PCI until recovery from the acute episode, and others limiting the procedure to patients with recurrent symptoms or evidence of ischemia," noted Dr. Wald, an interventional cardiologist at the Wolfson Institute of Preventive Medicine of the Queen Mary University of London.

Dr. Wald acknowledged, however, that his study did not address whether patients would be better served by a staged approach that delayed preventive PCI of significant, noninfarct related stenoses in a second PCI procedure, whether the benefits extend to treating noninfarct stenoses that occlude less than half of a coronary artery, and whether a similar strategy would help patients with non-ST–elevation MI (NSTEMI).

The Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial enrolled consecutive patients of any age at five U.K. centers during April 2008 to January 2013. The study focused on STEMI patients because patients with a NSTEMI often do not have a clearly identifiable infarct-related artery. In addition, to qualify for entry, the patient’s infarct-related artery had to have been successfully treated by PCI and they had to have at least one other coronary artery with at least 50% stenosis judged treatable by PCI. Patients with coronary anatomy more appropriately treated with bypass surgery were excluded. The enrolled patients averaged 62 years of age, about three-quarters were men, and about 18% had diabetes. Roughly two-thirds had a second coronary artery with a greater than 50% stenosis, and the remaining patients had two coronary arteries with a significant lesion.

After successful treatment of the infarct-producing artery, patients with additional, significant lesions judged appropriate for PCI were randomized to either have their other significant lesions treated during the same procedure or to undergo no further intervention. This resulted in an average of 1.36 additional arteries undergoing PCI in the 234 patients randomized to the more aggressive protocol.

Following the PCI procedures, all patients received standard medical treatment: daily treatment with aspirin and a second antiplatelet drug, clopidogrel (Plavix), prasugrel (Effient), or ticagrelor (Brilinta). About 95% of patients in both study arms also received treatment with a statin, and about 90% received a beta-blocker and an angiotensin-converting enzyme inhibitor.

During an average follow-up of 23 months, the combined rate of death from cardiac causes, nonfatal MI, or refractory angina – the study’s primary endpoint – occurred in 9% of the patients randomized to immediate PCI of their noninfarct-related stenoses and in 23% of the 231 patients in the control arm, a statistically significant difference. The 14-percentage-point absolute reduction in endpoints translated into a 65% relative risk reduction. The rate of cardiac death or nonfatal MI was 5% in the patients who received added PCI while in the catheterization laboratory and 12% among those only treated in their infarct-related artery, also a statistically significant difference.

Additional analyses also showed statistically significantly lower rates of both nonfatal MI and refractory angina in the patients treated in multiple arteries when these endpoints were tallied individually and a strong trend toward fewer cardiac deaths in these patients as well. Kaplan-Meier analysis showed that the risk reduction in the preventive-PCI group was evident after 6 months of follow-up and then increased with continued follow-up.

These results were not materially affected by patient age, sex, diabetes status, infarct location, or the number of coronary arteries with significant stenoses. In addition, the complication rates, including procedure-related strokes, bleeding requiring transfusions or surgery, and contrast-induced nephropathy requiring dialysis, were similar in the two study arms.

The results were consistent with reports from two prior randomized trials that also assessed the value of preventive PCI in patients with acute STEMI, but in fewer patients. One of these prior studies involved a total of 69 patients (Int. J. Cardiovasc. Intervent. 2004;6:128-33), and the second enrolled a total of 214 patients (Heart 2010;96:662-7); both were limited by a lack of statistical power, and both relied on repeat revascularization as an endpoint, which may be subject to bias, Dr. Wald said.

Dr. Wald said that he a director for and shareholder in Polypill Ltd.

[email protected]

On Twitter @mitchelzoler

AMSTERDAM – In patients with acute ST-segment elevation myocardial infarction, stenting of significant coronary stenoses not responsible for the infarction as well as the infarct-producing lesion led to substantially better outcomes than an intervention that only targeted the infarct-related stenosis in a randomized, multicenter trial with 465 patients.

The results appeared to refute the prevailing recommendation from cardiology societies to limit the percutaneous coronary intervention (PCI) done during acute treatment of ST-segment elevation myocardial infarction (STEMI) to the infarct-related lesion, especially when the secondary lesions are not clearly causing ongoing hemodynamic instability.

Mitchel L. Zoler/IMNG Medial Media

The new findings "make it clear that preventive PCI is a better strategy than restricting a further intervention to those patients with refractory angina or a subsequent myocardial infarction," Dr. David S. Wald reported on Sept. 1 at the annual congress of the European Society of Cardiology. Simultaneous with Dr. Wald’s report, the results appeared in an article published online (N. Engl. J. Med. 2013 [doi:10.156/NEJMoa1305520]).

Current guidelines on management of STEMI recommend PCI for the infarct-related artery only (Eur. Heart J. 2012;33:2569-619; Circulation 2013;127:529-55), primarily because, until now, scant evidence existed that a different strategy helped patients. "This uncertainty has led to variations in practice, with some cardiologists performing immediate preventive PCI in spite of the guidelines, some delaying preventive PCI until recovery from the acute episode, and others limiting the procedure to patients with recurrent symptoms or evidence of ischemia," noted Dr. Wald, an interventional cardiologist at the Wolfson Institute of Preventive Medicine of the Queen Mary University of London.

Dr. Wald acknowledged, however, that his study did not address whether patients would be better served by a staged approach that delayed preventive PCI of significant, noninfarct related stenoses in a second PCI procedure, whether the benefits extend to treating noninfarct stenoses that occlude less than half of a coronary artery, and whether a similar strategy would help patients with non-ST–elevation MI (NSTEMI).

The Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial enrolled consecutive patients of any age at five U.K. centers during April 2008 to January 2013. The study focused on STEMI patients because patients with a NSTEMI often do not have a clearly identifiable infarct-related artery. In addition, to qualify for entry, the patient’s infarct-related artery had to have been successfully treated by PCI and they had to have at least one other coronary artery with at least 50% stenosis judged treatable by PCI. Patients with coronary anatomy more appropriately treated with bypass surgery were excluded. The enrolled patients averaged 62 years of age, about three-quarters were men, and about 18% had diabetes. Roughly two-thirds had a second coronary artery with a greater than 50% stenosis, and the remaining patients had two coronary arteries with a significant lesion.

After successful treatment of the infarct-producing artery, patients with additional, significant lesions judged appropriate for PCI were randomized to either have their other significant lesions treated during the same procedure or to undergo no further intervention. This resulted in an average of 1.36 additional arteries undergoing PCI in the 234 patients randomized to the more aggressive protocol.

Following the PCI procedures, all patients received standard medical treatment: daily treatment with aspirin and a second antiplatelet drug, clopidogrel (Plavix), prasugrel (Effient), or ticagrelor (Brilinta). About 95% of patients in both study arms also received treatment with a statin, and about 90% received a beta-blocker and an angiotensin-converting enzyme inhibitor.

During an average follow-up of 23 months, the combined rate of death from cardiac causes, nonfatal MI, or refractory angina – the study’s primary endpoint – occurred in 9% of the patients randomized to immediate PCI of their noninfarct-related stenoses and in 23% of the 231 patients in the control arm, a statistically significant difference. The 14-percentage-point absolute reduction in endpoints translated into a 65% relative risk reduction. The rate of cardiac death or nonfatal MI was 5% in the patients who received added PCI while in the catheterization laboratory and 12% among those only treated in their infarct-related artery, also a statistically significant difference.

Additional analyses also showed statistically significantly lower rates of both nonfatal MI and refractory angina in the patients treated in multiple arteries when these endpoints were tallied individually and a strong trend toward fewer cardiac deaths in these patients as well. Kaplan-Meier analysis showed that the risk reduction in the preventive-PCI group was evident after 6 months of follow-up and then increased with continued follow-up.

These results were not materially affected by patient age, sex, diabetes status, infarct location, or the number of coronary arteries with significant stenoses. In addition, the complication rates, including procedure-related strokes, bleeding requiring transfusions or surgery, and contrast-induced nephropathy requiring dialysis, were similar in the two study arms.

The results were consistent with reports from two prior randomized trials that also assessed the value of preventive PCI in patients with acute STEMI, but in fewer patients. One of these prior studies involved a total of 69 patients (Int. J. Cardiovasc. Intervent. 2004;6:128-33), and the second enrolled a total of 214 patients (Heart 2010;96:662-7); both were limited by a lack of statistical power, and both relied on repeat revascularization as an endpoint, which may be subject to bias, Dr. Wald said.

Dr. Wald said that he a director for and shareholder in Polypill Ltd.

[email protected]

On Twitter @mitchelzoler

Manual thrombus aspiration before percutaneous coronary intervention provided no significant benefit to early mortality over PCI alone in patients with ST-segment elevation myocardial infarction in the registry-based, randomized TASTE trial.

Among 7,244 patients with STEMI, the primary endpoint of all-cause mortality at 30 days was 2.8% with thrombus aspiration plus PCI and 3.0% with PCI alone, a nonsignificant difference. The per-protocol analysis was also similar, at 2.6% and 2.9%, respectively.

Further, there was no significant effect of thrombus aspiration on any of the prespecified secondary outcomes, according to results presented at the annual congress of the European Society of Cardiology by Dr. Ole Fröbert and simultaneously published online (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1308789]).

The multicenter TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) trial provides intriguing results, but is unlikely to settle the debate over the benefits of using manual thrombus aspiration in this setting.

Based on the current TASTE results, the mortality benefit observed with thrombus aspiration in earlier clinical trials "may have been a chance finding," interventional cardiologists Dr. Robert A. Byrne and Dr. Adnan Kastrati, with the German heart center, Technical University of Munich, wrote in an accompanying editorial (N. Engl. J. Med. 2013 [doi:10.1056/NEJMe1310361]).

However, "many interventional cardiologists will continue to perform thrombus aspiration for now, contending that the results of the TASTE trial do not entirely exclude the possibility of a potential benefit of the procedure."

The editorialists, as well as Dr. Fröbert, pointed to the need for an updated analysis of outcomes at 12 months since it wasn’t until 12 months of follow-up that a significant mortality benefit emerged in the single-center Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study (TAPAS).

In addition, the reinfarction rate in TASTE was 40% lower with thrombus aspiration, and this magnitude of effect was significant at 1 year in TAPAS, said Dr. Fröbert of the department of cardiology, Örebro (Sweden) University Hospital.

The TASTE investigators enrolled 7,244 participants with STEMI or left bundle branch block from the online national Swedish Coronary Angiography and Angioplasty Registry (SCAAR), and randomized them 1:1 to manual thrombus aspiration followed by PCI or PCI alone. The use of platelet inhibitors or anticoagulants was at physician discretion.

SCAAR is part of the SWEDEHEART (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry of consecutive patients from all 29 Swedish coronary intervention centers and 1 Icelandic center. An additional center in Denmark was also included in the trial.

At 30 days, the aspiration-plus-PCI and PCI-only groups had similar rates of stent thrombosis (0.2% vs. 0.5%), target lesion revascularization (1.2% vs. 1.6%), and target vessel revascularization (1.8% vs. 2.2%), Dr. Fröbert reported.

Although a recent meta-analysis of 21 randomized trials identified a trend toward a higher risk of stroke with thrombectomy in STEMI patients undergoing primary angioplasty (Int. J. Cardiol. 2013;166:606-12), stroke and neurologic complications at discharge were identical at 0.5% (19 events vs. 18 events; odds ratio,1.06; P = .87).

In subgroup analyses, the results for 30-day mortality were consistent across all prespecified subgroups, including high-risk patients such as those with a TIMI (Thrombolysis in Myocardial Infarction) flow grade 0 or 1, thrombus grade 4 or 5 on a 5-point scale, and smokers, Dr. Fröbert reported.

The current results contrast with those of other studies, however, including a 2010 report by Dr. Fröbert showing higher mortality, after adjustment, with thrombus aspiration than PCI alone among a Swedish population (Int. J. Cardiol. 2010;145:572-3).

The inconsistent findings may be attributable to differences in follow-up, duration of symptoms, number of participating centers, and the finding that mechanical thrombectomy devices may be inferior to manual aspiration catheters, he noted in the article. Clot-busting drugs may also be more effective, as suggested by the INFUSE-AMI trial.

Further insights are expected from another larger manual thrombectomy trial, TOTAL, with a composite end point of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or new or worsening heart failure at 180 days.

Still, the TASTE trial is being heralded for its design and low-cost approach as a breakthrough in research that "can potentially release us from the circular (and expensive) trap of the randomized-versus-registry debate," wrote Dr. Michael S. Lauer, director, division of cardiovascular sciences, National Heart, Lung, and Blood Institute and Ralph D’Agostino Sr., Ph.D., professor of mathematics/Statistics, biostatistics, and epidemiology, Boston University, in a second editorial accompanying the study (N. Engl. J. Med. 2013 [doi:10.1056/NEJMe1310102]).

They acknowledged that a variety of hurdles must be overcome, including undertaking randomized registry trials in places where health care and clinical data are fragmented and of lower quality, but also that society can no longer afford to undertake randomized effectiveness trials that cost tens or hundreds of millions of dollars at a time when registries and other powerful digital platforms are available.

"Today it may be possible to design and conduct megatrials with what we have: bigger data and smaller budgets," they wrote. "Yet we must also recognize and acknowledge the daunting challenges that diverse groups of researchers and stakeholders must overcome to get there."

TASTE was funded by the Swedish Research Council and Swedish Association of Local Authorities and Regions. Dr. Fröbert also reported unrestricted grants from Terumo, Medtronic, and Vascular Solutions, and consultancy for Stentys and Biotronik. His coauthors reported financial ties with numerous research and commercial entities. Dr. Lauer, Dr. D’Agostino, and Dr. Byrne reported having no relevant financial conflicts. Dr. Kastrati reported receiving fees from Biotronik, the Medicines, Astra-Zeneca, MSD, St. Jude Medical, and Biosensors.

[email protected]

Manual thrombus aspiration before percutaneous coronary intervention provided no significant benefit to early mortality over PCI alone in patients with ST-segment elevation myocardial infarction in the registry-based, randomized TASTE trial.

Among 7,244 patients with STEMI, the primary endpoint of all-cause mortality at 30 days was 2.8% with thrombus aspiration plus PCI and 3.0% with PCI alone, a nonsignificant difference. The per-protocol analysis was also similar, at 2.6% and 2.9%, respectively.

Further, there was no significant effect of thrombus aspiration on any of the prespecified secondary outcomes, according to results presented at the annual congress of the European Society of Cardiology by Dr. Ole Fröbert and simultaneously published online (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1308789]).

The multicenter TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) trial provides intriguing results, but is unlikely to settle the debate over the benefits of using manual thrombus aspiration in this setting.

Based on the current TASTE results, the mortality benefit observed with thrombus aspiration in earlier clinical trials "may have been a chance finding," interventional cardiologists Dr. Robert A. Byrne and Dr. Adnan Kastrati, with the German heart center, Technical University of Munich, wrote in an accompanying editorial (N. Engl. J. Med. 2013 [doi:10.1056/NEJMe1310361]).

However, "many interventional cardiologists will continue to perform thrombus aspiration for now, contending that the results of the TASTE trial do not entirely exclude the possibility of a potential benefit of the procedure."

The editorialists, as well as Dr. Fröbert, pointed to the need for an updated analysis of outcomes at 12 months since it wasn’t until 12 months of follow-up that a significant mortality benefit emerged in the single-center Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study (TAPAS).

In addition, the reinfarction rate in TASTE was 40% lower with thrombus aspiration, and this magnitude of effect was significant at 1 year in TAPAS, said Dr. Fröbert of the department of cardiology, Örebro (Sweden) University Hospital.

The TASTE investigators enrolled 7,244 participants with STEMI or left bundle branch block from the online national Swedish Coronary Angiography and Angioplasty Registry (SCAAR), and randomized them 1:1 to manual thrombus aspiration followed by PCI or PCI alone. The use of platelet inhibitors or anticoagulants was at physician discretion.

SCAAR is part of the SWEDEHEART (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry of consecutive patients from all 29 Swedish coronary intervention centers and 1 Icelandic center. An additional center in Denmark was also included in the trial.

At 30 days, the aspiration-plus-PCI and PCI-only groups had similar rates of stent thrombosis (0.2% vs. 0.5%), target lesion revascularization (1.2% vs. 1.6%), and target vessel revascularization (1.8% vs. 2.2%), Dr. Fröbert reported.

Although a recent meta-analysis of 21 randomized trials identified a trend toward a higher risk of stroke with thrombectomy in STEMI patients undergoing primary angioplasty (Int. J. Cardiol. 2013;166:606-12), stroke and neurologic complications at discharge were identical at 0.5% (19 events vs. 18 events; odds ratio,1.06; P = .87).

In subgroup analyses, the results for 30-day mortality were consistent across all prespecified subgroups, including high-risk patients such as those with a TIMI (Thrombolysis in Myocardial Infarction) flow grade 0 or 1, thrombus grade 4 or 5 on a 5-point scale, and smokers, Dr. Fröbert reported.

The current results contrast with those of other studies, however, including a 2010 report by Dr. Fröbert showing higher mortality, after adjustment, with thrombus aspiration than PCI alone among a Swedish population (Int. J. Cardiol. 2010;145:572-3).

The inconsistent findings may be attributable to differences in follow-up, duration of symptoms, number of participating centers, and the finding that mechanical thrombectomy devices may be inferior to manual aspiration catheters, he noted in the article. Clot-busting drugs may also be more effective, as suggested by the INFUSE-AMI trial.

Further insights are expected from another larger manual thrombectomy trial, TOTAL, with a composite end point of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or new or worsening heart failure at 180 days.

Still, the TASTE trial is being heralded for its design and low-cost approach as a breakthrough in research that "can potentially release us from the circular (and expensive) trap of the randomized-versus-registry debate," wrote Dr. Michael S. Lauer, director, division of cardiovascular sciences, National Heart, Lung, and Blood Institute and Ralph D’Agostino Sr., Ph.D., professor of mathematics/Statistics, biostatistics, and epidemiology, Boston University, in a second editorial accompanying the study (N. Engl. J. Med. 2013 [doi:10.1056/NEJMe1310102]).

They acknowledged that a variety of hurdles must be overcome, including undertaking randomized registry trials in places where health care and clinical data are fragmented and of lower quality, but also that society can no longer afford to undertake randomized effectiveness trials that cost tens or hundreds of millions of dollars at a time when registries and other powerful digital platforms are available.

"Today it may be possible to design and conduct megatrials with what we have: bigger data and smaller budgets," they wrote. "Yet we must also recognize and acknowledge the daunting challenges that diverse groups of researchers and stakeholders must overcome to get there."

TASTE was funded by the Swedish Research Council and Swedish Association of Local Authorities and Regions. Dr. Fröbert also reported unrestricted grants from Terumo, Medtronic, and Vascular Solutions, and consultancy for Stentys and Biotronik. His coauthors reported financial ties with numerous research and commercial entities. Dr. Lauer, Dr. D’Agostino, and Dr. Byrne reported having no relevant financial conflicts. Dr. Kastrati reported receiving fees from Biotronik, the Medicines, Astra-Zeneca, MSD, St. Jude Medical, and Biosensors.

[email protected]

Manual thrombus aspiration before percutaneous coronary intervention provided no significant benefit to early mortality over PCI alone in patients with ST-segment elevation myocardial infarction in the registry-based, randomized TASTE trial.

Among 7,244 patients with STEMI, the primary endpoint of all-cause mortality at 30 days was 2.8% with thrombus aspiration plus PCI and 3.0% with PCI alone, a nonsignificant difference. The per-protocol analysis was also similar, at 2.6% and 2.9%, respectively.

Further, there was no significant effect of thrombus aspiration on any of the prespecified secondary outcomes, according to results presented at the annual congress of the European Society of Cardiology by Dr. Ole Fröbert and simultaneously published online (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1308789]).

The multicenter TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) trial provides intriguing results, but is unlikely to settle the debate over the benefits of using manual thrombus aspiration in this setting.

Based on the current TASTE results, the mortality benefit observed with thrombus aspiration in earlier clinical trials "may have been a chance finding," interventional cardiologists Dr. Robert A. Byrne and Dr. Adnan Kastrati, with the German heart center, Technical University of Munich, wrote in an accompanying editorial (N. Engl. J. Med. 2013 [doi:10.1056/NEJMe1310361]).

However, "many interventional cardiologists will continue to perform thrombus aspiration for now, contending that the results of the TASTE trial do not entirely exclude the possibility of a potential benefit of the procedure."

The editorialists, as well as Dr. Fröbert, pointed to the need for an updated analysis of outcomes at 12 months since it wasn’t until 12 months of follow-up that a significant mortality benefit emerged in the single-center Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study (TAPAS).

In addition, the reinfarction rate in TASTE was 40% lower with thrombus aspiration, and this magnitude of effect was significant at 1 year in TAPAS, said Dr. Fröbert of the department of cardiology, Örebro (Sweden) University Hospital.

The TASTE investigators enrolled 7,244 participants with STEMI or left bundle branch block from the online national Swedish Coronary Angiography and Angioplasty Registry (SCAAR), and randomized them 1:1 to manual thrombus aspiration followed by PCI or PCI alone. The use of platelet inhibitors or anticoagulants was at physician discretion.

SCAAR is part of the SWEDEHEART (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry of consecutive patients from all 29 Swedish coronary intervention centers and 1 Icelandic center. An additional center in Denmark was also included in the trial.

At 30 days, the aspiration-plus-PCI and PCI-only groups had similar rates of stent thrombosis (0.2% vs. 0.5%), target lesion revascularization (1.2% vs. 1.6%), and target vessel revascularization (1.8% vs. 2.2%), Dr. Fröbert reported.

Although a recent meta-analysis of 21 randomized trials identified a trend toward a higher risk of stroke with thrombectomy in STEMI patients undergoing primary angioplasty (Int. J. Cardiol. 2013;166:606-12), stroke and neurologic complications at discharge were identical at 0.5% (19 events vs. 18 events; odds ratio,1.06; P = .87).

In subgroup analyses, the results for 30-day mortality were consistent across all prespecified subgroups, including high-risk patients such as those with a TIMI (Thrombolysis in Myocardial Infarction) flow grade 0 or 1, thrombus grade 4 or 5 on a 5-point scale, and smokers, Dr. Fröbert reported.

The current results contrast with those of other studies, however, including a 2010 report by Dr. Fröbert showing higher mortality, after adjustment, with thrombus aspiration than PCI alone among a Swedish population (Int. J. Cardiol. 2010;145:572-3).

The inconsistent findings may be attributable to differences in follow-up, duration of symptoms, number of participating centers, and the finding that mechanical thrombectomy devices may be inferior to manual aspiration catheters, he noted in the article. Clot-busting drugs may also be more effective, as suggested by the INFUSE-AMI trial.

Further insights are expected from another larger manual thrombectomy trial, TOTAL, with a composite end point of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or new or worsening heart failure at 180 days.

Still, the TASTE trial is being heralded for its design and low-cost approach as a breakthrough in research that "can potentially release us from the circular (and expensive) trap of the randomized-versus-registry debate," wrote Dr. Michael S. Lauer, director, division of cardiovascular sciences, National Heart, Lung, and Blood Institute and Ralph D’Agostino Sr., Ph.D., professor of mathematics/Statistics, biostatistics, and epidemiology, Boston University, in a second editorial accompanying the study (N. Engl. J. Med. 2013 [doi:10.1056/NEJMe1310102]).

They acknowledged that a variety of hurdles must be overcome, including undertaking randomized registry trials in places where health care and clinical data are fragmented and of lower quality, but also that society can no longer afford to undertake randomized effectiveness trials that cost tens or hundreds of millions of dollars at a time when registries and other powerful digital platforms are available.

"Today it may be possible to design and conduct megatrials with what we have: bigger data and smaller budgets," they wrote. "Yet we must also recognize and acknowledge the daunting challenges that diverse groups of researchers and stakeholders must overcome to get there."

TASTE was funded by the Swedish Research Council and Swedish Association of Local Authorities and Regions. Dr. Fröbert also reported unrestricted grants from Terumo, Medtronic, and Vascular Solutions, and consultancy for Stentys and Biotronik. His coauthors reported financial ties with numerous research and commercial entities. Dr. Lauer, Dr. D’Agostino, and Dr. Byrne reported having no relevant financial conflicts. Dr. Kastrati reported receiving fees from Biotronik, the Medicines, Astra-Zeneca, MSD, St. Jude Medical, and Biosensors.

[email protected]

AMSTERDAM – Elderly patients who received the highest total equivalent doses of high-potency statins, such as atorvastatin or rosuvastatin, had a threefold decrease in the risk of developing dementia, according to a retrospective, observational study in Taiwan.

Dr. Tin-Tse Lin, who presented the study at the annual congress of the European Society of Cardiology, said that the mechanism might be due to the statins’ effect on cholesterol reduction, antithrombotic activity, and their anti-inflammatory effect. The study, however, showed that lesser-prescribed lovastatin at a higher dose was positively associated with dementia development. 

The findings add another piece to the statin-dementia puzzle and may alleviate some of the concerns with the so-called "brain fog" effect of statins, experts said.

Dr. Kim Williams Sr., chair of cardiology at Wayne State University, Detroit, said that the study "was very reassuring in that there was no real evidence of dementia with the statins that we tend to use, which are the more powerful ones." Older statins like lovastatin, however, are still of concern, said Dr. Williams, vice president of the American College of Cardiology, who was not involved in the study.

In 2012, the Food and Drug Administration added a warning to the statins’ label that the drugs could cause temporary memory loss and confusion.  Meanwhile, several studies, including a 2012 review, have found no causality or conclusive relationship between statins and cognitive impairment. 

For the Taiwanese study, researchers used a random sample of 1,000,000 people covered by the country’s National Health Insurance. They identified nearly 58,000 patients who were older than 65 years of age and without a history of dementia in 1997 and 1998. The patients were followed up for an average of 4.5 years. 

The study was divided into tertiles – low, medium, and high dosage – according to mean daily equivalent or total (across the entire follow-up period) equivalent dosage. 

The primary endpoint was new diagnosis of presenile and senile dementia. Patients with vascular dementia were excluded. 

More than 5,500 developed dementia. The remaining 52,000 patient served as controls. 

Results showed that the adjusted hazard ratios for dementia were significantly inversely associated with increased total or daily equivalent statin dosage among the tertiles. For total equivalent statin dosage, the hazard ratios for dementia were 0.77 (low dosage), 0.63 (medium), and 0.33 (high), compared with controls, all significant differences. For mean equivalent daily dosage, HRs for dementia were 0.62, 0.70, 0.42, respectively, compared with controls, also significant differences. 

The authors said that the protective effect of statins remained robust in different age, gender, and cardiovascular risk subgroups, with strong statistical trends. 

Dr. Lin of the National Taiwan University Hospital, Hsin-Chu, Taiwan, said he did not know whether the findings would apply to other ethnicities. 

He hypothesized that because disorders of cholesterol metabolism could lead to an increased incidence of cerebrovascular disease, and elevation of the cholesterol level may result in a high inflammatory status associated with neurodegeneration, "I think it is reasonable to say that statins may facilitate lowering the risk of dementia."

Prof. Terje R. Pedersen of the University of Oslo (Norway), who commented on the study, said that "It is implausible that statins have any impact on progression of Alzheimer’s disease, but it might be plausible to think that when you prevent extensive atherosclerosis, then you also prevent dementia."

The bottom line, said Dr. Williams, is that the study "adds another dimension to the idea that the stronger statins that are used in the highest doses have the best benefit. That’s certainly true for the cardiovascular risk and now with dementia prevention."

Dr. Lin and Dr. Williams had no relevant disclosures. Prof. Pedersen has received research grants from Merck and Pfizer; consultation fees from Merck, AstraZeneca, Pfizer, and Amgen; speaker honoraria from Merck, Pfizer, AstraZeneca, Roche, Novartis, Amgen, and GlaxoSmithKline.

[email protected]

On Twitter @NaseemSMiller

AMSTERDAM – Elderly patients who received the highest total equivalent doses of high-potency statins, such as atorvastatin or rosuvastatin, had a threefold decrease in the risk of developing dementia, according to a retrospective, observational study in Taiwan.

Dr. Tin-Tse Lin, who presented the study at the annual congress of the European Society of Cardiology, said that the mechanism might be due to the statins’ effect on cholesterol reduction, antithrombotic activity, and their anti-inflammatory effect. The study, however, showed that lesser-prescribed lovastatin at a higher dose was positively associated with dementia development. 

The findings add another piece to the statin-dementia puzzle and may alleviate some of the concerns with the so-called "brain fog" effect of statins, experts said.

Dr. Kim Williams Sr., chair of cardiology at Wayne State University, Detroit, said that the study "was very reassuring in that there was no real evidence of dementia with the statins that we tend to use, which are the more powerful ones." Older statins like lovastatin, however, are still of concern, said Dr. Williams, vice president of the American College of Cardiology, who was not involved in the study.

In 2012, the Food and Drug Administration added a warning to the statins’ label that the drugs could cause temporary memory loss and confusion.  Meanwhile, several studies, including a 2012 review, have found no causality or conclusive relationship between statins and cognitive impairment. 

For the Taiwanese study, researchers used a random sample of 1,000,000 people covered by the country’s National Health Insurance. They identified nearly 58,000 patients who were older than 65 years of age and without a history of dementia in 1997 and 1998. The patients were followed up for an average of 4.5 years. 

The study was divided into tertiles – low, medium, and high dosage – according to mean daily equivalent or total (across the entire follow-up period) equivalent dosage. 

The primary endpoint was new diagnosis of presenile and senile dementia. Patients with vascular dementia were excluded. 

More than 5,500 developed dementia. The remaining 52,000 patient served as controls. 

Results showed that the adjusted hazard ratios for dementia were significantly inversely associated with increased total or daily equivalent statin dosage among the tertiles. For total equivalent statin dosage, the hazard ratios for dementia were 0.77 (low dosage), 0.63 (medium), and 0.33 (high), compared with controls, all significant differences. For mean equivalent daily dosage, HRs for dementia were 0.62, 0.70, 0.42, respectively, compared with controls, also significant differences. 

The authors said that the protective effect of statins remained robust in different age, gender, and cardiovascular risk subgroups, with strong statistical trends. 

Dr. Lin of the National Taiwan University Hospital, Hsin-Chu, Taiwan, said he did not know whether the findings would apply to other ethnicities. 

He hypothesized that because disorders of cholesterol metabolism could lead to an increased incidence of cerebrovascular disease, and elevation of the cholesterol level may result in a high inflammatory status associated with neurodegeneration, "I think it is reasonable to say that statins may facilitate lowering the risk of dementia."

Prof. Terje R. Pedersen of the University of Oslo (Norway), who commented on the study, said that "It is implausible that statins have any impact on progression of Alzheimer’s disease, but it might be plausible to think that when you prevent extensive atherosclerosis, then you also prevent dementia."

The bottom line, said Dr. Williams, is that the study "adds another dimension to the idea that the stronger statins that are used in the highest doses have the best benefit. That’s certainly true for the cardiovascular risk and now with dementia prevention."

Dr. Lin and Dr. Williams had no relevant disclosures. Prof. Pedersen has received research grants from Merck and Pfizer; consultation fees from Merck, AstraZeneca, Pfizer, and Amgen; speaker honoraria from Merck, Pfizer, AstraZeneca, Roche, Novartis, Amgen, and GlaxoSmithKline.

[email protected]

On Twitter @NaseemSMiller

AMSTERDAM – Elderly patients who received the highest total equivalent doses of high-potency statins, such as atorvastatin or rosuvastatin, had a threefold decrease in the risk of developing dementia, according to a retrospective, observational study in Taiwan.

Dr. Tin-Tse Lin, who presented the study at the annual congress of the European Society of Cardiology, said that the mechanism might be due to the statins’ effect on cholesterol reduction, antithrombotic activity, and their anti-inflammatory effect. The study, however, showed that lesser-prescribed lovastatin at a higher dose was positively associated with dementia development. 

The findings add another piece to the statin-dementia puzzle and may alleviate some of the concerns with the so-called "brain fog" effect of statins, experts said.

Dr. Kim Williams Sr., chair of cardiology at Wayne State University, Detroit, said that the study "was very reassuring in that there was no real evidence of dementia with the statins that we tend to use, which are the more powerful ones." Older statins like lovastatin, however, are still of concern, said Dr. Williams, vice president of the American College of Cardiology, who was not involved in the study.

In 2012, the Food and Drug Administration added a warning to the statins’ label that the drugs could cause temporary memory loss and confusion.  Meanwhile, several studies, including a 2012 review, have found no causality or conclusive relationship between statins and cognitive impairment. 

For the Taiwanese study, researchers used a random sample of 1,000,000 people covered by the country’s National Health Insurance. They identified nearly 58,000 patients who were older than 65 years of age and without a history of dementia in 1997 and 1998. The patients were followed up for an average of 4.5 years. 

The study was divided into tertiles – low, medium, and high dosage – according to mean daily equivalent or total (across the entire follow-up period) equivalent dosage. 

The primary endpoint was new diagnosis of presenile and senile dementia. Patients with vascular dementia were excluded. 

More than 5,500 developed dementia. The remaining 52,000 patient served as controls. 

Results showed that the adjusted hazard ratios for dementia were significantly inversely associated with increased total or daily equivalent statin dosage among the tertiles. For total equivalent statin dosage, the hazard ratios for dementia were 0.77 (low dosage), 0.63 (medium), and 0.33 (high), compared with controls, all significant differences. For mean equivalent daily dosage, HRs for dementia were 0.62, 0.70, 0.42, respectively, compared with controls, also significant differences. 

The authors said that the protective effect of statins remained robust in different age, gender, and cardiovascular risk subgroups, with strong statistical trends. 

Dr. Lin of the National Taiwan University Hospital, Hsin-Chu, Taiwan, said he did not know whether the findings would apply to other ethnicities. 

He hypothesized that because disorders of cholesterol metabolism could lead to an increased incidence of cerebrovascular disease, and elevation of the cholesterol level may result in a high inflammatory status associated with neurodegeneration, "I think it is reasonable to say that statins may facilitate lowering the risk of dementia."

Prof. Terje R. Pedersen of the University of Oslo (Norway), who commented on the study, said that "It is implausible that statins have any impact on progression of Alzheimer’s disease, but it might be plausible to think that when you prevent extensive atherosclerosis, then you also prevent dementia."

The bottom line, said Dr. Williams, is that the study "adds another dimension to the idea that the stronger statins that are used in the highest doses have the best benefit. That’s certainly true for the cardiovascular risk and now with dementia prevention."

Dr. Lin and Dr. Williams had no relevant disclosures. Prof. Pedersen has received research grants from Merck and Pfizer; consultation fees from Merck, AstraZeneca, Pfizer, and Amgen; speaker honoraria from Merck, Pfizer, AstraZeneca, Roche, Novartis, Amgen, and GlaxoSmithKline.

[email protected]

On Twitter @NaseemSMiller