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VIDEO: Anacetrapib doubles HDL, but patients gain from its modest LDL cut
BARCELONA – After years of neutral study results in pivotal trials, a drug that raises patients’ high-density lipoprotein cholesterol finally showed a statistically significant and clinically meaningful benefit in a major trial with more than 30,000 patients run for 4 years.
The only catch? It didn’t seem to work by raising HDL.
Instead, it was the off-target effect of also lowering low density lipoprotein (LDL) cholesterol that seems to have driven a modest but clinically significant benefit from anacetrapib, a member of the class of drugs that inhibit the cholesterol ester transfer protein that includes the trial flame-out agents torcetrapib, dalcetrapib, and evacetrapib.
Daily treatment with 100 mg of anacetrapib on top of intensive therapy with atorvastatin led to a 9% relative risk reduction in major coronary events that didn’t become apparent compared with placebo until patients took the drug for more than 2 years, and was “well tolerated,” with a notably benign safety profile, Martin Landray, MD, said at the annual congress of the European Society of Cardiology.
“This is a drug that would have a role clinically, along the lines of ezetimibe,” said Louise Bowman, MD, a clinical epidemiologist and clinical trialist at Oxford who served with Dr. Landray as coprincipal investigator on the study.
Even at a time when proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors are now routinely available to produce profound reductions in LDL cholesterol, a drug like anacetrapib that produces a more modest reduction can have a clinically useful role, she said. Having anacetrapib available as another option for safely lowering LDL cholesterol “could be complementary” to the lipid-lowering drug classes already in use, Dr. Bowman stressed in a video interview.
“This was a very well treated population on an intensive statin dosage, but when we added the new drug on top of that we saw a clear additional benefit.”
Despite this now proven potential to make a clinical impact, executives at Merck, the company developing anacetrapib, and a cosponsor of this trial, have not yet decided how to follow up on the results. A statement released by the company just before Dr. Landray’s report said: “Merck continues to review the results of the trial with external experts, and will consider whether to file new drug applications with the [Food and Drug Administration] and other regulatory agencies.”
The results also provided a striking lesson that proving a new drug’s value can require running a very large trial for several years.
“Why was this trial positive” when the earlier trials with torcetrapib, dalcetrapib, and evacetrapib were not? “One reason is that our trial had twice as many patients and twice as many events with much longer follow-up,” Dr. Landray said.
Concurrently with his report, the results appeared in an article published online (N Engl J Med. 2017 Aug 29. doi: 10.1056/NEJMoa1706444).
The Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial enrolled 30,449 patients at 431 centers in North America, Europe, and China. The average age of the patients was 67 years. Patients had to have established arterial disease: 88% had coronary artery disease, 22% had cerebrovascular disease, and 8% had peripheral artery disease (numbers total more than 100% because some patients had documented disease in more than one arterial bed). The average level of LDL cholesterol was 61 mg/dL, HDL cholesterol was 40 mg/dL, and non-HDL cholesterol averaged 92 mg/dL. During anacetrapib treatment HDL levels roughly doubled, while levels of non-HDL cholesterol fell by an average of 18%.
After a median treatment time of 4.1 years, the study’s primary endpoint – the combined rate of coronary death, nonfatal MI, or need for coronary revascularization – occurred in 10.8% of the patient on anacetrapib and in 11.8% of those in the placebo-control group, a 9% relative risk reduction that was consistent across all prespecified subgroups of patients in the study.
This level of benefit compared with the degree of non-HDL cholesterol lowering observed was strikingly consistent with the relationships between achieved lipid reductions and the clinical results seen in all the published studies with statins and with ezetimibe.
“Anacetrapib lowers LDL and raises HDL, so we knew it would be difficult to disentangle” which effects led to the clinical benefits seen, said Dr. Bowman. But the magnitude of the non-HDL lowering effect relative to the observed benefit “lined up very nicely” with the effects in the statin and ezetimibe trials. On the other hand, “if you double HDL cholesterol you’d expect to see a substantial contribution from that, and we did not, so if the HDL-lowering has an effect it’s probably small,” she said, cautioning that right now this is just an unproven inference. “Our findings are consistent with an LDL effect.”
REVEAL’s other major finding was anacetrapib’s good safety and tolerance profile, with 85% of patients randomized to receive anacetrapib continuing to take the drug through the end of the study. Treatment with the drug linked with a small but statistically significant 0.6% drop in the incidence of diabetes compared with placebo patients, and a small but statistically significant 0.84% increase in new onset stage 3 chronic kidney disease but with no increase in serious adverse events associated with kidney failure. The drug’s use showed no suggestion of a link with cancer, liver disease, muscle effects, cognitive effects, infections, or other serious or nonserious adverse effects. Patients on anacetrapib had on average a systolic blood pressure that was 0.7 mm Hg higher than that of patients on placebo and a diastolic blood pressure that averaged 0.3 mm Hg higher compared with the placebo group. The rate of hypertension-associated serious adverse events was low and virtually identical in the two study groups.
REVEAL received partial funding from Merck, the company developing anacetrapib. Dr. Landray and Dr. Bowman had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @mitchelzoler
The REVEAL results show for the first time that targeting the cholesterol ester transfer protein mechanism can result in a decrease in coronary events, even in patients with low baseline levels of cholesterol. The findings hold promise for the strategy of targeting this mechanism. But it’s very difficult to dissect out whether the benefits seen were largely due to increasing HDL cholesterol or reducing LDL cholesterol.
About half the enrolled patients had a baseline HDL cholesterol level of less than 40 mg/dL, the type of patient most likely to benefit from raising HDL levels. Another uncertainty when raising HDL cholesterol is whether the induced HDL has the physical and functional properties of the HDL cholesterol that exists in healthy people with normal HDL levels. We can’t exclude the possibility that the HDL cholesterol induced by anacetrapib doesn’t translate into improved physiologic function and clinical benefit. On the other hand, we cannot exclude a possible contribution from HDL.
It is also worth noting that the potential exists to pair anacetrapib treatment with another lipid-lowering treatment with a complimentary mechanism of action, specifically ezetimibe.
M. John Chapman, PhD , is a professor at the Pierre and Marie Curie University in Paris. He has received honoraria from Merck and also from Amgen, Kowa, Pfizer, Regeneron, Sanofi, Servier, and Unilever. He made these comments as designated discussant for the REVEAL report.
The REVEAL results show for the first time that targeting the cholesterol ester transfer protein mechanism can result in a decrease in coronary events, even in patients with low baseline levels of cholesterol. The findings hold promise for the strategy of targeting this mechanism. But it’s very difficult to dissect out whether the benefits seen were largely due to increasing HDL cholesterol or reducing LDL cholesterol.
About half the enrolled patients had a baseline HDL cholesterol level of less than 40 mg/dL, the type of patient most likely to benefit from raising HDL levels. Another uncertainty when raising HDL cholesterol is whether the induced HDL has the physical and functional properties of the HDL cholesterol that exists in healthy people with normal HDL levels. We can’t exclude the possibility that the HDL cholesterol induced by anacetrapib doesn’t translate into improved physiologic function and clinical benefit. On the other hand, we cannot exclude a possible contribution from HDL.
It is also worth noting that the potential exists to pair anacetrapib treatment with another lipid-lowering treatment with a complimentary mechanism of action, specifically ezetimibe.
M. John Chapman, PhD , is a professor at the Pierre and Marie Curie University in Paris. He has received honoraria from Merck and also from Amgen, Kowa, Pfizer, Regeneron, Sanofi, Servier, and Unilever. He made these comments as designated discussant for the REVEAL report.
The REVEAL results show for the first time that targeting the cholesterol ester transfer protein mechanism can result in a decrease in coronary events, even in patients with low baseline levels of cholesterol. The findings hold promise for the strategy of targeting this mechanism. But it’s very difficult to dissect out whether the benefits seen were largely due to increasing HDL cholesterol or reducing LDL cholesterol.
About half the enrolled patients had a baseline HDL cholesterol level of less than 40 mg/dL, the type of patient most likely to benefit from raising HDL levels. Another uncertainty when raising HDL cholesterol is whether the induced HDL has the physical and functional properties of the HDL cholesterol that exists in healthy people with normal HDL levels. We can’t exclude the possibility that the HDL cholesterol induced by anacetrapib doesn’t translate into improved physiologic function and clinical benefit. On the other hand, we cannot exclude a possible contribution from HDL.
It is also worth noting that the potential exists to pair anacetrapib treatment with another lipid-lowering treatment with a complimentary mechanism of action, specifically ezetimibe.
M. John Chapman, PhD , is a professor at the Pierre and Marie Curie University in Paris. He has received honoraria from Merck and also from Amgen, Kowa, Pfizer, Regeneron, Sanofi, Servier, and Unilever. He made these comments as designated discussant for the REVEAL report.
BARCELONA – After years of neutral study results in pivotal trials, a drug that raises patients’ high-density lipoprotein cholesterol finally showed a statistically significant and clinically meaningful benefit in a major trial with more than 30,000 patients run for 4 years.
The only catch? It didn’t seem to work by raising HDL.
Instead, it was the off-target effect of also lowering low density lipoprotein (LDL) cholesterol that seems to have driven a modest but clinically significant benefit from anacetrapib, a member of the class of drugs that inhibit the cholesterol ester transfer protein that includes the trial flame-out agents torcetrapib, dalcetrapib, and evacetrapib.
Daily treatment with 100 mg of anacetrapib on top of intensive therapy with atorvastatin led to a 9% relative risk reduction in major coronary events that didn’t become apparent compared with placebo until patients took the drug for more than 2 years, and was “well tolerated,” with a notably benign safety profile, Martin Landray, MD, said at the annual congress of the European Society of Cardiology.
“This is a drug that would have a role clinically, along the lines of ezetimibe,” said Louise Bowman, MD, a clinical epidemiologist and clinical trialist at Oxford who served with Dr. Landray as coprincipal investigator on the study.
Even at a time when proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors are now routinely available to produce profound reductions in LDL cholesterol, a drug like anacetrapib that produces a more modest reduction can have a clinically useful role, she said. Having anacetrapib available as another option for safely lowering LDL cholesterol “could be complementary” to the lipid-lowering drug classes already in use, Dr. Bowman stressed in a video interview.
“This was a very well treated population on an intensive statin dosage, but when we added the new drug on top of that we saw a clear additional benefit.”
Despite this now proven potential to make a clinical impact, executives at Merck, the company developing anacetrapib, and a cosponsor of this trial, have not yet decided how to follow up on the results. A statement released by the company just before Dr. Landray’s report said: “Merck continues to review the results of the trial with external experts, and will consider whether to file new drug applications with the [Food and Drug Administration] and other regulatory agencies.”
The results also provided a striking lesson that proving a new drug’s value can require running a very large trial for several years.
“Why was this trial positive” when the earlier trials with torcetrapib, dalcetrapib, and evacetrapib were not? “One reason is that our trial had twice as many patients and twice as many events with much longer follow-up,” Dr. Landray said.
Concurrently with his report, the results appeared in an article published online (N Engl J Med. 2017 Aug 29. doi: 10.1056/NEJMoa1706444).
The Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial enrolled 30,449 patients at 431 centers in North America, Europe, and China. The average age of the patients was 67 years. Patients had to have established arterial disease: 88% had coronary artery disease, 22% had cerebrovascular disease, and 8% had peripheral artery disease (numbers total more than 100% because some patients had documented disease in more than one arterial bed). The average level of LDL cholesterol was 61 mg/dL, HDL cholesterol was 40 mg/dL, and non-HDL cholesterol averaged 92 mg/dL. During anacetrapib treatment HDL levels roughly doubled, while levels of non-HDL cholesterol fell by an average of 18%.
After a median treatment time of 4.1 years, the study’s primary endpoint – the combined rate of coronary death, nonfatal MI, or need for coronary revascularization – occurred in 10.8% of the patient on anacetrapib and in 11.8% of those in the placebo-control group, a 9% relative risk reduction that was consistent across all prespecified subgroups of patients in the study.
This level of benefit compared with the degree of non-HDL cholesterol lowering observed was strikingly consistent with the relationships between achieved lipid reductions and the clinical results seen in all the published studies with statins and with ezetimibe.
“Anacetrapib lowers LDL and raises HDL, so we knew it would be difficult to disentangle” which effects led to the clinical benefits seen, said Dr. Bowman. But the magnitude of the non-HDL lowering effect relative to the observed benefit “lined up very nicely” with the effects in the statin and ezetimibe trials. On the other hand, “if you double HDL cholesterol you’d expect to see a substantial contribution from that, and we did not, so if the HDL-lowering has an effect it’s probably small,” she said, cautioning that right now this is just an unproven inference. “Our findings are consistent with an LDL effect.”
REVEAL’s other major finding was anacetrapib’s good safety and tolerance profile, with 85% of patients randomized to receive anacetrapib continuing to take the drug through the end of the study. Treatment with the drug linked with a small but statistically significant 0.6% drop in the incidence of diabetes compared with placebo patients, and a small but statistically significant 0.84% increase in new onset stage 3 chronic kidney disease but with no increase in serious adverse events associated with kidney failure. The drug’s use showed no suggestion of a link with cancer, liver disease, muscle effects, cognitive effects, infections, or other serious or nonserious adverse effects. Patients on anacetrapib had on average a systolic blood pressure that was 0.7 mm Hg higher than that of patients on placebo and a diastolic blood pressure that averaged 0.3 mm Hg higher compared with the placebo group. The rate of hypertension-associated serious adverse events was low and virtually identical in the two study groups.
REVEAL received partial funding from Merck, the company developing anacetrapib. Dr. Landray and Dr. Bowman had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @mitchelzoler
BARCELONA – After years of neutral study results in pivotal trials, a drug that raises patients’ high-density lipoprotein cholesterol finally showed a statistically significant and clinically meaningful benefit in a major trial with more than 30,000 patients run for 4 years.
The only catch? It didn’t seem to work by raising HDL.
Instead, it was the off-target effect of also lowering low density lipoprotein (LDL) cholesterol that seems to have driven a modest but clinically significant benefit from anacetrapib, a member of the class of drugs that inhibit the cholesterol ester transfer protein that includes the trial flame-out agents torcetrapib, dalcetrapib, and evacetrapib.
Daily treatment with 100 mg of anacetrapib on top of intensive therapy with atorvastatin led to a 9% relative risk reduction in major coronary events that didn’t become apparent compared with placebo until patients took the drug for more than 2 years, and was “well tolerated,” with a notably benign safety profile, Martin Landray, MD, said at the annual congress of the European Society of Cardiology.
“This is a drug that would have a role clinically, along the lines of ezetimibe,” said Louise Bowman, MD, a clinical epidemiologist and clinical trialist at Oxford who served with Dr. Landray as coprincipal investigator on the study.
Even at a time when proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors are now routinely available to produce profound reductions in LDL cholesterol, a drug like anacetrapib that produces a more modest reduction can have a clinically useful role, she said. Having anacetrapib available as another option for safely lowering LDL cholesterol “could be complementary” to the lipid-lowering drug classes already in use, Dr. Bowman stressed in a video interview.
“This was a very well treated population on an intensive statin dosage, but when we added the new drug on top of that we saw a clear additional benefit.”
Despite this now proven potential to make a clinical impact, executives at Merck, the company developing anacetrapib, and a cosponsor of this trial, have not yet decided how to follow up on the results. A statement released by the company just before Dr. Landray’s report said: “Merck continues to review the results of the trial with external experts, and will consider whether to file new drug applications with the [Food and Drug Administration] and other regulatory agencies.”
The results also provided a striking lesson that proving a new drug’s value can require running a very large trial for several years.
“Why was this trial positive” when the earlier trials with torcetrapib, dalcetrapib, and evacetrapib were not? “One reason is that our trial had twice as many patients and twice as many events with much longer follow-up,” Dr. Landray said.
Concurrently with his report, the results appeared in an article published online (N Engl J Med. 2017 Aug 29. doi: 10.1056/NEJMoa1706444).
The Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial enrolled 30,449 patients at 431 centers in North America, Europe, and China. The average age of the patients was 67 years. Patients had to have established arterial disease: 88% had coronary artery disease, 22% had cerebrovascular disease, and 8% had peripheral artery disease (numbers total more than 100% because some patients had documented disease in more than one arterial bed). The average level of LDL cholesterol was 61 mg/dL, HDL cholesterol was 40 mg/dL, and non-HDL cholesterol averaged 92 mg/dL. During anacetrapib treatment HDL levels roughly doubled, while levels of non-HDL cholesterol fell by an average of 18%.
After a median treatment time of 4.1 years, the study’s primary endpoint – the combined rate of coronary death, nonfatal MI, or need for coronary revascularization – occurred in 10.8% of the patient on anacetrapib and in 11.8% of those in the placebo-control group, a 9% relative risk reduction that was consistent across all prespecified subgroups of patients in the study.
This level of benefit compared with the degree of non-HDL cholesterol lowering observed was strikingly consistent with the relationships between achieved lipid reductions and the clinical results seen in all the published studies with statins and with ezetimibe.
“Anacetrapib lowers LDL and raises HDL, so we knew it would be difficult to disentangle” which effects led to the clinical benefits seen, said Dr. Bowman. But the magnitude of the non-HDL lowering effect relative to the observed benefit “lined up very nicely” with the effects in the statin and ezetimibe trials. On the other hand, “if you double HDL cholesterol you’d expect to see a substantial contribution from that, and we did not, so if the HDL-lowering has an effect it’s probably small,” she said, cautioning that right now this is just an unproven inference. “Our findings are consistent with an LDL effect.”
REVEAL’s other major finding was anacetrapib’s good safety and tolerance profile, with 85% of patients randomized to receive anacetrapib continuing to take the drug through the end of the study. Treatment with the drug linked with a small but statistically significant 0.6% drop in the incidence of diabetes compared with placebo patients, and a small but statistically significant 0.84% increase in new onset stage 3 chronic kidney disease but with no increase in serious adverse events associated with kidney failure. The drug’s use showed no suggestion of a link with cancer, liver disease, muscle effects, cognitive effects, infections, or other serious or nonserious adverse effects. Patients on anacetrapib had on average a systolic blood pressure that was 0.7 mm Hg higher than that of patients on placebo and a diastolic blood pressure that averaged 0.3 mm Hg higher compared with the placebo group. The rate of hypertension-associated serious adverse events was low and virtually identical in the two study groups.
REVEAL received partial funding from Merck, the company developing anacetrapib. Dr. Landray and Dr. Bowman had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: Patients treated with anacetrapib had a statistically significant 9% decrease in major coronary events, compared with placebo-treated controls.
Data source: REVEAL, a multicenter, pivotal trial with 30,449 patients treated for about 4 years.
Disclosures: REVEAL received partial funding from Merck, the company developing anacetrapib. Dr. Landray and Dr. Bowman had no disclosures.
VIDEO: Prescription-strength ibuprofen worsens blood pressure more than other NSAIDs
BARCELONA – Prescription-strength ibuprofen has a bigger adverse effect on blood pressure than celecoxib or naproxen, a finding that suggests a likely mechanism for the worse cardiovascular event rate documented in ibuprofen-treated arthritis patients in the PRECISION trial, Frank Ruschitzka, MD, said at the annual congress of the European Society of Cardiology.
“Prescription-strength ibuprofen is under pressure – it has a high incidence of new-onset hypertension, particularly when compared to the more selective COX-2 inhibitor celecoxib. Before we did this study, many would have said it’s the other way around,” observed Dr. Ruschitzka, professor of cardiology at the University of Zurich.
He presented the results of PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement).
“These results will have impact on your daily practice when you go home,” the cardiologist promised.
PRECISION-ABPM was a prespecified double-blind, randomized, 60-center substudy of the published PRECISION trial, which included 24,081 U.S. patients who needed daily NSAIDs for arthritis and were also at increased cardiovascular risk. They were randomized to the COX-2 inhibitor celecoxib at 100-200 mg b.i.d. or the nonselective NSAIDs ibuprofen at 600-800 mg three times a day or naproxen at 375-500 mg twice daily. Participants also received a proton pump inhibitor to protect against NSAID-related GI bleeding. In the on-treatment analysis, the ibuprofen group was significantly more likely to experience cardiovascular and all-cause mortality and renal events than were those on celecoxib (N Engl J Med. 2016 Dec 29;375[26]:2519-29).
The PRECISION-ABPM substudy included 444 arthritis patients, 92% of whom had osteoarthritis. During the 4-month study, investigators amassed roughly 60,000 automated blood pressure measurements across the three study arms.
The primary outcome was change from baseline in mean 24-hour systolic blood pressure (SBP). It increased by 3.7 mm Hg in the ibuprofen group and declined by 0.3 mm Hg in the celecoxib group, while the naproxen group occupied the middle ground with a 1.6-mm Hg increase.
The nearly 4-mm Hg increase in mean 24-hour SBP at 4 months in the ibuprofen group is of sufficient magnitude to be clinically important, Dr. Ruschitzka noted. He noted that fully 23.2% of ibuprofen-treated patients who had normal baseline blood pressure developed hypertension as defined by a mean 24-hour SBP of at least 130 and/or a diastolic blood pressure of at least 80 mm Hg. In contrast, incident hypertension occurred in only 10.3% of the celecoxib group and 19% of naproxen-treated patients. Thus, the likelihood of developing hypertension was 61% less with celecoxib than ibuprofen and 51% less with celecoxib than naproxen.
Not treating chronic arthritic pain to avoid the cardiovascular risk of NSAIDs is not a legitimate option.
“Pain is a cardiovascular risk factor,” Dr. Ruschitzka emphasized. “It’s unethical not to treat it. If you don’t treat pain, the patient’s blood pressure goes up, heart rate goes up, and you’re driving patients into inactivity.”
Although he’s convinced there’s no such thing as a safe NSAID from a cardiovascular risk standpoint, the PRECISION and PRECISION-ABPM data show celecoxib is less unsafe than ibuprofen. And as for the oft-heard statement that naproxen is the safest NSAID for the heart, Dr. Ruschitzka snorted, “What an urban legend.”
Discussant Scott Solomon, MD, opined that, while PRECISION-ABPM doesn’t support the notion that conventional NSAIDs such as naproxen or ibuprofen are any safer than celecoxib, it would be wrong to conclude from the study that celecoxib doesn’t affect blood pressure and is safer than the others from a cardiovascular standpoint. That’s because the three study drugs weren’t compared in an equipotent way. Because of safety concerns, the Food and Drug Administration required that the daily dose of celecoxib be capped at the low end of the therapeutic range, while no such constraints were placed on the two nonselective NSAIDS.
“Compared to placebo, all NSAIDs likely raise blood pressure, especially in patients prone to hypertension, those with chronic kidney disease, the elderly – and this is exactly the type of patients who require NSAIDs for arthritis. Whichever NSAID is chosen, clinicians should be aware of this effect and treat hypertension according to guidelines,” said Dr. Solomon, director of noninvasive cardiology at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
Dr. Solomon has been a key figure in the COX-2 inhibitor controversy of the last decade. He was lead author of a 2005 review of data from clinical trials of COX-2 inhibitors for colorectal adenoma prevention, which concluded that the drugs had a cardiovascular safety issue in that setting (N Engl J Med. 2005 Mar 17;352[11]:1071-80).
“Our analysis of celecoxib concluded that a dose-dependent increase in cardiovascular events was there, was real, but notably occurred at doses which were substantially higher than what we typically use for patients with arthritis,” he said.
That report triggered a fevered reaction.
“Amid an enormous amount of hype, hyperbole, and hysteria, the safety of these agents was thrown into question, leading to the withdrawal of all but one of them from the market and a black-box warning around the one remaining agent, celecoxib,” he recalled.
Dr. Ruschitzka discussed his findings in a video interview.
PRECISION-ABPM was sponsored by Pfizer. Dr. Ruschitzka and Dr. Solomon reported having no financial conflicts of interest regarding their presentations.
BARCELONA – Prescription-strength ibuprofen has a bigger adverse effect on blood pressure than celecoxib or naproxen, a finding that suggests a likely mechanism for the worse cardiovascular event rate documented in ibuprofen-treated arthritis patients in the PRECISION trial, Frank Ruschitzka, MD, said at the annual congress of the European Society of Cardiology.
“Prescription-strength ibuprofen is under pressure – it has a high incidence of new-onset hypertension, particularly when compared to the more selective COX-2 inhibitor celecoxib. Before we did this study, many would have said it’s the other way around,” observed Dr. Ruschitzka, professor of cardiology at the University of Zurich.
He presented the results of PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement).
“These results will have impact on your daily practice when you go home,” the cardiologist promised.
PRECISION-ABPM was a prespecified double-blind, randomized, 60-center substudy of the published PRECISION trial, which included 24,081 U.S. patients who needed daily NSAIDs for arthritis and were also at increased cardiovascular risk. They were randomized to the COX-2 inhibitor celecoxib at 100-200 mg b.i.d. or the nonselective NSAIDs ibuprofen at 600-800 mg three times a day or naproxen at 375-500 mg twice daily. Participants also received a proton pump inhibitor to protect against NSAID-related GI bleeding. In the on-treatment analysis, the ibuprofen group was significantly more likely to experience cardiovascular and all-cause mortality and renal events than were those on celecoxib (N Engl J Med. 2016 Dec 29;375[26]:2519-29).
The PRECISION-ABPM substudy included 444 arthritis patients, 92% of whom had osteoarthritis. During the 4-month study, investigators amassed roughly 60,000 automated blood pressure measurements across the three study arms.
The primary outcome was change from baseline in mean 24-hour systolic blood pressure (SBP). It increased by 3.7 mm Hg in the ibuprofen group and declined by 0.3 mm Hg in the celecoxib group, while the naproxen group occupied the middle ground with a 1.6-mm Hg increase.
The nearly 4-mm Hg increase in mean 24-hour SBP at 4 months in the ibuprofen group is of sufficient magnitude to be clinically important, Dr. Ruschitzka noted. He noted that fully 23.2% of ibuprofen-treated patients who had normal baseline blood pressure developed hypertension as defined by a mean 24-hour SBP of at least 130 and/or a diastolic blood pressure of at least 80 mm Hg. In contrast, incident hypertension occurred in only 10.3% of the celecoxib group and 19% of naproxen-treated patients. Thus, the likelihood of developing hypertension was 61% less with celecoxib than ibuprofen and 51% less with celecoxib than naproxen.
Not treating chronic arthritic pain to avoid the cardiovascular risk of NSAIDs is not a legitimate option.
“Pain is a cardiovascular risk factor,” Dr. Ruschitzka emphasized. “It’s unethical not to treat it. If you don’t treat pain, the patient’s blood pressure goes up, heart rate goes up, and you’re driving patients into inactivity.”
Although he’s convinced there’s no such thing as a safe NSAID from a cardiovascular risk standpoint, the PRECISION and PRECISION-ABPM data show celecoxib is less unsafe than ibuprofen. And as for the oft-heard statement that naproxen is the safest NSAID for the heart, Dr. Ruschitzka snorted, “What an urban legend.”
Discussant Scott Solomon, MD, opined that, while PRECISION-ABPM doesn’t support the notion that conventional NSAIDs such as naproxen or ibuprofen are any safer than celecoxib, it would be wrong to conclude from the study that celecoxib doesn’t affect blood pressure and is safer than the others from a cardiovascular standpoint. That’s because the three study drugs weren’t compared in an equipotent way. Because of safety concerns, the Food and Drug Administration required that the daily dose of celecoxib be capped at the low end of the therapeutic range, while no such constraints were placed on the two nonselective NSAIDS.
“Compared to placebo, all NSAIDs likely raise blood pressure, especially in patients prone to hypertension, those with chronic kidney disease, the elderly – and this is exactly the type of patients who require NSAIDs for arthritis. Whichever NSAID is chosen, clinicians should be aware of this effect and treat hypertension according to guidelines,” said Dr. Solomon, director of noninvasive cardiology at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
Dr. Solomon has been a key figure in the COX-2 inhibitor controversy of the last decade. He was lead author of a 2005 review of data from clinical trials of COX-2 inhibitors for colorectal adenoma prevention, which concluded that the drugs had a cardiovascular safety issue in that setting (N Engl J Med. 2005 Mar 17;352[11]:1071-80).
“Our analysis of celecoxib concluded that a dose-dependent increase in cardiovascular events was there, was real, but notably occurred at doses which were substantially higher than what we typically use for patients with arthritis,” he said.
That report triggered a fevered reaction.
“Amid an enormous amount of hype, hyperbole, and hysteria, the safety of these agents was thrown into question, leading to the withdrawal of all but one of them from the market and a black-box warning around the one remaining agent, celecoxib,” he recalled.
Dr. Ruschitzka discussed his findings in a video interview.
PRECISION-ABPM was sponsored by Pfizer. Dr. Ruschitzka and Dr. Solomon reported having no financial conflicts of interest regarding their presentations.
BARCELONA – Prescription-strength ibuprofen has a bigger adverse effect on blood pressure than celecoxib or naproxen, a finding that suggests a likely mechanism for the worse cardiovascular event rate documented in ibuprofen-treated arthritis patients in the PRECISION trial, Frank Ruschitzka, MD, said at the annual congress of the European Society of Cardiology.
“Prescription-strength ibuprofen is under pressure – it has a high incidence of new-onset hypertension, particularly when compared to the more selective COX-2 inhibitor celecoxib. Before we did this study, many would have said it’s the other way around,” observed Dr. Ruschitzka, professor of cardiology at the University of Zurich.
He presented the results of PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement).
“These results will have impact on your daily practice when you go home,” the cardiologist promised.
PRECISION-ABPM was a prespecified double-blind, randomized, 60-center substudy of the published PRECISION trial, which included 24,081 U.S. patients who needed daily NSAIDs for arthritis and were also at increased cardiovascular risk. They were randomized to the COX-2 inhibitor celecoxib at 100-200 mg b.i.d. or the nonselective NSAIDs ibuprofen at 600-800 mg three times a day or naproxen at 375-500 mg twice daily. Participants also received a proton pump inhibitor to protect against NSAID-related GI bleeding. In the on-treatment analysis, the ibuprofen group was significantly more likely to experience cardiovascular and all-cause mortality and renal events than were those on celecoxib (N Engl J Med. 2016 Dec 29;375[26]:2519-29).
The PRECISION-ABPM substudy included 444 arthritis patients, 92% of whom had osteoarthritis. During the 4-month study, investigators amassed roughly 60,000 automated blood pressure measurements across the three study arms.
The primary outcome was change from baseline in mean 24-hour systolic blood pressure (SBP). It increased by 3.7 mm Hg in the ibuprofen group and declined by 0.3 mm Hg in the celecoxib group, while the naproxen group occupied the middle ground with a 1.6-mm Hg increase.
The nearly 4-mm Hg increase in mean 24-hour SBP at 4 months in the ibuprofen group is of sufficient magnitude to be clinically important, Dr. Ruschitzka noted. He noted that fully 23.2% of ibuprofen-treated patients who had normal baseline blood pressure developed hypertension as defined by a mean 24-hour SBP of at least 130 and/or a diastolic blood pressure of at least 80 mm Hg. In contrast, incident hypertension occurred in only 10.3% of the celecoxib group and 19% of naproxen-treated patients. Thus, the likelihood of developing hypertension was 61% less with celecoxib than ibuprofen and 51% less with celecoxib than naproxen.
Not treating chronic arthritic pain to avoid the cardiovascular risk of NSAIDs is not a legitimate option.
“Pain is a cardiovascular risk factor,” Dr. Ruschitzka emphasized. “It’s unethical not to treat it. If you don’t treat pain, the patient’s blood pressure goes up, heart rate goes up, and you’re driving patients into inactivity.”
Although he’s convinced there’s no such thing as a safe NSAID from a cardiovascular risk standpoint, the PRECISION and PRECISION-ABPM data show celecoxib is less unsafe than ibuprofen. And as for the oft-heard statement that naproxen is the safest NSAID for the heart, Dr. Ruschitzka snorted, “What an urban legend.”
Discussant Scott Solomon, MD, opined that, while PRECISION-ABPM doesn’t support the notion that conventional NSAIDs such as naproxen or ibuprofen are any safer than celecoxib, it would be wrong to conclude from the study that celecoxib doesn’t affect blood pressure and is safer than the others from a cardiovascular standpoint. That’s because the three study drugs weren’t compared in an equipotent way. Because of safety concerns, the Food and Drug Administration required that the daily dose of celecoxib be capped at the low end of the therapeutic range, while no such constraints were placed on the two nonselective NSAIDS.
“Compared to placebo, all NSAIDs likely raise blood pressure, especially in patients prone to hypertension, those with chronic kidney disease, the elderly – and this is exactly the type of patients who require NSAIDs for arthritis. Whichever NSAID is chosen, clinicians should be aware of this effect and treat hypertension according to guidelines,” said Dr. Solomon, director of noninvasive cardiology at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
Dr. Solomon has been a key figure in the COX-2 inhibitor controversy of the last decade. He was lead author of a 2005 review of data from clinical trials of COX-2 inhibitors for colorectal adenoma prevention, which concluded that the drugs had a cardiovascular safety issue in that setting (N Engl J Med. 2005 Mar 17;352[11]:1071-80).
“Our analysis of celecoxib concluded that a dose-dependent increase in cardiovascular events was there, was real, but notably occurred at doses which were substantially higher than what we typically use for patients with arthritis,” he said.
That report triggered a fevered reaction.
“Amid an enormous amount of hype, hyperbole, and hysteria, the safety of these agents was thrown into question, leading to the withdrawal of all but one of them from the market and a black-box warning around the one remaining agent, celecoxib,” he recalled.
Dr. Ruschitzka discussed his findings in a video interview.
PRECISION-ABPM was sponsored by Pfizer. Dr. Ruschitzka and Dr. Solomon reported having no financial conflicts of interest regarding their presentations.
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: Incident hypertension occurred within 4 months in 23.2% of arthritis patients on ibuprofen, compared with 10.3% taking celecoxib and 19% on naproxen.
Data source: This was a randomized, double-blind, multicenter, prospective trial including 444 arthritis patients at increased cardiovascular risk who underwent 4 months of ambulatory blood pressure monitoring after being assigned to prescription-strength ibuprofen, naproxen, or celecoxib.
Disclosures: The PRECISION-ABPM trial was sponsored by Pfizer. The presenter reported having no financial conflicts of interest.
VIDEO: Rivaroxaban plus aspirin cut cardiovascular events in stable patients
BARCELONA – Combined treatment with a very low dosage of the anticoagulant rivaroxaban plus low-dose aspirin produced significant cuts in major adverse coronary, cerebral, and peripheral artery disease events with just a modest rise in major bleeding events in patients with stable disease in the COMPASS pivotal, randomized trial with more than 27,000 patients.
The benefits from the rivaroxaban plus aspirin regimen included a statistically significant 24% relative risk reduction in the study’s primary, combined endpoint, and a significant 18% relative risk reduction in all-cause death compared with a standard regimen of aspirin only, John W. Eikelboom, MD, said at the annual congress of the European Society of Cardiology. In addition, analysis of the net clinical benefit from treatment that took into account both the major adverse cardiovascular events prevented and major bleeding events induced, showed that the rivaroxaban-plus-aspirin regimen cut these by a statistically significant 20%, compared with aspirin alone.
Other notable benefits documented by the findings included a statistically significant 42% relative risk reduction for stroke and a statistically significant 46% relative risk reduction in the incidence of major adverse limb events among the roughly one-quarter of enrolled patients who entered the study with evidence of peripheral artery disease.
These risk reductions are similar in magnitude to the secondary-prevention benefits produced by controlling hypertension or dyslipidemia, noted Dr. Eikelboom, a researcher at McMaster University in Hamilton, Ont. “In the future, rivaroxaban will take its place among the other foundational treatments for long-term, secondary prevention,” he predicted in a video interview.
The COMPASS trial produced “unambiguous results that should change guidelines and the management of stable coronary artery disease,” commented Eugene Braunwald, MD, designated discussant for Dr. Eikelboom’s report. The results are “an important step for thrombocardiology,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston.
Concurrently with Dr. Eikelboom’s report the results appeared in an article published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1709118). This publication also include an editorial by Dr. Braunwald (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMe1710241).
The Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial enrolled 27,395 patients with stable coronary, carotid, or peripheral artery disease, or a combination of two or more of these, at 602 centers in 33 countries. About 90% of enrolled patients had coronary artery disease and 27% had peripheral artery disease. The enrolled patients averaged 68 year old and were an average of 7 years removed from their index arterial event. Randomization assigned patients to receive 2.5 mg rivaroxaban (Xarelto) twice daily plus 100 mg aspirin daily, 5 mg rivaroxaban twice daily, or 100 mg aspirin once daily. The trial stopped early, after an average follow-up of 23 months, because of the overwhelming benefit seen for the rivaroxaban plus aspirin combination. The rivaroxaban-monotherapy arm failed to show any statistically significant benefits, compared with the aspirin-monotherapy control group.
The study’s primary endpoint – the combined rate of cardiovascular disease death, nonfatal stroke, and nonfatal MI – occurred in 4.1% of patients in the rivaroxaban-plus-aspirin group and in 5.4% of patients on aspirin alone. The rate of major bleeding events was 3.1% among patients on rivaroxaban plus aspirin and 1.9% in those who received aspirin only, a 51% relative increase among patients on the dual regimen, but the results showed no statistically significant increase in the rates of fatal bleeds, intracerebral bleeds, or bleeding in other critical organs.
Sonia Anand, MD, a colleague of Dr. Eikelboom’s at McMaster, presented a separate set of analyses that focused on the 7,470 enrolled patients who had been diagnosed at enrollment with peripheral artery disease. In this subgroup, the rivaroxaban-plus-aspirin regimen produced a statistically significant 28% relative risk reduction in the rate of the primary endpoint, compared with the aspirin control group. The dual regimen also produced a statistically significant 46% relative risk reduction in major adverse limb events and a significant 70% relative reduction in the incidence of major lower-extremity amputations, reported Dr. Anand, professor of medicine and director of the vascular medicine clinic at McMaster.
The COMPASS findings follow a 2012 published report from the ATLAS ACS 2-TIMI 51 trial showing that treatment with the same low-dose rivaroxaban regimen plus aspirin and a thienopyridine (clopidogrel or ticlopidine) reduced the same combined triple endpoint by a statistically significant 16%, compared with aspirin and a thienopyridine alone, in patients with a recent acute coronary syndrome event (N Engl J Med. 2012 Jan 5;366[1]:9-19). Despite this evidence, the Food and Drug Administration never approved the 2.5-mg formulation of rivaroxaban, nor did it approve marketing of rivaroxaban for this acute coronary syndrome population. This decision may have been driven in part by a problem with incomplete follow-up of several of the enrolled patients.
The COMPASS results were “very consistent” with the ATLAS ACS 2-TIMI 51 results. noted Dr. Eikelboom. “I think it’s time to look at these two trials in combination,” he suggested. Availability of the 2.5-mg rivaroxaban formulation used in both trials would allow “a treatment strategy that could start early after an acute coronary syndrome event and then extend long term,” he said.
COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.
[email protected]
On Twitter @mitchelzoler
The key message from COMPASS was that, although adding a very low dosage of rivaroxaban to aspirin in patients with stable coronary or peripheral artery disease resulted in a clear increase in major bleeding events, patients received an overall net beneficial effect from the combined regimen. The finding that clinches the net benefit from the rivaroxaban plus aspirin combination, compared with aspirin alone, was that the combined regimen produced a statistically significant relative risk reduction of 18% for all-cause mortality. This finding reinforces the idea that the primary outcome was beneficial despite an increase in major bleeding events.
The finding that rivaroxaban plus aspirin produced benefit with a modest increase in bleeding risk in patients with peripheral artery disease (PAD) is especially important because PAD is really difficult to treat. Very few interventions have previously been proven to have a beneficial effect for patients with PAD. It’s very important to find an intervention that can reduce critical limb ischemia events in addition to reducing coronary events, stroke, and overall mortality.
The very low dosage of rivaroxaban used in COMPASS, 2.5 mg twice daily, seems to be a very important part of the study’s design. This dosage appeared to hit the sweet spot of being large enough to reduce events but with a gentle enough anticoagulation effect to avoid a significant increase in fatal, intracerebral, or critical organ bleeds. However, the patients enrolled in COMPASS, like most patients who enter trials, were generally at a lower risk for bleeding complications than we usually see in routine practice in patients with stable coronary or peripheral artery disease. Presuming that the Food and Drug Administration will soon approve the 2.5-mg formulation of rivaroxaban used in COMPASS, clinicians will need to be careful using this regimen on patients at increased risk for bleeding, such as frail or elderly patients with a history of bleeding events or taking other treatments that could increase bleeding risk, such as nonsteroidal anti-inflammatory drugs. In general, clinicians are wary of using treatments that increase bleeding risk, and so they may hesitate to use this combination of rivaroxaban plus aspirin in patients with a high bleeding risk.
The success of the approach used in COMPASS became possible with the introduction of the new oral anticoagulant drugs. Now that this class of agents has been available for a few years, clinicians have grown increasingly comfortable with them, compared with warfarin. When the new oral anticoagulants first came out, many considered them similar to warfarin. Today, there is a better appreciation that these drugs are distinct from warfarin by really causing fewer bleeding complications.
Christopher B. Granger, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research support from Bayer and from other drugs companies that market new oral anticoagulants. He made these comments in an interview.
The key message from COMPASS was that, although adding a very low dosage of rivaroxaban to aspirin in patients with stable coronary or peripheral artery disease resulted in a clear increase in major bleeding events, patients received an overall net beneficial effect from the combined regimen. The finding that clinches the net benefit from the rivaroxaban plus aspirin combination, compared with aspirin alone, was that the combined regimen produced a statistically significant relative risk reduction of 18% for all-cause mortality. This finding reinforces the idea that the primary outcome was beneficial despite an increase in major bleeding events.
The finding that rivaroxaban plus aspirin produced benefit with a modest increase in bleeding risk in patients with peripheral artery disease (PAD) is especially important because PAD is really difficult to treat. Very few interventions have previously been proven to have a beneficial effect for patients with PAD. It’s very important to find an intervention that can reduce critical limb ischemia events in addition to reducing coronary events, stroke, and overall mortality.
The very low dosage of rivaroxaban used in COMPASS, 2.5 mg twice daily, seems to be a very important part of the study’s design. This dosage appeared to hit the sweet spot of being large enough to reduce events but with a gentle enough anticoagulation effect to avoid a significant increase in fatal, intracerebral, or critical organ bleeds. However, the patients enrolled in COMPASS, like most patients who enter trials, were generally at a lower risk for bleeding complications than we usually see in routine practice in patients with stable coronary or peripheral artery disease. Presuming that the Food and Drug Administration will soon approve the 2.5-mg formulation of rivaroxaban used in COMPASS, clinicians will need to be careful using this regimen on patients at increased risk for bleeding, such as frail or elderly patients with a history of bleeding events or taking other treatments that could increase bleeding risk, such as nonsteroidal anti-inflammatory drugs. In general, clinicians are wary of using treatments that increase bleeding risk, and so they may hesitate to use this combination of rivaroxaban plus aspirin in patients with a high bleeding risk.
The success of the approach used in COMPASS became possible with the introduction of the new oral anticoagulant drugs. Now that this class of agents has been available for a few years, clinicians have grown increasingly comfortable with them, compared with warfarin. When the new oral anticoagulants first came out, many considered them similar to warfarin. Today, there is a better appreciation that these drugs are distinct from warfarin by really causing fewer bleeding complications.
Christopher B. Granger, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research support from Bayer and from other drugs companies that market new oral anticoagulants. He made these comments in an interview.
The key message from COMPASS was that, although adding a very low dosage of rivaroxaban to aspirin in patients with stable coronary or peripheral artery disease resulted in a clear increase in major bleeding events, patients received an overall net beneficial effect from the combined regimen. The finding that clinches the net benefit from the rivaroxaban plus aspirin combination, compared with aspirin alone, was that the combined regimen produced a statistically significant relative risk reduction of 18% for all-cause mortality. This finding reinforces the idea that the primary outcome was beneficial despite an increase in major bleeding events.
The finding that rivaroxaban plus aspirin produced benefit with a modest increase in bleeding risk in patients with peripheral artery disease (PAD) is especially important because PAD is really difficult to treat. Very few interventions have previously been proven to have a beneficial effect for patients with PAD. It’s very important to find an intervention that can reduce critical limb ischemia events in addition to reducing coronary events, stroke, and overall mortality.
The very low dosage of rivaroxaban used in COMPASS, 2.5 mg twice daily, seems to be a very important part of the study’s design. This dosage appeared to hit the sweet spot of being large enough to reduce events but with a gentle enough anticoagulation effect to avoid a significant increase in fatal, intracerebral, or critical organ bleeds. However, the patients enrolled in COMPASS, like most patients who enter trials, were generally at a lower risk for bleeding complications than we usually see in routine practice in patients with stable coronary or peripheral artery disease. Presuming that the Food and Drug Administration will soon approve the 2.5-mg formulation of rivaroxaban used in COMPASS, clinicians will need to be careful using this regimen on patients at increased risk for bleeding, such as frail or elderly patients with a history of bleeding events or taking other treatments that could increase bleeding risk, such as nonsteroidal anti-inflammatory drugs. In general, clinicians are wary of using treatments that increase bleeding risk, and so they may hesitate to use this combination of rivaroxaban plus aspirin in patients with a high bleeding risk.
The success of the approach used in COMPASS became possible with the introduction of the new oral anticoagulant drugs. Now that this class of agents has been available for a few years, clinicians have grown increasingly comfortable with them, compared with warfarin. When the new oral anticoagulants first came out, many considered them similar to warfarin. Today, there is a better appreciation that these drugs are distinct from warfarin by really causing fewer bleeding complications.
Christopher B. Granger, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research support from Bayer and from other drugs companies that market new oral anticoagulants. He made these comments in an interview.
BARCELONA – Combined treatment with a very low dosage of the anticoagulant rivaroxaban plus low-dose aspirin produced significant cuts in major adverse coronary, cerebral, and peripheral artery disease events with just a modest rise in major bleeding events in patients with stable disease in the COMPASS pivotal, randomized trial with more than 27,000 patients.
The benefits from the rivaroxaban plus aspirin regimen included a statistically significant 24% relative risk reduction in the study’s primary, combined endpoint, and a significant 18% relative risk reduction in all-cause death compared with a standard regimen of aspirin only, John W. Eikelboom, MD, said at the annual congress of the European Society of Cardiology. In addition, analysis of the net clinical benefit from treatment that took into account both the major adverse cardiovascular events prevented and major bleeding events induced, showed that the rivaroxaban-plus-aspirin regimen cut these by a statistically significant 20%, compared with aspirin alone.
Other notable benefits documented by the findings included a statistically significant 42% relative risk reduction for stroke and a statistically significant 46% relative risk reduction in the incidence of major adverse limb events among the roughly one-quarter of enrolled patients who entered the study with evidence of peripheral artery disease.
These risk reductions are similar in magnitude to the secondary-prevention benefits produced by controlling hypertension or dyslipidemia, noted Dr. Eikelboom, a researcher at McMaster University in Hamilton, Ont. “In the future, rivaroxaban will take its place among the other foundational treatments for long-term, secondary prevention,” he predicted in a video interview.
The COMPASS trial produced “unambiguous results that should change guidelines and the management of stable coronary artery disease,” commented Eugene Braunwald, MD, designated discussant for Dr. Eikelboom’s report. The results are “an important step for thrombocardiology,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston.
Concurrently with Dr. Eikelboom’s report the results appeared in an article published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1709118). This publication also include an editorial by Dr. Braunwald (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMe1710241).
The Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial enrolled 27,395 patients with stable coronary, carotid, or peripheral artery disease, or a combination of two or more of these, at 602 centers in 33 countries. About 90% of enrolled patients had coronary artery disease and 27% had peripheral artery disease. The enrolled patients averaged 68 year old and were an average of 7 years removed from their index arterial event. Randomization assigned patients to receive 2.5 mg rivaroxaban (Xarelto) twice daily plus 100 mg aspirin daily, 5 mg rivaroxaban twice daily, or 100 mg aspirin once daily. The trial stopped early, after an average follow-up of 23 months, because of the overwhelming benefit seen for the rivaroxaban plus aspirin combination. The rivaroxaban-monotherapy arm failed to show any statistically significant benefits, compared with the aspirin-monotherapy control group.
The study’s primary endpoint – the combined rate of cardiovascular disease death, nonfatal stroke, and nonfatal MI – occurred in 4.1% of patients in the rivaroxaban-plus-aspirin group and in 5.4% of patients on aspirin alone. The rate of major bleeding events was 3.1% among patients on rivaroxaban plus aspirin and 1.9% in those who received aspirin only, a 51% relative increase among patients on the dual regimen, but the results showed no statistically significant increase in the rates of fatal bleeds, intracerebral bleeds, or bleeding in other critical organs.
Sonia Anand, MD, a colleague of Dr. Eikelboom’s at McMaster, presented a separate set of analyses that focused on the 7,470 enrolled patients who had been diagnosed at enrollment with peripheral artery disease. In this subgroup, the rivaroxaban-plus-aspirin regimen produced a statistically significant 28% relative risk reduction in the rate of the primary endpoint, compared with the aspirin control group. The dual regimen also produced a statistically significant 46% relative risk reduction in major adverse limb events and a significant 70% relative reduction in the incidence of major lower-extremity amputations, reported Dr. Anand, professor of medicine and director of the vascular medicine clinic at McMaster.
The COMPASS findings follow a 2012 published report from the ATLAS ACS 2-TIMI 51 trial showing that treatment with the same low-dose rivaroxaban regimen plus aspirin and a thienopyridine (clopidogrel or ticlopidine) reduced the same combined triple endpoint by a statistically significant 16%, compared with aspirin and a thienopyridine alone, in patients with a recent acute coronary syndrome event (N Engl J Med. 2012 Jan 5;366[1]:9-19). Despite this evidence, the Food and Drug Administration never approved the 2.5-mg formulation of rivaroxaban, nor did it approve marketing of rivaroxaban for this acute coronary syndrome population. This decision may have been driven in part by a problem with incomplete follow-up of several of the enrolled patients.
The COMPASS results were “very consistent” with the ATLAS ACS 2-TIMI 51 results. noted Dr. Eikelboom. “I think it’s time to look at these two trials in combination,” he suggested. Availability of the 2.5-mg rivaroxaban formulation used in both trials would allow “a treatment strategy that could start early after an acute coronary syndrome event and then extend long term,” he said.
COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.
[email protected]
On Twitter @mitchelzoler
BARCELONA – Combined treatment with a very low dosage of the anticoagulant rivaroxaban plus low-dose aspirin produced significant cuts in major adverse coronary, cerebral, and peripheral artery disease events with just a modest rise in major bleeding events in patients with stable disease in the COMPASS pivotal, randomized trial with more than 27,000 patients.
The benefits from the rivaroxaban plus aspirin regimen included a statistically significant 24% relative risk reduction in the study’s primary, combined endpoint, and a significant 18% relative risk reduction in all-cause death compared with a standard regimen of aspirin only, John W. Eikelboom, MD, said at the annual congress of the European Society of Cardiology. In addition, analysis of the net clinical benefit from treatment that took into account both the major adverse cardiovascular events prevented and major bleeding events induced, showed that the rivaroxaban-plus-aspirin regimen cut these by a statistically significant 20%, compared with aspirin alone.
Other notable benefits documented by the findings included a statistically significant 42% relative risk reduction for stroke and a statistically significant 46% relative risk reduction in the incidence of major adverse limb events among the roughly one-quarter of enrolled patients who entered the study with evidence of peripheral artery disease.
These risk reductions are similar in magnitude to the secondary-prevention benefits produced by controlling hypertension or dyslipidemia, noted Dr. Eikelboom, a researcher at McMaster University in Hamilton, Ont. “In the future, rivaroxaban will take its place among the other foundational treatments for long-term, secondary prevention,” he predicted in a video interview.
The COMPASS trial produced “unambiguous results that should change guidelines and the management of stable coronary artery disease,” commented Eugene Braunwald, MD, designated discussant for Dr. Eikelboom’s report. The results are “an important step for thrombocardiology,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston.
Concurrently with Dr. Eikelboom’s report the results appeared in an article published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1709118). This publication also include an editorial by Dr. Braunwald (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMe1710241).
The Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial enrolled 27,395 patients with stable coronary, carotid, or peripheral artery disease, or a combination of two or more of these, at 602 centers in 33 countries. About 90% of enrolled patients had coronary artery disease and 27% had peripheral artery disease. The enrolled patients averaged 68 year old and were an average of 7 years removed from their index arterial event. Randomization assigned patients to receive 2.5 mg rivaroxaban (Xarelto) twice daily plus 100 mg aspirin daily, 5 mg rivaroxaban twice daily, or 100 mg aspirin once daily. The trial stopped early, after an average follow-up of 23 months, because of the overwhelming benefit seen for the rivaroxaban plus aspirin combination. The rivaroxaban-monotherapy arm failed to show any statistically significant benefits, compared with the aspirin-monotherapy control group.
The study’s primary endpoint – the combined rate of cardiovascular disease death, nonfatal stroke, and nonfatal MI – occurred in 4.1% of patients in the rivaroxaban-plus-aspirin group and in 5.4% of patients on aspirin alone. The rate of major bleeding events was 3.1% among patients on rivaroxaban plus aspirin and 1.9% in those who received aspirin only, a 51% relative increase among patients on the dual regimen, but the results showed no statistically significant increase in the rates of fatal bleeds, intracerebral bleeds, or bleeding in other critical organs.
Sonia Anand, MD, a colleague of Dr. Eikelboom’s at McMaster, presented a separate set of analyses that focused on the 7,470 enrolled patients who had been diagnosed at enrollment with peripheral artery disease. In this subgroup, the rivaroxaban-plus-aspirin regimen produced a statistically significant 28% relative risk reduction in the rate of the primary endpoint, compared with the aspirin control group. The dual regimen also produced a statistically significant 46% relative risk reduction in major adverse limb events and a significant 70% relative reduction in the incidence of major lower-extremity amputations, reported Dr. Anand, professor of medicine and director of the vascular medicine clinic at McMaster.
The COMPASS findings follow a 2012 published report from the ATLAS ACS 2-TIMI 51 trial showing that treatment with the same low-dose rivaroxaban regimen plus aspirin and a thienopyridine (clopidogrel or ticlopidine) reduced the same combined triple endpoint by a statistically significant 16%, compared with aspirin and a thienopyridine alone, in patients with a recent acute coronary syndrome event (N Engl J Med. 2012 Jan 5;366[1]:9-19). Despite this evidence, the Food and Drug Administration never approved the 2.5-mg formulation of rivaroxaban, nor did it approve marketing of rivaroxaban for this acute coronary syndrome population. This decision may have been driven in part by a problem with incomplete follow-up of several of the enrolled patients.
The COMPASS results were “very consistent” with the ATLAS ACS 2-TIMI 51 results. noted Dr. Eikelboom. “I think it’s time to look at these two trials in combination,” he suggested. Availability of the 2.5-mg rivaroxaban formulation used in both trials would allow “a treatment strategy that could start early after an acute coronary syndrome event and then extend long term,” he said.
COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.
[email protected]
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: The dual regimen reduced the combined rate of cardiovascular disease events by 24%, compared with aspirin alone.
Data source: COMPASS is a multicenter, randomized controlled trial with 27,395 patients.
Disclosures: COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.
CANTOS sings of novel strategy for cardiovascular, cancer prevention
BARCELONA – Inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer in the groundbreaking phase III CANTOS trial, Paul M. Ridker, MD, reported at the annual congress of the European Society of Cardiology.
“These data provide the first proof that inflammation inhibition in the absence of lipid lowering can improve atherogenic outcomes and potentially alter progression of some fatal cancers,” declared Dr. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
“Just like we’ve learned that lower LDL is better, I think we’re now learning that lower inflammation is better,” he said.
CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) was a randomized, double-blind, placebo-controlled trial involving 10,061 patients in 39 countries, all of whom had a previous MI and a chronically high level of systemic inflammation as reflected in a median baseline high-sensitivity C-reactive protein (CRP) level of 4.1 mg/L. Ninety-one percent of participants were on statin therapy, with a median LDL cholesterol of 82 mg/dL when randomized to subcutaneous canakinumab at 50, 150, or 300 mg or to placebo once every 3 months.
Canakinumab is a fully human monoclonal antibody targeting IL-1B, a key player in systemic inflammation. The cytokine is activated by the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, a part of the innate immune system. Canakinumab is approved as Ilaris for treatment of several uncommon rheumatologic diseases, including cryopryin-associated periodic syndrome and systemic juvenile idiopathic arthritis.
At a median follow-up of 3.7 years, the incidence of the primary composite efficacy endpoint of nonfatal MI, nonfatal stroke, or cardiovascular death was 4.5 events per 100 person-years in the control group, significantly higher than the 3.86 and 3.9 events per 100 person-years in patients on canakinumab at 150 and 300 mg, respectively.
Since event rates were virtually identical in the 150- and 300-mg study arms, Dr. Ridker combined those two patient groups in his analysis. They showed a 15% reduction in the risk of the primary efficacy endpoint, compared with placebo-treated controls, along with a 39% reduction from baseline in CRP. They also were 30% less likely to undergo percutaneous coronary intervention or coronary artery bypass graft during follow-up.
“That’s quite important, because that’s a progression-of-atherosclerosis endpoint and also obviously a cost and financial endpoint,” he observed.
A key finding in CANTOS was that patients with a reduction in CRP at or exceeding the median decrease just 3 months into the study – that is, after a single injection – had a 27% reduction in major vascular events during follow-up. Patients with a lesser reduction in CRP at that point did not experience a significant reduction in the primary endpoint, compared with placebo.
“The clinician in me would say we probably ought to give a single dose of the drug, see what happens, and if you get a large inflammation reduction we could perhaps consider treating that patient, but if you did not get a large reduction perhaps this is not a therapy for that patient. Why not avoid the toxicity in people who aren’t going to respond?” Dr. Ridker said.
Side effects related to canakinumab consisted of mild leukopenia and a small but statistically significant increase in fatal infections, which he called “not surprising.”
“It’s in the same range as one gets in treating rheumatoid arthritis with a biologic drug, which rheumatologists are very comfortable doing. You would imagine that if this does become a treatment, physicians will get much better at bringing patients in early when they have signs and symptoms of infection,” the cardiologist continued.
Patients on canakinumab showed significant reductions in incident rheumatoid arthritis, gout, and osteoarthritis. The drug had no kidney or liver adverse events.
Cancer was a prespecified secondary outcome in CANTOS. The investigators saw the trial as an opportunity to test a longstanding hypothesis that inhibiting IL-1B would have a positive impact on lung cancer in particular.
“Smoking, exposure to diesel fuel, inhalation of asbestos or other silicates – these cause inflammation which activates the NLRP3 inflammasome, but in the pulmonary system rather than the arteries,” Dr. Ridker explained.
An entry requirement in CANTOS was that patients needed to be free of known cancer. During study follow-up, 129 patients were diagnosed with lung cancer. The risk was reduced in dose-dependent fashion with canakinumab: by 39% relative to placebo in the 150-mg group and by 67% in the 300-mg group. Lung cancer mortality was reduced by 77% in the canakinumab 300-mg group.
“I don’t think this is about oncogenesis per se. I think the tumors are already there, but they don’t progress because we’ve altered the tumor’s inflammatory microenvironment,” he continued.
Since CANTOS was first and foremost a study of atherosclerotic disease prevention, the cancer results need to be replicated on a high-priority basis. Dr. Ridker predicted that Novartis, which sponsored CANTOS, will quickly mount a clinical trial examining canakinumab’s potential as an adjunctive treatment to either chemotherapy or radiation following resection of lung cancer.
He stressed that CANTOS is only the beginning stanza in what will be an entirely new approach to preventive cardiology. Numerous other inflammatory pathways also might serve as targets.
“I think this is going to open up all kinds of approaches using a variety of agents that have really been in the rheumatology and immunology world,” the cardiologist predicted.
For example, he is principal investigator in the ongoing National Heart, Lung, and Blood Institute–sponsored Cardiovascular Inflammation Reduction Trial (CIRT), a randomized, double-blind, placebo-controlled study of low-dose methotrexate for prevention of cardiovascular events in a planned 7,000 patients with type 2 diabetes or metabolic syndrome who’ve had an MI or have multivessel CAD. Results are probably 4-6 years off.
“Right now, we know canakinumab works. If methotrexate were to work, then we’d have a generic, inexpensive approach as well,” Dr. Ridker noted.
Novartis officials indicated that, on the basis of the positive CANTOS results, the company plans to file for an expanded indication for canakinumab for cardiovascular prevention. The company also is gearing up for studies of the drug in oncology.
Simultaneous with Dr. Ridker’s presentation in Barcelona, both the atherosclerotic disease findings (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914) and the cancer findings (Lancet. 2017 Aug 27. doi: 10.1016/S0140-6736(17)32247-X) were published.
He reported serving as a consultant to Novartis.
BARCELONA – Inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer in the groundbreaking phase III CANTOS trial, Paul M. Ridker, MD, reported at the annual congress of the European Society of Cardiology.
“These data provide the first proof that inflammation inhibition in the absence of lipid lowering can improve atherogenic outcomes and potentially alter progression of some fatal cancers,” declared Dr. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
“Just like we’ve learned that lower LDL is better, I think we’re now learning that lower inflammation is better,” he said.
CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) was a randomized, double-blind, placebo-controlled trial involving 10,061 patients in 39 countries, all of whom had a previous MI and a chronically high level of systemic inflammation as reflected in a median baseline high-sensitivity C-reactive protein (CRP) level of 4.1 mg/L. Ninety-one percent of participants were on statin therapy, with a median LDL cholesterol of 82 mg/dL when randomized to subcutaneous canakinumab at 50, 150, or 300 mg or to placebo once every 3 months.
Canakinumab is a fully human monoclonal antibody targeting IL-1B, a key player in systemic inflammation. The cytokine is activated by the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, a part of the innate immune system. Canakinumab is approved as Ilaris for treatment of several uncommon rheumatologic diseases, including cryopryin-associated periodic syndrome and systemic juvenile idiopathic arthritis.
At a median follow-up of 3.7 years, the incidence of the primary composite efficacy endpoint of nonfatal MI, nonfatal stroke, or cardiovascular death was 4.5 events per 100 person-years in the control group, significantly higher than the 3.86 and 3.9 events per 100 person-years in patients on canakinumab at 150 and 300 mg, respectively.
Since event rates were virtually identical in the 150- and 300-mg study arms, Dr. Ridker combined those two patient groups in his analysis. They showed a 15% reduction in the risk of the primary efficacy endpoint, compared with placebo-treated controls, along with a 39% reduction from baseline in CRP. They also were 30% less likely to undergo percutaneous coronary intervention or coronary artery bypass graft during follow-up.
“That’s quite important, because that’s a progression-of-atherosclerosis endpoint and also obviously a cost and financial endpoint,” he observed.
A key finding in CANTOS was that patients with a reduction in CRP at or exceeding the median decrease just 3 months into the study – that is, after a single injection – had a 27% reduction in major vascular events during follow-up. Patients with a lesser reduction in CRP at that point did not experience a significant reduction in the primary endpoint, compared with placebo.
“The clinician in me would say we probably ought to give a single dose of the drug, see what happens, and if you get a large inflammation reduction we could perhaps consider treating that patient, but if you did not get a large reduction perhaps this is not a therapy for that patient. Why not avoid the toxicity in people who aren’t going to respond?” Dr. Ridker said.
Side effects related to canakinumab consisted of mild leukopenia and a small but statistically significant increase in fatal infections, which he called “not surprising.”
“It’s in the same range as one gets in treating rheumatoid arthritis with a biologic drug, which rheumatologists are very comfortable doing. You would imagine that if this does become a treatment, physicians will get much better at bringing patients in early when they have signs and symptoms of infection,” the cardiologist continued.
Patients on canakinumab showed significant reductions in incident rheumatoid arthritis, gout, and osteoarthritis. The drug had no kidney or liver adverse events.
Cancer was a prespecified secondary outcome in CANTOS. The investigators saw the trial as an opportunity to test a longstanding hypothesis that inhibiting IL-1B would have a positive impact on lung cancer in particular.
“Smoking, exposure to diesel fuel, inhalation of asbestos or other silicates – these cause inflammation which activates the NLRP3 inflammasome, but in the pulmonary system rather than the arteries,” Dr. Ridker explained.
An entry requirement in CANTOS was that patients needed to be free of known cancer. During study follow-up, 129 patients were diagnosed with lung cancer. The risk was reduced in dose-dependent fashion with canakinumab: by 39% relative to placebo in the 150-mg group and by 67% in the 300-mg group. Lung cancer mortality was reduced by 77% in the canakinumab 300-mg group.
“I don’t think this is about oncogenesis per se. I think the tumors are already there, but they don’t progress because we’ve altered the tumor’s inflammatory microenvironment,” he continued.
Since CANTOS was first and foremost a study of atherosclerotic disease prevention, the cancer results need to be replicated on a high-priority basis. Dr. Ridker predicted that Novartis, which sponsored CANTOS, will quickly mount a clinical trial examining canakinumab’s potential as an adjunctive treatment to either chemotherapy or radiation following resection of lung cancer.
He stressed that CANTOS is only the beginning stanza in what will be an entirely new approach to preventive cardiology. Numerous other inflammatory pathways also might serve as targets.
“I think this is going to open up all kinds of approaches using a variety of agents that have really been in the rheumatology and immunology world,” the cardiologist predicted.
For example, he is principal investigator in the ongoing National Heart, Lung, and Blood Institute–sponsored Cardiovascular Inflammation Reduction Trial (CIRT), a randomized, double-blind, placebo-controlled study of low-dose methotrexate for prevention of cardiovascular events in a planned 7,000 patients with type 2 diabetes or metabolic syndrome who’ve had an MI or have multivessel CAD. Results are probably 4-6 years off.
“Right now, we know canakinumab works. If methotrexate were to work, then we’d have a generic, inexpensive approach as well,” Dr. Ridker noted.
Novartis officials indicated that, on the basis of the positive CANTOS results, the company plans to file for an expanded indication for canakinumab for cardiovascular prevention. The company also is gearing up for studies of the drug in oncology.
Simultaneous with Dr. Ridker’s presentation in Barcelona, both the atherosclerotic disease findings (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914) and the cancer findings (Lancet. 2017 Aug 27. doi: 10.1016/S0140-6736(17)32247-X) were published.
He reported serving as a consultant to Novartis.
BARCELONA – Inhibiting the interleukin-1 beta innate immunity pathway with canakinumab reduced recurrent cardiovascular events and lung cancer in the groundbreaking phase III CANTOS trial, Paul M. Ridker, MD, reported at the annual congress of the European Society of Cardiology.
“These data provide the first proof that inflammation inhibition in the absence of lipid lowering can improve atherogenic outcomes and potentially alter progression of some fatal cancers,” declared Dr. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, Boston, and professor of medicine at Harvard Medical School.
“Just like we’ve learned that lower LDL is better, I think we’re now learning that lower inflammation is better,” he said.
CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) was a randomized, double-blind, placebo-controlled trial involving 10,061 patients in 39 countries, all of whom had a previous MI and a chronically high level of systemic inflammation as reflected in a median baseline high-sensitivity C-reactive protein (CRP) level of 4.1 mg/L. Ninety-one percent of participants were on statin therapy, with a median LDL cholesterol of 82 mg/dL when randomized to subcutaneous canakinumab at 50, 150, or 300 mg or to placebo once every 3 months.
Canakinumab is a fully human monoclonal antibody targeting IL-1B, a key player in systemic inflammation. The cytokine is activated by the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, a part of the innate immune system. Canakinumab is approved as Ilaris for treatment of several uncommon rheumatologic diseases, including cryopryin-associated periodic syndrome and systemic juvenile idiopathic arthritis.
At a median follow-up of 3.7 years, the incidence of the primary composite efficacy endpoint of nonfatal MI, nonfatal stroke, or cardiovascular death was 4.5 events per 100 person-years in the control group, significantly higher than the 3.86 and 3.9 events per 100 person-years in patients on canakinumab at 150 and 300 mg, respectively.
Since event rates were virtually identical in the 150- and 300-mg study arms, Dr. Ridker combined those two patient groups in his analysis. They showed a 15% reduction in the risk of the primary efficacy endpoint, compared with placebo-treated controls, along with a 39% reduction from baseline in CRP. They also were 30% less likely to undergo percutaneous coronary intervention or coronary artery bypass graft during follow-up.
“That’s quite important, because that’s a progression-of-atherosclerosis endpoint and also obviously a cost and financial endpoint,” he observed.
A key finding in CANTOS was that patients with a reduction in CRP at or exceeding the median decrease just 3 months into the study – that is, after a single injection – had a 27% reduction in major vascular events during follow-up. Patients with a lesser reduction in CRP at that point did not experience a significant reduction in the primary endpoint, compared with placebo.
“The clinician in me would say we probably ought to give a single dose of the drug, see what happens, and if you get a large inflammation reduction we could perhaps consider treating that patient, but if you did not get a large reduction perhaps this is not a therapy for that patient. Why not avoid the toxicity in people who aren’t going to respond?” Dr. Ridker said.
Side effects related to canakinumab consisted of mild leukopenia and a small but statistically significant increase in fatal infections, which he called “not surprising.”
“It’s in the same range as one gets in treating rheumatoid arthritis with a biologic drug, which rheumatologists are very comfortable doing. You would imagine that if this does become a treatment, physicians will get much better at bringing patients in early when they have signs and symptoms of infection,” the cardiologist continued.
Patients on canakinumab showed significant reductions in incident rheumatoid arthritis, gout, and osteoarthritis. The drug had no kidney or liver adverse events.
Cancer was a prespecified secondary outcome in CANTOS. The investigators saw the trial as an opportunity to test a longstanding hypothesis that inhibiting IL-1B would have a positive impact on lung cancer in particular.
“Smoking, exposure to diesel fuel, inhalation of asbestos or other silicates – these cause inflammation which activates the NLRP3 inflammasome, but in the pulmonary system rather than the arteries,” Dr. Ridker explained.
An entry requirement in CANTOS was that patients needed to be free of known cancer. During study follow-up, 129 patients were diagnosed with lung cancer. The risk was reduced in dose-dependent fashion with canakinumab: by 39% relative to placebo in the 150-mg group and by 67% in the 300-mg group. Lung cancer mortality was reduced by 77% in the canakinumab 300-mg group.
“I don’t think this is about oncogenesis per se. I think the tumors are already there, but they don’t progress because we’ve altered the tumor’s inflammatory microenvironment,” he continued.
Since CANTOS was first and foremost a study of atherosclerotic disease prevention, the cancer results need to be replicated on a high-priority basis. Dr. Ridker predicted that Novartis, which sponsored CANTOS, will quickly mount a clinical trial examining canakinumab’s potential as an adjunctive treatment to either chemotherapy or radiation following resection of lung cancer.
He stressed that CANTOS is only the beginning stanza in what will be an entirely new approach to preventive cardiology. Numerous other inflammatory pathways also might serve as targets.
“I think this is going to open up all kinds of approaches using a variety of agents that have really been in the rheumatology and immunology world,” the cardiologist predicted.
For example, he is principal investigator in the ongoing National Heart, Lung, and Blood Institute–sponsored Cardiovascular Inflammation Reduction Trial (CIRT), a randomized, double-blind, placebo-controlled study of low-dose methotrexate for prevention of cardiovascular events in a planned 7,000 patients with type 2 diabetes or metabolic syndrome who’ve had an MI or have multivessel CAD. Results are probably 4-6 years off.
“Right now, we know canakinumab works. If methotrexate were to work, then we’d have a generic, inexpensive approach as well,” Dr. Ridker noted.
Novartis officials indicated that, on the basis of the positive CANTOS results, the company plans to file for an expanded indication for canakinumab for cardiovascular prevention. The company also is gearing up for studies of the drug in oncology.
Simultaneous with Dr. Ridker’s presentation in Barcelona, both the atherosclerotic disease findings (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914) and the cancer findings (Lancet. 2017 Aug 27. doi: 10.1016/S0140-6736(17)32247-X) were published.
He reported serving as a consultant to Novartis.
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: Canakinumab reduced the risk of recurrent cardiovascular events in a very-high-risk population by 15%, compared with placebo, while cutting incident lung cancer by 67% in a major clinical trial.
Data source: CANTOS was a phase III, randomized, double-blind, placebo-controlled trial involving 10,061 patients in 39 countries, all with a previous MI and chronically high systemic inflammation.
Disclosures: The study was sponsored by Novartis. The presenter reported serving as a consultant to the company.
Forgo supplemental oxygen in adequately perfused patients with acute MI, study suggests
Supplemental oxygen did not prevent mortality or rehospitalization among patients with suspected myocardial infarction whose oxygen saturation on room air exceeded 90%, investigators reported.
Rates of all-cause mortality at 1 year were 5% among patients who received supplemental oxygen through an open face mask (6 liters per minute for 6-12 hours) and 5.1% among patients who breathed room air, said Robin Hofmann, MD, of Karolinska Institutet, Stockholm, and his associates. In addition, rehospitalization for MI occurred in 3.8% of patients who received supplemental oxygen and 3.3% of those breathed room air. The findings of the randomized registry-based trial of 6,629 patients were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.
Guidelines recommend oxygen supplementation in MI, and the practice has persisted for more than a century, but adequately powered trials of hard clinical endpoints are lacking. Above-normal oxygen saturation can potentially worsen reperfusion injury by causing coronary vasoconstriction and increasing production of reactive oxygen species, the researchers noted.
Notably, the Australian Air Versus Oxygen in Myocardial Infarction (AVOID) trial found that oxygen supplementation was associated with larger infarct sizes in patients with ST-segment elevation myocardial infarction, and a recent Cochrane report did not support routine oxygen supplementation for MI.
The current trial enrolled patients aged 30 years and older who had chest pain or shortness of breath lasting less than 6 hours, an oxygen saturation of at least 90% on pulse oximetry, and either electrocardiographic evidence of ischemia or elevated cardiac troponin T or I levels (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMoa1706222).
Oxygen therapy lasted a median of 11.6 hours, after which median oxygen saturation levels were 99% in the intervention group and 97% in the control group.
A total of 62 patients (2%) who received oxygen developed hypoxemia, as did 254 patients (8%) who breathed room air. Median highest troponin levels during hospitalization were 946.5 ng per L and 983.0 ng per L, respectively. A total of 166 (5%) patients in the oxygen group and 168 (5.1%) control patients died from any cause by a year after treatment (hazard ratio, 0.97; P = .8). Likewise, supplemental oxygen did not prevent rehospitalization with MI within 1 year (HR, 1.13; P = .3).
“Because power for evaluation of the primary endpoint was lower than anticipated, we cannot completely rule out a small beneficial or detrimental effect of oxygen on mortality,” the researchers wrote. But clinical differences were unlikely, based on the superimposable time-to-event curves through 12 months, the consistent results across subgroups, and the neutral findings on secondary clinical endpoints, they added.
The Swedish Research Council, the Swedish Heart-Lung Foundation, and the Swedish Foundation for Strategic Research funded the study. Dr. Hofmann disclosed research grants from these entities.
The study by Hofmann and coworkers provides definitive evidence for a lack of benefit of supplemental oxygen therapy in patients with acute myocardial infarction who have normal oxygen saturation. Although the mechanisms underlying physiological and biochemical adaptation to myocardial ischemia are complex, the answer to the question is straightforward, and its implications for coronary care are indisputable: Supplemental oxygen provides no benefit to patients with acute coronary syndromes who do not have hypoxemia. It is clearly time for clinical practice to change to reflect this definitive evidence.
Joseph Loscalzo, MD, PhD, is in the department of medicine, Brigham and Women’s Hospital, Boston. He is an editor-at-large for the New England Journal of Medicine. He had no other disclosures. These comments are from his accompanying editorial (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMe1709250).
The study by Hofmann and coworkers provides definitive evidence for a lack of benefit of supplemental oxygen therapy in patients with acute myocardial infarction who have normal oxygen saturation. Although the mechanisms underlying physiological and biochemical adaptation to myocardial ischemia are complex, the answer to the question is straightforward, and its implications for coronary care are indisputable: Supplemental oxygen provides no benefit to patients with acute coronary syndromes who do not have hypoxemia. It is clearly time for clinical practice to change to reflect this definitive evidence.
Joseph Loscalzo, MD, PhD, is in the department of medicine, Brigham and Women’s Hospital, Boston. He is an editor-at-large for the New England Journal of Medicine. He had no other disclosures. These comments are from his accompanying editorial (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMe1709250).
The study by Hofmann and coworkers provides definitive evidence for a lack of benefit of supplemental oxygen therapy in patients with acute myocardial infarction who have normal oxygen saturation. Although the mechanisms underlying physiological and biochemical adaptation to myocardial ischemia are complex, the answer to the question is straightforward, and its implications for coronary care are indisputable: Supplemental oxygen provides no benefit to patients with acute coronary syndromes who do not have hypoxemia. It is clearly time for clinical practice to change to reflect this definitive evidence.
Joseph Loscalzo, MD, PhD, is in the department of medicine, Brigham and Women’s Hospital, Boston. He is an editor-at-large for the New England Journal of Medicine. He had no other disclosures. These comments are from his accompanying editorial (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMe1709250).
Supplemental oxygen did not prevent mortality or rehospitalization among patients with suspected myocardial infarction whose oxygen saturation on room air exceeded 90%, investigators reported.
Rates of all-cause mortality at 1 year were 5% among patients who received supplemental oxygen through an open face mask (6 liters per minute for 6-12 hours) and 5.1% among patients who breathed room air, said Robin Hofmann, MD, of Karolinska Institutet, Stockholm, and his associates. In addition, rehospitalization for MI occurred in 3.8% of patients who received supplemental oxygen and 3.3% of those breathed room air. The findings of the randomized registry-based trial of 6,629 patients were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.
Guidelines recommend oxygen supplementation in MI, and the practice has persisted for more than a century, but adequately powered trials of hard clinical endpoints are lacking. Above-normal oxygen saturation can potentially worsen reperfusion injury by causing coronary vasoconstriction and increasing production of reactive oxygen species, the researchers noted.
Notably, the Australian Air Versus Oxygen in Myocardial Infarction (AVOID) trial found that oxygen supplementation was associated with larger infarct sizes in patients with ST-segment elevation myocardial infarction, and a recent Cochrane report did not support routine oxygen supplementation for MI.
The current trial enrolled patients aged 30 years and older who had chest pain or shortness of breath lasting less than 6 hours, an oxygen saturation of at least 90% on pulse oximetry, and either electrocardiographic evidence of ischemia or elevated cardiac troponin T or I levels (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMoa1706222).
Oxygen therapy lasted a median of 11.6 hours, after which median oxygen saturation levels were 99% in the intervention group and 97% in the control group.
A total of 62 patients (2%) who received oxygen developed hypoxemia, as did 254 patients (8%) who breathed room air. Median highest troponin levels during hospitalization were 946.5 ng per L and 983.0 ng per L, respectively. A total of 166 (5%) patients in the oxygen group and 168 (5.1%) control patients died from any cause by a year after treatment (hazard ratio, 0.97; P = .8). Likewise, supplemental oxygen did not prevent rehospitalization with MI within 1 year (HR, 1.13; P = .3).
“Because power for evaluation of the primary endpoint was lower than anticipated, we cannot completely rule out a small beneficial or detrimental effect of oxygen on mortality,” the researchers wrote. But clinical differences were unlikely, based on the superimposable time-to-event curves through 12 months, the consistent results across subgroups, and the neutral findings on secondary clinical endpoints, they added.
The Swedish Research Council, the Swedish Heart-Lung Foundation, and the Swedish Foundation for Strategic Research funded the study. Dr. Hofmann disclosed research grants from these entities.
Supplemental oxygen did not prevent mortality or rehospitalization among patients with suspected myocardial infarction whose oxygen saturation on room air exceeded 90%, investigators reported.
Rates of all-cause mortality at 1 year were 5% among patients who received supplemental oxygen through an open face mask (6 liters per minute for 6-12 hours) and 5.1% among patients who breathed room air, said Robin Hofmann, MD, of Karolinska Institutet, Stockholm, and his associates. In addition, rehospitalization for MI occurred in 3.8% of patients who received supplemental oxygen and 3.3% of those breathed room air. The findings of the randomized registry-based trial of 6,629 patients were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.
Guidelines recommend oxygen supplementation in MI, and the practice has persisted for more than a century, but adequately powered trials of hard clinical endpoints are lacking. Above-normal oxygen saturation can potentially worsen reperfusion injury by causing coronary vasoconstriction and increasing production of reactive oxygen species, the researchers noted.
Notably, the Australian Air Versus Oxygen in Myocardial Infarction (AVOID) trial found that oxygen supplementation was associated with larger infarct sizes in patients with ST-segment elevation myocardial infarction, and a recent Cochrane report did not support routine oxygen supplementation for MI.
The current trial enrolled patients aged 30 years and older who had chest pain or shortness of breath lasting less than 6 hours, an oxygen saturation of at least 90% on pulse oximetry, and either electrocardiographic evidence of ischemia or elevated cardiac troponin T or I levels (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMoa1706222).
Oxygen therapy lasted a median of 11.6 hours, after which median oxygen saturation levels were 99% in the intervention group and 97% in the control group.
A total of 62 patients (2%) who received oxygen developed hypoxemia, as did 254 patients (8%) who breathed room air. Median highest troponin levels during hospitalization were 946.5 ng per L and 983.0 ng per L, respectively. A total of 166 (5%) patients in the oxygen group and 168 (5.1%) control patients died from any cause by a year after treatment (hazard ratio, 0.97; P = .8). Likewise, supplemental oxygen did not prevent rehospitalization with MI within 1 year (HR, 1.13; P = .3).
“Because power for evaluation of the primary endpoint was lower than anticipated, we cannot completely rule out a small beneficial or detrimental effect of oxygen on mortality,” the researchers wrote. But clinical differences were unlikely, based on the superimposable time-to-event curves through 12 months, the consistent results across subgroups, and the neutral findings on secondary clinical endpoints, they added.
The Swedish Research Council, the Swedish Heart-Lung Foundation, and the Swedish Foundation for Strategic Research funded the study. Dr. Hofmann disclosed research grants from these entities.
FROM THE ESC CONGRESS 2017
Key clinical point: Supplemental oxygen did not benefit patients with suspected myocardial infarction who did not have hypoxemia.
Major finding: At 1 year, rates of all-cause mortality were 5% among patients who received supplemental oxygen and 5.1% among those who received no oxygen.
Data source: A registry-based, randomized clinical trial of 6,629 patients with suspected myocardial infarction without hypoxemia.
Disclosures: The Swedish Research Council, the Swedish Heart-Lung Foundation, and the Swedish Foundation for Strategic Research funded the study. Dr. Hofmann disclosed research grants from these entities.
Study finds bivalirudin efficacy for PCI no better than heparin
A large study of more than 6,000 heart patients in Sweden has found that patients having percutaneous coronary intervention who received bivalirudin did not have lower rates of deleterious outcomes – death, heart attack, or major bleeding – than did patients who received heparin monotherapy, a contrast to previous trials that found that bivalirudin had a lower bleeding risk than heparin alone after PCI.
The findings were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.
The study sought to explain the conflicting findings of previous trials investigating the efficacy of bivalirudin vs. heparin monotherapy. The VALIDATE-SWEDEHEART trial evaluated 6,006 patients who had PCI from June 2014 to September 2016, 90.3% via radial-artery access. This trial differed from previous studies because it was conducted after radial-artery access was routine and potent P2Y12 inhibitors were available, and earlier trials did not compare bivalirudin to heparin monotherapy, said David Erlinge, MD, PhD, of Lund (Sweden) University, and 38 coauthors (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1706443).
The Swedish investigators evaluated the primary endpoint – the composite of any-cause death, MI or major bleeding – during 180 days of follow-up. Among the study patients, 3,005 had ST-segment elevation MI (STEMI) and 3,001 non-STEMI (NSTEMI). All had undergone urgent PCI and most were also on P2Y inhibitors. The P2Y12 inhibitors used were ticagrelor in 5,697 patients (94.9%), prasugrel in 125 (2.1%) and cangrelor in 21 (0.3%).
Study patients with STEMI were permitted to receive up to 5,000 U of intravenous unfractionated heparin before arrival in the catheterization laboratory, and both STEMI and non-STEMI patients who had not received heparin previously could receive up to 3,000 U of intra-arterial heparin before angiography. All patients received aspirin pretreatment, and 62% received potent P2Y12 inhibitors at least one hour before PCI.
After angiography, but before PCI, patients were randomized 1:1 to receive in an open-label fashion either intravenous bivalirudin (The Medicines Company), or intra-arterial unfractionated heparin (LEO Pharma). Bivalirudin was administered as a bolus of 0.75 mg/kg of body weight followed by an infusion of 1.7 mg/kg per hour.
Research nurses contacted patients by phone 7 and 180 days after PCI. Baseline characteristics were similar between the bivalirudin and heparin groups. For example, around 31% of both groups had hyperlipidemia, and 15.2% of the bivalirudin group and 14.2% of the heparin group had a previous PCI.
“The rate of the primary endpoint did not differ significantly between the treatment groups at 30 days after PCI,” Dr. Erlinge and his coauthors noted. At 30 days, 7.2% of the bivalirudin patients and 8% of the heparin group had one of the primary endpoint outcomes, a nonsignificant difference. At 180 days, 12.3% of the bivalirudin group and 12.8% of those receiving heparin had one of the primary endpoint outcomes, also a nonsignificant difference.
Specific outcomes in the bivalirudin vs. heparin patients, respectively, at 180 days were: MI, 2% vs. 2.4%; major bleeding, 8.6% in both groups; stent thrombosis, 0.4% vs. 0.7%; and death from any cause, 2.9% vs. 2.8%, all nonsignificant differences.
“Results were consistent between patients with STEMI and those with NSTEMI and across all other prespecified subgroups,” the researchers wrote. They noted that women in the bivalirudin group had a lower, although not statistically significant, primary endpoint rate than did women in the heparin group.
In this trial, the high rate of radial-artery access and the low use of glycoprotein IIb/IIIa inhibitors may explain the low bleeding rates, the researchers said.
Among the study limitations were that patients excluded from the trial were at higher risk for a primary endpoint than those enrolled, the open-label design may have biased participating physicians in identifying outcomes, the telephone call-based follow-up may have been inherently unreliable, and the fact that most patients received a small dose of heparin before randomization may have reconciled any differences between the two drugs.
Coauthors Stefan James, MD, and Ollie Ostlund, MD, disclosed receiving grants from Astra Zeneca, and The Medicines Company. Dr. Erlinge and other coauthors had no financial relationships relevant to the work.
After considering the findings of the VALIDATE-SWEDEHEART trial, Gregg W. Stone, MD, said in an accompanying editorial, “there is no definitive answer to the question of whether to use bivalirudin or heparin during PCI.”
Dr. Stone, of New York–Presbyterian Hospital, Columbia University Medical Center, and the Cardiovascular Research Foundation, New York, noted four potential flaws in the study findings. One, the 30-day interval may be a better for evaluating procedural anticoagulation than 180 days – and at 30 days the Swedish study showed “a nonsignificant trend in favor of bivalirudin.” Two, the composite primary endpoint could bias outcomes because individual measures could essentially cancel each other out. Three, differences between treatment groups could have been further minimized because 91% of patients who received bivalirudin also received a substantial dose of heparin before and during PCI. Finally, Dr. Stone said, the study was underpowered to examine the individual components of outcomes.
The data comparing outcomes in STEMI and NSTEMI patients did not show separate results for death, bleeding, and stent thrombosis. Dr. Stone pointed to a meta-analysis of six randomized trials of 14,095 patients with STEMI, showing that bivalirudin had lower rates of major bleeding and 30-day death but higher rates of stent thrombosis than heparin, and that mortality was lower regardless of the use of femoral artery or radial-artery access or other procedural factors. By contrast, previous trials did show similar rates of death, MI, and stent thrombosis between both treatment groups, although lower bleeding rates were seen with bivalirudin.
More definitive answers may lie in investigators from the large-scale randomized trials comparing the anticoagulant agents, including the Swedish authors, combining their data on more than 36,000 patients into a single database, as they have agreed to do, Dr. Stone said. That “should provide robust evidence to guide decisions regarding anticoagulation among patients with STEMI and NSTEMI,” he concluded.
Dr. Stone had no relevant financial relationships to disclose. He made his comments in an invited editorial in the New England Journal of Medicine (doi: 10.1056/NEJMe1709247).
After considering the findings of the VALIDATE-SWEDEHEART trial, Gregg W. Stone, MD, said in an accompanying editorial, “there is no definitive answer to the question of whether to use bivalirudin or heparin during PCI.”
Dr. Stone, of New York–Presbyterian Hospital, Columbia University Medical Center, and the Cardiovascular Research Foundation, New York, noted four potential flaws in the study findings. One, the 30-day interval may be a better for evaluating procedural anticoagulation than 180 days – and at 30 days the Swedish study showed “a nonsignificant trend in favor of bivalirudin.” Two, the composite primary endpoint could bias outcomes because individual measures could essentially cancel each other out. Three, differences between treatment groups could have been further minimized because 91% of patients who received bivalirudin also received a substantial dose of heparin before and during PCI. Finally, Dr. Stone said, the study was underpowered to examine the individual components of outcomes.
The data comparing outcomes in STEMI and NSTEMI patients did not show separate results for death, bleeding, and stent thrombosis. Dr. Stone pointed to a meta-analysis of six randomized trials of 14,095 patients with STEMI, showing that bivalirudin had lower rates of major bleeding and 30-day death but higher rates of stent thrombosis than heparin, and that mortality was lower regardless of the use of femoral artery or radial-artery access or other procedural factors. By contrast, previous trials did show similar rates of death, MI, and stent thrombosis between both treatment groups, although lower bleeding rates were seen with bivalirudin.
More definitive answers may lie in investigators from the large-scale randomized trials comparing the anticoagulant agents, including the Swedish authors, combining their data on more than 36,000 patients into a single database, as they have agreed to do, Dr. Stone said. That “should provide robust evidence to guide decisions regarding anticoagulation among patients with STEMI and NSTEMI,” he concluded.
Dr. Stone had no relevant financial relationships to disclose. He made his comments in an invited editorial in the New England Journal of Medicine (doi: 10.1056/NEJMe1709247).
After considering the findings of the VALIDATE-SWEDEHEART trial, Gregg W. Stone, MD, said in an accompanying editorial, “there is no definitive answer to the question of whether to use bivalirudin or heparin during PCI.”
Dr. Stone, of New York–Presbyterian Hospital, Columbia University Medical Center, and the Cardiovascular Research Foundation, New York, noted four potential flaws in the study findings. One, the 30-day interval may be a better for evaluating procedural anticoagulation than 180 days – and at 30 days the Swedish study showed “a nonsignificant trend in favor of bivalirudin.” Two, the composite primary endpoint could bias outcomes because individual measures could essentially cancel each other out. Three, differences between treatment groups could have been further minimized because 91% of patients who received bivalirudin also received a substantial dose of heparin before and during PCI. Finally, Dr. Stone said, the study was underpowered to examine the individual components of outcomes.
The data comparing outcomes in STEMI and NSTEMI patients did not show separate results for death, bleeding, and stent thrombosis. Dr. Stone pointed to a meta-analysis of six randomized trials of 14,095 patients with STEMI, showing that bivalirudin had lower rates of major bleeding and 30-day death but higher rates of stent thrombosis than heparin, and that mortality was lower regardless of the use of femoral artery or radial-artery access or other procedural factors. By contrast, previous trials did show similar rates of death, MI, and stent thrombosis between both treatment groups, although lower bleeding rates were seen with bivalirudin.
More definitive answers may lie in investigators from the large-scale randomized trials comparing the anticoagulant agents, including the Swedish authors, combining their data on more than 36,000 patients into a single database, as they have agreed to do, Dr. Stone said. That “should provide robust evidence to guide decisions regarding anticoagulation among patients with STEMI and NSTEMI,” he concluded.
Dr. Stone had no relevant financial relationships to disclose. He made his comments in an invited editorial in the New England Journal of Medicine (doi: 10.1056/NEJMe1709247).
A large study of more than 6,000 heart patients in Sweden has found that patients having percutaneous coronary intervention who received bivalirudin did not have lower rates of deleterious outcomes – death, heart attack, or major bleeding – than did patients who received heparin monotherapy, a contrast to previous trials that found that bivalirudin had a lower bleeding risk than heparin alone after PCI.
The findings were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.
The study sought to explain the conflicting findings of previous trials investigating the efficacy of bivalirudin vs. heparin monotherapy. The VALIDATE-SWEDEHEART trial evaluated 6,006 patients who had PCI from June 2014 to September 2016, 90.3% via radial-artery access. This trial differed from previous studies because it was conducted after radial-artery access was routine and potent P2Y12 inhibitors were available, and earlier trials did not compare bivalirudin to heparin monotherapy, said David Erlinge, MD, PhD, of Lund (Sweden) University, and 38 coauthors (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1706443).
The Swedish investigators evaluated the primary endpoint – the composite of any-cause death, MI or major bleeding – during 180 days of follow-up. Among the study patients, 3,005 had ST-segment elevation MI (STEMI) and 3,001 non-STEMI (NSTEMI). All had undergone urgent PCI and most were also on P2Y inhibitors. The P2Y12 inhibitors used were ticagrelor in 5,697 patients (94.9%), prasugrel in 125 (2.1%) and cangrelor in 21 (0.3%).
Study patients with STEMI were permitted to receive up to 5,000 U of intravenous unfractionated heparin before arrival in the catheterization laboratory, and both STEMI and non-STEMI patients who had not received heparin previously could receive up to 3,000 U of intra-arterial heparin before angiography. All patients received aspirin pretreatment, and 62% received potent P2Y12 inhibitors at least one hour before PCI.
After angiography, but before PCI, patients were randomized 1:1 to receive in an open-label fashion either intravenous bivalirudin (The Medicines Company), or intra-arterial unfractionated heparin (LEO Pharma). Bivalirudin was administered as a bolus of 0.75 mg/kg of body weight followed by an infusion of 1.7 mg/kg per hour.
Research nurses contacted patients by phone 7 and 180 days after PCI. Baseline characteristics were similar between the bivalirudin and heparin groups. For example, around 31% of both groups had hyperlipidemia, and 15.2% of the bivalirudin group and 14.2% of the heparin group had a previous PCI.
“The rate of the primary endpoint did not differ significantly between the treatment groups at 30 days after PCI,” Dr. Erlinge and his coauthors noted. At 30 days, 7.2% of the bivalirudin patients and 8% of the heparin group had one of the primary endpoint outcomes, a nonsignificant difference. At 180 days, 12.3% of the bivalirudin group and 12.8% of those receiving heparin had one of the primary endpoint outcomes, also a nonsignificant difference.
Specific outcomes in the bivalirudin vs. heparin patients, respectively, at 180 days were: MI, 2% vs. 2.4%; major bleeding, 8.6% in both groups; stent thrombosis, 0.4% vs. 0.7%; and death from any cause, 2.9% vs. 2.8%, all nonsignificant differences.
“Results were consistent between patients with STEMI and those with NSTEMI and across all other prespecified subgroups,” the researchers wrote. They noted that women in the bivalirudin group had a lower, although not statistically significant, primary endpoint rate than did women in the heparin group.
In this trial, the high rate of radial-artery access and the low use of glycoprotein IIb/IIIa inhibitors may explain the low bleeding rates, the researchers said.
Among the study limitations were that patients excluded from the trial were at higher risk for a primary endpoint than those enrolled, the open-label design may have biased participating physicians in identifying outcomes, the telephone call-based follow-up may have been inherently unreliable, and the fact that most patients received a small dose of heparin before randomization may have reconciled any differences between the two drugs.
Coauthors Stefan James, MD, and Ollie Ostlund, MD, disclosed receiving grants from Astra Zeneca, and The Medicines Company. Dr. Erlinge and other coauthors had no financial relationships relevant to the work.
A large study of more than 6,000 heart patients in Sweden has found that patients having percutaneous coronary intervention who received bivalirudin did not have lower rates of deleterious outcomes – death, heart attack, or major bleeding – than did patients who received heparin monotherapy, a contrast to previous trials that found that bivalirudin had a lower bleeding risk than heparin alone after PCI.
The findings were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.
The study sought to explain the conflicting findings of previous trials investigating the efficacy of bivalirudin vs. heparin monotherapy. The VALIDATE-SWEDEHEART trial evaluated 6,006 patients who had PCI from June 2014 to September 2016, 90.3% via radial-artery access. This trial differed from previous studies because it was conducted after radial-artery access was routine and potent P2Y12 inhibitors were available, and earlier trials did not compare bivalirudin to heparin monotherapy, said David Erlinge, MD, PhD, of Lund (Sweden) University, and 38 coauthors (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1706443).
The Swedish investigators evaluated the primary endpoint – the composite of any-cause death, MI or major bleeding – during 180 days of follow-up. Among the study patients, 3,005 had ST-segment elevation MI (STEMI) and 3,001 non-STEMI (NSTEMI). All had undergone urgent PCI and most were also on P2Y inhibitors. The P2Y12 inhibitors used were ticagrelor in 5,697 patients (94.9%), prasugrel in 125 (2.1%) and cangrelor in 21 (0.3%).
Study patients with STEMI were permitted to receive up to 5,000 U of intravenous unfractionated heparin before arrival in the catheterization laboratory, and both STEMI and non-STEMI patients who had not received heparin previously could receive up to 3,000 U of intra-arterial heparin before angiography. All patients received aspirin pretreatment, and 62% received potent P2Y12 inhibitors at least one hour before PCI.
After angiography, but before PCI, patients were randomized 1:1 to receive in an open-label fashion either intravenous bivalirudin (The Medicines Company), or intra-arterial unfractionated heparin (LEO Pharma). Bivalirudin was administered as a bolus of 0.75 mg/kg of body weight followed by an infusion of 1.7 mg/kg per hour.
Research nurses contacted patients by phone 7 and 180 days after PCI. Baseline characteristics were similar between the bivalirudin and heparin groups. For example, around 31% of both groups had hyperlipidemia, and 15.2% of the bivalirudin group and 14.2% of the heparin group had a previous PCI.
“The rate of the primary endpoint did not differ significantly between the treatment groups at 30 days after PCI,” Dr. Erlinge and his coauthors noted. At 30 days, 7.2% of the bivalirudin patients and 8% of the heparin group had one of the primary endpoint outcomes, a nonsignificant difference. At 180 days, 12.3% of the bivalirudin group and 12.8% of those receiving heparin had one of the primary endpoint outcomes, also a nonsignificant difference.
Specific outcomes in the bivalirudin vs. heparin patients, respectively, at 180 days were: MI, 2% vs. 2.4%; major bleeding, 8.6% in both groups; stent thrombosis, 0.4% vs. 0.7%; and death from any cause, 2.9% vs. 2.8%, all nonsignificant differences.
“Results were consistent between patients with STEMI and those with NSTEMI and across all other prespecified subgroups,” the researchers wrote. They noted that women in the bivalirudin group had a lower, although not statistically significant, primary endpoint rate than did women in the heparin group.
In this trial, the high rate of radial-artery access and the low use of glycoprotein IIb/IIIa inhibitors may explain the low bleeding rates, the researchers said.
Among the study limitations were that patients excluded from the trial were at higher risk for a primary endpoint than those enrolled, the open-label design may have biased participating physicians in identifying outcomes, the telephone call-based follow-up may have been inherently unreliable, and the fact that most patients received a small dose of heparin before randomization may have reconciled any differences between the two drugs.
Coauthors Stefan James, MD, and Ollie Ostlund, MD, disclosed receiving grants from Astra Zeneca, and The Medicines Company. Dr. Erlinge and other coauthors had no financial relationships relevant to the work.
FROM THE ESC CONGRESS 2017
Key clinical point: The rates of composite death, MI, or major bleeding for patients having PCI for MI were similar regardless of whether they received bivalirudin or heparin monotherapy.
Major finding: At 180 days, 12.3% of the bivalirudin patients and 12.8% of the heparin patients had one of the primary endpoint outcomes.
Data source: VALIDATE-SWEDEHEART, a registry-based, multicenter, randomized, controlled, open-label clinical trial of 6,006 patients who had PCI between June 2014 and September 2016.
Disclosure: Coauthors Stefan James, MD, and Ollie Ostlund, MD, disclosed receiving grants from AstraZeneca, and The Medicines Company. Dr. Erlinge and other coauthors had no financial relationships relevant to the work.
VIDEO: Inflammation’s role in atherosclerosis confirmed in CANTOS
BARCELONA – The results of the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) mark the validation of many years of research on inflammation for Peter Libby, MD, Mallinckrodt Professor of Medicine, Harvard Medical School, Boston.
The CANTOS investigator said that, although some trials, most notably JUPITER, have linked reduced markers of inflammation with reduced cardiovascular events, none have been able to separate the effects of lowering LDL cholesterol from those of lowering the inflammatory marker interleukin-1B.
But using the monoclonal antibody canakinumab to target only interleukin-1B in CANTOS reduced the composite endpoint of nonfatal MI, nonfatal stroke, or cardiovascular death by 15% at the highest dosage tested, compared with placebo, while lowering high-sensitivity C-reactive protein by 39 percentage points.
Dr. Libby has been studying interleukin-1B since the 1980s. “Now, today, for the first time, in a rigorous trial, we can show that an anti-inflammatory agent that is neutral for lipids (that doesn’t lower LDL) can provide a benefit for our patients, and that’s a real step forward,” Dr. Libby said in a video interview at the annual congress of the European Society of Cardiology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Importantly, a dividend of the investigation was that “we found a decrease in fatal cancers, particularly lung cancer. So this again opens the door toward a whole new therapeutic window in patients not just in the cardiovascular space, but also in oncology. So it’s a doubly exciting day for us.”
CANTOS was presented at the meeting by Paul Ridker, MD, also of Harvard Medical School; the results were also published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914).
BARCELONA – The results of the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) mark the validation of many years of research on inflammation for Peter Libby, MD, Mallinckrodt Professor of Medicine, Harvard Medical School, Boston.
The CANTOS investigator said that, although some trials, most notably JUPITER, have linked reduced markers of inflammation with reduced cardiovascular events, none have been able to separate the effects of lowering LDL cholesterol from those of lowering the inflammatory marker interleukin-1B.
But using the monoclonal antibody canakinumab to target only interleukin-1B in CANTOS reduced the composite endpoint of nonfatal MI, nonfatal stroke, or cardiovascular death by 15% at the highest dosage tested, compared with placebo, while lowering high-sensitivity C-reactive protein by 39 percentage points.
Dr. Libby has been studying interleukin-1B since the 1980s. “Now, today, for the first time, in a rigorous trial, we can show that an anti-inflammatory agent that is neutral for lipids (that doesn’t lower LDL) can provide a benefit for our patients, and that’s a real step forward,” Dr. Libby said in a video interview at the annual congress of the European Society of Cardiology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Importantly, a dividend of the investigation was that “we found a decrease in fatal cancers, particularly lung cancer. So this again opens the door toward a whole new therapeutic window in patients not just in the cardiovascular space, but also in oncology. So it’s a doubly exciting day for us.”
CANTOS was presented at the meeting by Paul Ridker, MD, also of Harvard Medical School; the results were also published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914).
BARCELONA – The results of the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) mark the validation of many years of research on inflammation for Peter Libby, MD, Mallinckrodt Professor of Medicine, Harvard Medical School, Boston.
The CANTOS investigator said that, although some trials, most notably JUPITER, have linked reduced markers of inflammation with reduced cardiovascular events, none have been able to separate the effects of lowering LDL cholesterol from those of lowering the inflammatory marker interleukin-1B.
But using the monoclonal antibody canakinumab to target only interleukin-1B in CANTOS reduced the composite endpoint of nonfatal MI, nonfatal stroke, or cardiovascular death by 15% at the highest dosage tested, compared with placebo, while lowering high-sensitivity C-reactive protein by 39 percentage points.
Dr. Libby has been studying interleukin-1B since the 1980s. “Now, today, for the first time, in a rigorous trial, we can show that an anti-inflammatory agent that is neutral for lipids (that doesn’t lower LDL) can provide a benefit for our patients, and that’s a real step forward,” Dr. Libby said in a video interview at the annual congress of the European Society of Cardiology.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Importantly, a dividend of the investigation was that “we found a decrease in fatal cancers, particularly lung cancer. So this again opens the door toward a whole new therapeutic window in patients not just in the cardiovascular space, but also in oncology. So it’s a doubly exciting day for us.”
CANTOS was presented at the meeting by Paul Ridker, MD, also of Harvard Medical School; the results were also published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1707914).
AT THE ESC CONGRESS 2017
Orsiro coronary DES outperforms Xience
BARCELONA – A new model of drug-eluting coronary stent outperformed the reigning benchmark Xience stent in a head-to-head, pivotal comparison with 1,334 patients.
The results “advance a new standard for drug eluting stents,” David E. Kandzari, MD, said at the annual congress of the European Society of Cardiology. The trial tested the Orsiro stent, which features very thin, 60-micron-thick cobalt chromium struts, a bioresorbable polymer, and sirolimus as the antiproliferative drug that’s released during the first 90 days of stent placement.
“To our knowledge, this is the only trial that has demonstrated superiority [of a new stent] to the Xience drug-eluting stent in a large, randomized trial. This is a landmark in interventional cardiology that raises the bar for future comparisons” of drug eluting coronary stents, Dr. Kandzari said in an interview.
The study’s primary endpoint of target lesion failure after 12 months of follow-up – a rate that combined the incidence of cardiovascular death, target-vessel related MI, and ischemia-driven target-lesion revascularization – stood at 6.2% for the 884 patients treated with the Orsiro stent and 9.6% of the 450 randomized to treatment with the Xience stent, which has struts that are 81 microns wide, and a durable polymer that releases everolimus as the antiproliferative drug.
The difference in the primary endpoint was driven primarily by a 3.6% absolute difference in the rate of target-vessel related MIs, a statistically significant difference, plus the Orsiro-treated patients showed numerically smaller rates of cardiac death and ischemia-driven target lesion revascularization, although the between-group differences for each of these two endpoints were not statistically significant. The Orsiro stent also showed a significantly reduced rate of late stent thrombosis, occurring during day 31 through 1 year, a 0.1% rate in the Orsiro-treated patients and a 0.9% rate in those who received Xience stents.
“These are remarkable results,” said Michael Haude, MD, an interventional cardiologist at Lukas Hospital in Neuss, Germany, and a cochair of the session in which Dr. Kandzari gave his report.
These results from the Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in Subjects With Coronary Artery Lesions (BIOFLOW-V) trial will be the centerpiece of an application for U.S. marketing approval for the Orsiro stent, Dr. Kandzari said. The BIOFLOW-V trial enrolled patients at 90 centers in 13 countries including the United States.
Concurrently with his report, the results were published online (Lancet. 2017 Aug 26. doi: 10.1016/S0140-6736[17]32249-3).
The potential advantage of a thinner-strut drug eluting stent showed up during the initial treatment phase, with a procedural success rate of 94% using the Orsiro stent and 90% with the Xience stent. This difference in procedural success seemed largely the result of an increased rate of periprocedural MIs, a difference that might be explained by the difference in strut thickness, said Dr. Kandzari, of Piedmont Heart Institute, Atlanta. Based on this success, designers of future drug-eluting stents may focus on thinner-strut models, he suggested.
An additional analysis that Dr. Kandzari reported combined results from two prior randomized comparisons of the Orsiro and Xience stents, creating a pooled analysis with 2,208 patients. This Bayesian analysis calculated a 100% probability of noninferiority of the Orsiro stent compared with the Xience stent, and a 97% probability of superiority. This 97% probability of superiority fell just short of the 97.5% threshold for establishing superiority that Dr. Kandzari and his associates had prespecified for this analysis.
[email protected]
On Twitter @mitchelzoler
BARCELONA – A new model of drug-eluting coronary stent outperformed the reigning benchmark Xience stent in a head-to-head, pivotal comparison with 1,334 patients.
The results “advance a new standard for drug eluting stents,” David E. Kandzari, MD, said at the annual congress of the European Society of Cardiology. The trial tested the Orsiro stent, which features very thin, 60-micron-thick cobalt chromium struts, a bioresorbable polymer, and sirolimus as the antiproliferative drug that’s released during the first 90 days of stent placement.
“To our knowledge, this is the only trial that has demonstrated superiority [of a new stent] to the Xience drug-eluting stent in a large, randomized trial. This is a landmark in interventional cardiology that raises the bar for future comparisons” of drug eluting coronary stents, Dr. Kandzari said in an interview.
The study’s primary endpoint of target lesion failure after 12 months of follow-up – a rate that combined the incidence of cardiovascular death, target-vessel related MI, and ischemia-driven target-lesion revascularization – stood at 6.2% for the 884 patients treated with the Orsiro stent and 9.6% of the 450 randomized to treatment with the Xience stent, which has struts that are 81 microns wide, and a durable polymer that releases everolimus as the antiproliferative drug.
The difference in the primary endpoint was driven primarily by a 3.6% absolute difference in the rate of target-vessel related MIs, a statistically significant difference, plus the Orsiro-treated patients showed numerically smaller rates of cardiac death and ischemia-driven target lesion revascularization, although the between-group differences for each of these two endpoints were not statistically significant. The Orsiro stent also showed a significantly reduced rate of late stent thrombosis, occurring during day 31 through 1 year, a 0.1% rate in the Orsiro-treated patients and a 0.9% rate in those who received Xience stents.
“These are remarkable results,” said Michael Haude, MD, an interventional cardiologist at Lukas Hospital in Neuss, Germany, and a cochair of the session in which Dr. Kandzari gave his report.
These results from the Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in Subjects With Coronary Artery Lesions (BIOFLOW-V) trial will be the centerpiece of an application for U.S. marketing approval for the Orsiro stent, Dr. Kandzari said. The BIOFLOW-V trial enrolled patients at 90 centers in 13 countries including the United States.
Concurrently with his report, the results were published online (Lancet. 2017 Aug 26. doi: 10.1016/S0140-6736[17]32249-3).
The potential advantage of a thinner-strut drug eluting stent showed up during the initial treatment phase, with a procedural success rate of 94% using the Orsiro stent and 90% with the Xience stent. This difference in procedural success seemed largely the result of an increased rate of periprocedural MIs, a difference that might be explained by the difference in strut thickness, said Dr. Kandzari, of Piedmont Heart Institute, Atlanta. Based on this success, designers of future drug-eluting stents may focus on thinner-strut models, he suggested.
An additional analysis that Dr. Kandzari reported combined results from two prior randomized comparisons of the Orsiro and Xience stents, creating a pooled analysis with 2,208 patients. This Bayesian analysis calculated a 100% probability of noninferiority of the Orsiro stent compared with the Xience stent, and a 97% probability of superiority. This 97% probability of superiority fell just short of the 97.5% threshold for establishing superiority that Dr. Kandzari and his associates had prespecified for this analysis.
[email protected]
On Twitter @mitchelzoler
BARCELONA – A new model of drug-eluting coronary stent outperformed the reigning benchmark Xience stent in a head-to-head, pivotal comparison with 1,334 patients.
The results “advance a new standard for drug eluting stents,” David E. Kandzari, MD, said at the annual congress of the European Society of Cardiology. The trial tested the Orsiro stent, which features very thin, 60-micron-thick cobalt chromium struts, a bioresorbable polymer, and sirolimus as the antiproliferative drug that’s released during the first 90 days of stent placement.
“To our knowledge, this is the only trial that has demonstrated superiority [of a new stent] to the Xience drug-eluting stent in a large, randomized trial. This is a landmark in interventional cardiology that raises the bar for future comparisons” of drug eluting coronary stents, Dr. Kandzari said in an interview.
The study’s primary endpoint of target lesion failure after 12 months of follow-up – a rate that combined the incidence of cardiovascular death, target-vessel related MI, and ischemia-driven target-lesion revascularization – stood at 6.2% for the 884 patients treated with the Orsiro stent and 9.6% of the 450 randomized to treatment with the Xience stent, which has struts that are 81 microns wide, and a durable polymer that releases everolimus as the antiproliferative drug.
The difference in the primary endpoint was driven primarily by a 3.6% absolute difference in the rate of target-vessel related MIs, a statistically significant difference, plus the Orsiro-treated patients showed numerically smaller rates of cardiac death and ischemia-driven target lesion revascularization, although the between-group differences for each of these two endpoints were not statistically significant. The Orsiro stent also showed a significantly reduced rate of late stent thrombosis, occurring during day 31 through 1 year, a 0.1% rate in the Orsiro-treated patients and a 0.9% rate in those who received Xience stents.
“These are remarkable results,” said Michael Haude, MD, an interventional cardiologist at Lukas Hospital in Neuss, Germany, and a cochair of the session in which Dr. Kandzari gave his report.
These results from the Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in Subjects With Coronary Artery Lesions (BIOFLOW-V) trial will be the centerpiece of an application for U.S. marketing approval for the Orsiro stent, Dr. Kandzari said. The BIOFLOW-V trial enrolled patients at 90 centers in 13 countries including the United States.
Concurrently with his report, the results were published online (Lancet. 2017 Aug 26. doi: 10.1016/S0140-6736[17]32249-3).
The potential advantage of a thinner-strut drug eluting stent showed up during the initial treatment phase, with a procedural success rate of 94% using the Orsiro stent and 90% with the Xience stent. This difference in procedural success seemed largely the result of an increased rate of periprocedural MIs, a difference that might be explained by the difference in strut thickness, said Dr. Kandzari, of Piedmont Heart Institute, Atlanta. Based on this success, designers of future drug-eluting stents may focus on thinner-strut models, he suggested.
An additional analysis that Dr. Kandzari reported combined results from two prior randomized comparisons of the Orsiro and Xience stents, creating a pooled analysis with 2,208 patients. This Bayesian analysis calculated a 100% probability of noninferiority of the Orsiro stent compared with the Xience stent, and a 97% probability of superiority. This 97% probability of superiority fell just short of the 97.5% threshold for establishing superiority that Dr. Kandzari and his associates had prespecified for this analysis.
[email protected]
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: The target-lesion failure rate after 12 months was 6.2% with the Orsiro stent and 9.6% with the Xience stent.
Data source: BIOFLOW-V, a multicenter, randomized trial with 1,334 patients.
Disclosures: BIOFLOW-V was sponsored by Biotronik, the company that markets the Orsiro stent. Dr. Kandzari has been a consultant to and/or has received research funding from Biotronik, Boston Scientific, Medtronic, Micell Technologies, Abbott Vascular, St. Jude, Medinol, and OrbusNeich. Dr. Haude has been a consultant to and has received honoraria from Biotronik and from several other device and drug companies.
Big risk of serious falls after first episode of syncope
BARCELONA – Patients have an exorbitant 80% increased risk of hospitalization for falls resulting in fracture or head injury in the first year after discharge following a first-ever episode of syncope, according to a Danish national cohort study. One in five patients who sustained a fall resulting in hospitalization experienced a hip fracture, according to Anna-Karin Nume, MD, of the University of Copenhagen.
In this interview at the annual congress of the European Society of Cardiology, Dr. Nume highlights findings from her study, which included 125,763 Danish adults with first-time syncope.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
BARCELONA – Patients have an exorbitant 80% increased risk of hospitalization for falls resulting in fracture or head injury in the first year after discharge following a first-ever episode of syncope, according to a Danish national cohort study. One in five patients who sustained a fall resulting in hospitalization experienced a hip fracture, according to Anna-Karin Nume, MD, of the University of Copenhagen.
In this interview at the annual congress of the European Society of Cardiology, Dr. Nume highlights findings from her study, which included 125,763 Danish adults with first-time syncope.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
BARCELONA – Patients have an exorbitant 80% increased risk of hospitalization for falls resulting in fracture or head injury in the first year after discharge following a first-ever episode of syncope, according to a Danish national cohort study. One in five patients who sustained a fall resulting in hospitalization experienced a hip fracture, according to Anna-Karin Nume, MD, of the University of Copenhagen.
In this interview at the annual congress of the European Society of Cardiology, Dr. Nume highlights findings from her study, which included 125,763 Danish adults with first-time syncope.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE ESC CONGRESS 2017
In T1 diabetes, CABG seems better than PCI
In patients with type 1 diabetes in need of multivessel revascularization, coronary artery bypass graft (CABG) may be a better choice than percutaneous coronary intervention (PCI), according to results from a new comparative study presented at the annual congress of the European Society of Cardiology by Martin J. Holzmann, PhD, of the Karolinska Institute, Stockholm.
The two procedures had similar mortality rates, but PCI patients fared worse with respect to mortality due to myocardial infarction and several cardiovascular outcomes.
Previous studies had also suggested better outcomes with CABG than with PCI, but they lumped together patients with type 1 and type 2 diabetes, while the current study focused only on patients with type 1 diabetes.
The study included patients in Sweden with type 1 diabetes who underwent CABG (683 patients) or PCI (1,863 patients) between 1995 and 2013. During follow-up, 44.6% of patients in the PCI group died, compared with 53.3% in the CABG group. After adjustment for between-group differences, however, there was no significant difference in mortality risk between the two groups.
However, assessments of cause-specific mortality told a different story. Subjects in the PCI group had a greater risk of death from coronary artery disease (hazard ratio, 1.45; 95% confidence interval, 1.21-1.74).
Subjects in the PCI group were also more likely to suffer myocardial infarction (HR, 1.47; 95% CI, 1.21-1.77) and were more than five times more likely to undergo repeat vascularization (adjusted HR, 5.64; 95% CI, 4.67-6.82). The CABG group had a higher 30-day stroke risk (1.9% vs. 0.8%), but there was no difference in long-term risk.
The two groups had similar risks of hospitalization for heart failure.
The researchers noted a large difference between the two groups with respect to risk during the first year of follow-up, which suggests that some patients underwent PCI because they were too ill to undergo CABG. This limitation is also suggested by the greater proportion of previous stroke, heart failure, active cancer, and end-stage renal disease in the PCI group. The researchers adjusted for these differences, but it remains possible that there were residual confounders.
No source of funding was disclosed. One of the authors has received consultancy honoraria from Actelion and Pfizer. Dr. Domanski and Dr. Farkouh report no relevant financial relationships.
In patients with aggressive multivessel CAD and stable symptoms associated with diabetes or high SYNTAX score, the mechanisms of benefit of PCI and CABG are different, and this difference likely explains the superior results of CABG.
Better stents alone cannot change the superiority of CABG, compared with PCI for patients with aggressive CAD (diabetes or high SYNTAX score), because PCI addresses only a small portion of the coronary anatomy. This does not diminish the importance of continuing advances in stent technology, but rather, it puts into appropriate perspective what can be expected from these advances.
The findings of this important study help to better inform practice, and should influence decision-making for revascularization in patients with T1DM.
These remarks were taken from an editorial by Michael J. Domanski, MD, and Michael E. Farkouh, MD (J Am Coll Cardiol. 2017. doi: 10.1016/j.jacc.2017.07.781). Dr. Domanski is with the Peter Munk Cardiac Centre, Toronto, and the Heart and Stroke Richard Lewar Centre, University of Toronto. Dr. Farokouh is the director of clinical trials at the Peter Munk Cardiac Centre, University of Toronto.
In patients with aggressive multivessel CAD and stable symptoms associated with diabetes or high SYNTAX score, the mechanisms of benefit of PCI and CABG are different, and this difference likely explains the superior results of CABG.
Better stents alone cannot change the superiority of CABG, compared with PCI for patients with aggressive CAD (diabetes or high SYNTAX score), because PCI addresses only a small portion of the coronary anatomy. This does not diminish the importance of continuing advances in stent technology, but rather, it puts into appropriate perspective what can be expected from these advances.
The findings of this important study help to better inform practice, and should influence decision-making for revascularization in patients with T1DM.
These remarks were taken from an editorial by Michael J. Domanski, MD, and Michael E. Farkouh, MD (J Am Coll Cardiol. 2017. doi: 10.1016/j.jacc.2017.07.781). Dr. Domanski is with the Peter Munk Cardiac Centre, Toronto, and the Heart and Stroke Richard Lewar Centre, University of Toronto. Dr. Farokouh is the director of clinical trials at the Peter Munk Cardiac Centre, University of Toronto.
In patients with aggressive multivessel CAD and stable symptoms associated with diabetes or high SYNTAX score, the mechanisms of benefit of PCI and CABG are different, and this difference likely explains the superior results of CABG.
Better stents alone cannot change the superiority of CABG, compared with PCI for patients with aggressive CAD (diabetes or high SYNTAX score), because PCI addresses only a small portion of the coronary anatomy. This does not diminish the importance of continuing advances in stent technology, but rather, it puts into appropriate perspective what can be expected from these advances.
The findings of this important study help to better inform practice, and should influence decision-making for revascularization in patients with T1DM.
These remarks were taken from an editorial by Michael J. Domanski, MD, and Michael E. Farkouh, MD (J Am Coll Cardiol. 2017. doi: 10.1016/j.jacc.2017.07.781). Dr. Domanski is with the Peter Munk Cardiac Centre, Toronto, and the Heart and Stroke Richard Lewar Centre, University of Toronto. Dr. Farokouh is the director of clinical trials at the Peter Munk Cardiac Centre, University of Toronto.
In patients with type 1 diabetes in need of multivessel revascularization, coronary artery bypass graft (CABG) may be a better choice than percutaneous coronary intervention (PCI), according to results from a new comparative study presented at the annual congress of the European Society of Cardiology by Martin J. Holzmann, PhD, of the Karolinska Institute, Stockholm.
The two procedures had similar mortality rates, but PCI patients fared worse with respect to mortality due to myocardial infarction and several cardiovascular outcomes.
Previous studies had also suggested better outcomes with CABG than with PCI, but they lumped together patients with type 1 and type 2 diabetes, while the current study focused only on patients with type 1 diabetes.
The study included patients in Sweden with type 1 diabetes who underwent CABG (683 patients) or PCI (1,863 patients) between 1995 and 2013. During follow-up, 44.6% of patients in the PCI group died, compared with 53.3% in the CABG group. After adjustment for between-group differences, however, there was no significant difference in mortality risk between the two groups.
However, assessments of cause-specific mortality told a different story. Subjects in the PCI group had a greater risk of death from coronary artery disease (hazard ratio, 1.45; 95% confidence interval, 1.21-1.74).
Subjects in the PCI group were also more likely to suffer myocardial infarction (HR, 1.47; 95% CI, 1.21-1.77) and were more than five times more likely to undergo repeat vascularization (adjusted HR, 5.64; 95% CI, 4.67-6.82). The CABG group had a higher 30-day stroke risk (1.9% vs. 0.8%), but there was no difference in long-term risk.
The two groups had similar risks of hospitalization for heart failure.
The researchers noted a large difference between the two groups with respect to risk during the first year of follow-up, which suggests that some patients underwent PCI because they were too ill to undergo CABG. This limitation is also suggested by the greater proportion of previous stroke, heart failure, active cancer, and end-stage renal disease in the PCI group. The researchers adjusted for these differences, but it remains possible that there were residual confounders.
No source of funding was disclosed. One of the authors has received consultancy honoraria from Actelion and Pfizer. Dr. Domanski and Dr. Farkouh report no relevant financial relationships.
In patients with type 1 diabetes in need of multivessel revascularization, coronary artery bypass graft (CABG) may be a better choice than percutaneous coronary intervention (PCI), according to results from a new comparative study presented at the annual congress of the European Society of Cardiology by Martin J. Holzmann, PhD, of the Karolinska Institute, Stockholm.
The two procedures had similar mortality rates, but PCI patients fared worse with respect to mortality due to myocardial infarction and several cardiovascular outcomes.
Previous studies had also suggested better outcomes with CABG than with PCI, but they lumped together patients with type 1 and type 2 diabetes, while the current study focused only on patients with type 1 diabetes.
The study included patients in Sweden with type 1 diabetes who underwent CABG (683 patients) or PCI (1,863 patients) between 1995 and 2013. During follow-up, 44.6% of patients in the PCI group died, compared with 53.3% in the CABG group. After adjustment for between-group differences, however, there was no significant difference in mortality risk between the two groups.
However, assessments of cause-specific mortality told a different story. Subjects in the PCI group had a greater risk of death from coronary artery disease (hazard ratio, 1.45; 95% confidence interval, 1.21-1.74).
Subjects in the PCI group were also more likely to suffer myocardial infarction (HR, 1.47; 95% CI, 1.21-1.77) and were more than five times more likely to undergo repeat vascularization (adjusted HR, 5.64; 95% CI, 4.67-6.82). The CABG group had a higher 30-day stroke risk (1.9% vs. 0.8%), but there was no difference in long-term risk.
The two groups had similar risks of hospitalization for heart failure.
The researchers noted a large difference between the two groups with respect to risk during the first year of follow-up, which suggests that some patients underwent PCI because they were too ill to undergo CABG. This limitation is also suggested by the greater proportion of previous stroke, heart failure, active cancer, and end-stage renal disease in the PCI group. The researchers adjusted for these differences, but it remains possible that there were residual confounders.
No source of funding was disclosed. One of the authors has received consultancy honoraria from Actelion and Pfizer. Dr. Domanski and Dr. Farkouh report no relevant financial relationships.
FROM THE ESC CONGRESS 2017
Key clinical point: Patients undergoing PCI had worse cardiovascular outcomes than those receiving CABG.
Major finding: The PCI group had a 45% increased risk of death due to myocardial infarction.
Data source: Observational study (n = 2,546).
Disclosures: No source of funding was disclosed. One of the authors has received consultancy honoraria from Actelion and Pfizer. Dr. Domanski and Dr. Farkouh report no relevant financial relationships.