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SAN DIEGO – Two separate prospective, multicenter trials of statins stopped early when interim results showed they did not help – and potentially harmed – patients with moderate to severe chronic obstructive pulmonary disease or sepsis-associated acute respiratory distress syndrome.
The findings contradict previous observational data suggesting that the potential anti-inflammatory effects of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA) might benefit patients with these two diseases.
Statins did not significantly reduce rates of exacerbation of chronic obstructive pulmonary disease (COPD) or the time to first exacerbation in a study of 885 patients with moderate-to-severe COPD who were at high risk for exacerbations and who did not require statins for other indications. Patients in the STATCOPE trial (Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD) received a daily oral dose of either 40 mg simvastatin or placebo for 12-36 months.
The simvastatin group had a mean of 1.36 exacerbations/person-year, compared with 1.39/person-year in the placebo group. The median number of days to the first exacerbation was 223 on simvastatin and 231 on placebo, differences that were not significant, Dr. Gerard J. Criner and his associates reported at an international conference of the American Thoracic Society.
The results were published online by the New England Journal of Medicine (2014 May 18 [doi:10.1056/NEJMoa1403086]).
Among the 885 patients for whom follow-up information was available, 1,982 acute COPD exacerbations occurred, 965 in 430 patients on simvastatin and 1,017 exacerbations in 447 patients on placebo, said Dr. Criner, professor of medicine and director of the medical intensive care unit and the ventilator rehabilitation unit at Temple University, Philadelphia.
Overall, 34% of patients had three or more exacerbations of COPD, with similar numbers in each group – 141 in the simvastatin group and 155 in the placebo groups. The proportions of patients who received glucocorticoid therapy or antibiotics for exacerbations did not differ significantly between groups.
The simvastatin group had a significantly higher rate of nonfatal serious adverse events involving the GI tract (mainly nausea and bloating from simvastatin) in 30 patients (0.05 events/person-year), compared with events in 17 patients on placebo (0.02 events/person-year). Rates of other nonfatal adverse events were similar between groups, with pneumonia and other respiratory and cardiovascular events most common. Twenty-eight patients on simvastatin and 30 on placebo died.
Asked why he thinks the STATCOPE trial’s negative results didn’t confirm previous positive findings from observational studies including thousands of patients, Dr. Criner speculated that excluding patients with indications for statins may have removed patients with cardiovascular risks who were included in other studies. "I think a lot of the problems we’re seeing for exacerbations in COPD might be related to cardiovascular events in patients who aren’t appropriately treated with statins, who should be," he said.
Rosuvastatin sags in SAILS trial
In the separate double-blind SAILS trial (Statins for Acutely Injured Lungs [ARDS] From Sepsis), enteral rosuvastatin did not decrease mortality, compared with placebo, in 745 patients with sepsis-associated acute respiratory distress syndrome (ARDS). Dr. Jonathon D. Truwit and his associates are scheduled to report the results at the meeting on Tuesday. The findings also appeared online in the New England Journal of Medicine (2014 May 18 [doi:10.1056/NEJMoa1401520]).
Researchers found that 28.5% of patients on rosuvastatin and 25% on placebo died before hospital discharge or within 60 days if the patient was still in a health care facility, reported Dr. Truwit, professor of medicine at the Medical College of Wisconsin, Madison.
Patients in the rosuvastatin group received a loading dose of 40 mg followed by daily maintenance doses of 20 mg (or 10 mg for patients with a morning serum creatinine level of 2.8 mg/dL or more who were not receiving renal replacement therapy. Treatment continued until the third day of discharge from the ICU, hospital discharge, or death, whichever came first.
Both the rosuvastatin and placebo groups had a mean of 15 ventilator-free days.
Results also did not differ significantly between groups for the 339 patients who were in shock at the start of the study or for 109 patients who had used statins before the study and who underwent a 48-hour washout period before randomization.
Patients on rosuvastatin had a mean of 10.1 days free of renal failure and 10.8 days free of hepatic failure within the first 14 days, both significantly fewer compared with patients on placebo (11 and 11.8 days, respectively). "These differences in organ-failure-free days were small, and their significance may be spurious owing to the number of secondary endpoints analyzed. However, we cannot rule out a detrimental effect of rosuvastatin," the investigators wrote.
The results, combined with previous smaller randomized trials of other statins, suggest no benefits from starting or continuing statin therapy for sepsis-associated ARDS, Dr. Truwit said.
"The finding in observational studies that previous statin use provides a benefit may reflect better access to health care among patients who use statins than among those who do not, with a shorter time to the initiation of antibiotic therapy at the onset of symptoms of infection in statin users," according to the journal article.
The National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research funded the STATCOPE trial. The investigators reported financial associations with dozens of companies, including five of Dr. Criner’s coinvestigators who had financial associations with Merck, which makes simvastatin. The SAILS trial was sponsored by the NHLBI and by AstraZeneca, which makes rosuvastatin. Dr. Truwit reported having no financial disclosures. Three of his coinvestigators reported financial ties to AstraZeneca, and four reported associations with a total of 14 other companies.
On Twitter @sherryboschert
Dr. Jeffrey M. Drazen and Annetine C. Gelijns, Ph.D., comment:
Finding out that statins did not help in these two trials may be
disappointing, but not knowing that – if the studies had not been done –
would have been worse, Dr. Drazen and Dr. Gelijns wrote in an
accompanying editorial in the New England Journal of Medicine.
"The cynic would say that the public’s money had been wasted – we had struck out swinging," they wrote (N. Engl. J. Med. 2014 May 18 [doi: 10.1056/NEJMe1405032]).
Treatment
with statins seemed reasonable and, on the face of it, valid for both
moderate to severe chronic obstructive pulmonary disease (COPD) and
sepsis-associated acute respiratory distress syndrome (ARDS), conditions
in which inflammatory events are thought to drive disease pathobiology.
The known pleomorphic anti-inflammatory properties of statins made them
candidates, and previous observational data suggested that they helped
patients with these conditions. Because of meager therapeutic options
for these diseases, the studies of statins had to be done, Dr. Drazen
and Dr. Gelijns argued.
"It would have been a big mistake" to
accept the observational findings without a test, they wrote. "Had we
accepted the observational data at face value, we might have spent the
cost of the trials many times over in useless treatments before
recognizing our errors."
Dr. Jeffrey M. Drazen is editor in
chief of the Journal. He reported having no disclosures. Dr. Gelijns is a
professor and chair of Health Evidence and Policy at Mount Sinai School
of Medicine, New York. She reported a financial association with MERS
International, which developed a medical event reporting system.
Dr. Jeffrey M. Drazen and Annetine C. Gelijns, Ph.D., comment:
Finding out that statins did not help in these two trials may be
disappointing, but not knowing that – if the studies had not been done –
would have been worse, Dr. Drazen and Dr. Gelijns wrote in an
accompanying editorial in the New England Journal of Medicine.
"The cynic would say that the public’s money had been wasted – we had struck out swinging," they wrote (N. Engl. J. Med. 2014 May 18 [doi: 10.1056/NEJMe1405032]).
Treatment
with statins seemed reasonable and, on the face of it, valid for both
moderate to severe chronic obstructive pulmonary disease (COPD) and
sepsis-associated acute respiratory distress syndrome (ARDS), conditions
in which inflammatory events are thought to drive disease pathobiology.
The known pleomorphic anti-inflammatory properties of statins made them
candidates, and previous observational data suggested that they helped
patients with these conditions. Because of meager therapeutic options
for these diseases, the studies of statins had to be done, Dr. Drazen
and Dr. Gelijns argued.
"It would have been a big mistake" to
accept the observational findings without a test, they wrote. "Had we
accepted the observational data at face value, we might have spent the
cost of the trials many times over in useless treatments before
recognizing our errors."
Dr. Jeffrey M. Drazen is editor in
chief of the Journal. He reported having no disclosures. Dr. Gelijns is a
professor and chair of Health Evidence and Policy at Mount Sinai School
of Medicine, New York. She reported a financial association with MERS
International, which developed a medical event reporting system.
Dr. Jeffrey M. Drazen and Annetine C. Gelijns, Ph.D., comment:
Finding out that statins did not help in these two trials may be
disappointing, but not knowing that – if the studies had not been done –
would have been worse, Dr. Drazen and Dr. Gelijns wrote in an
accompanying editorial in the New England Journal of Medicine.
"The cynic would say that the public’s money had been wasted – we had struck out swinging," they wrote (N. Engl. J. Med. 2014 May 18 [doi: 10.1056/NEJMe1405032]).
Treatment
with statins seemed reasonable and, on the face of it, valid for both
moderate to severe chronic obstructive pulmonary disease (COPD) and
sepsis-associated acute respiratory distress syndrome (ARDS), conditions
in which inflammatory events are thought to drive disease pathobiology.
The known pleomorphic anti-inflammatory properties of statins made them
candidates, and previous observational data suggested that they helped
patients with these conditions. Because of meager therapeutic options
for these diseases, the studies of statins had to be done, Dr. Drazen
and Dr. Gelijns argued.
"It would have been a big mistake" to
accept the observational findings without a test, they wrote. "Had we
accepted the observational data at face value, we might have spent the
cost of the trials many times over in useless treatments before
recognizing our errors."
Dr. Jeffrey M. Drazen is editor in
chief of the Journal. He reported having no disclosures. Dr. Gelijns is a
professor and chair of Health Evidence and Policy at Mount Sinai School
of Medicine, New York. She reported a financial association with MERS
International, which developed a medical event reporting system.
SAN DIEGO – Two separate prospective, multicenter trials of statins stopped early when interim results showed they did not help – and potentially harmed – patients with moderate to severe chronic obstructive pulmonary disease or sepsis-associated acute respiratory distress syndrome.
The findings contradict previous observational data suggesting that the potential anti-inflammatory effects of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA) might benefit patients with these two diseases.
Statins did not significantly reduce rates of exacerbation of chronic obstructive pulmonary disease (COPD) or the time to first exacerbation in a study of 885 patients with moderate-to-severe COPD who were at high risk for exacerbations and who did not require statins for other indications. Patients in the STATCOPE trial (Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD) received a daily oral dose of either 40 mg simvastatin or placebo for 12-36 months.
The simvastatin group had a mean of 1.36 exacerbations/person-year, compared with 1.39/person-year in the placebo group. The median number of days to the first exacerbation was 223 on simvastatin and 231 on placebo, differences that were not significant, Dr. Gerard J. Criner and his associates reported at an international conference of the American Thoracic Society.
The results were published online by the New England Journal of Medicine (2014 May 18 [doi:10.1056/NEJMoa1403086]).
Among the 885 patients for whom follow-up information was available, 1,982 acute COPD exacerbations occurred, 965 in 430 patients on simvastatin and 1,017 exacerbations in 447 patients on placebo, said Dr. Criner, professor of medicine and director of the medical intensive care unit and the ventilator rehabilitation unit at Temple University, Philadelphia.
Overall, 34% of patients had three or more exacerbations of COPD, with similar numbers in each group – 141 in the simvastatin group and 155 in the placebo groups. The proportions of patients who received glucocorticoid therapy or antibiotics for exacerbations did not differ significantly between groups.
The simvastatin group had a significantly higher rate of nonfatal serious adverse events involving the GI tract (mainly nausea and bloating from simvastatin) in 30 patients (0.05 events/person-year), compared with events in 17 patients on placebo (0.02 events/person-year). Rates of other nonfatal adverse events were similar between groups, with pneumonia and other respiratory and cardiovascular events most common. Twenty-eight patients on simvastatin and 30 on placebo died.
Asked why he thinks the STATCOPE trial’s negative results didn’t confirm previous positive findings from observational studies including thousands of patients, Dr. Criner speculated that excluding patients with indications for statins may have removed patients with cardiovascular risks who were included in other studies. "I think a lot of the problems we’re seeing for exacerbations in COPD might be related to cardiovascular events in patients who aren’t appropriately treated with statins, who should be," he said.
Rosuvastatin sags in SAILS trial
In the separate double-blind SAILS trial (Statins for Acutely Injured Lungs [ARDS] From Sepsis), enteral rosuvastatin did not decrease mortality, compared with placebo, in 745 patients with sepsis-associated acute respiratory distress syndrome (ARDS). Dr. Jonathon D. Truwit and his associates are scheduled to report the results at the meeting on Tuesday. The findings also appeared online in the New England Journal of Medicine (2014 May 18 [doi:10.1056/NEJMoa1401520]).
Researchers found that 28.5% of patients on rosuvastatin and 25% on placebo died before hospital discharge or within 60 days if the patient was still in a health care facility, reported Dr. Truwit, professor of medicine at the Medical College of Wisconsin, Madison.
Patients in the rosuvastatin group received a loading dose of 40 mg followed by daily maintenance doses of 20 mg (or 10 mg for patients with a morning serum creatinine level of 2.8 mg/dL or more who were not receiving renal replacement therapy. Treatment continued until the third day of discharge from the ICU, hospital discharge, or death, whichever came first.
Both the rosuvastatin and placebo groups had a mean of 15 ventilator-free days.
Results also did not differ significantly between groups for the 339 patients who were in shock at the start of the study or for 109 patients who had used statins before the study and who underwent a 48-hour washout period before randomization.
Patients on rosuvastatin had a mean of 10.1 days free of renal failure and 10.8 days free of hepatic failure within the first 14 days, both significantly fewer compared with patients on placebo (11 and 11.8 days, respectively). "These differences in organ-failure-free days were small, and their significance may be spurious owing to the number of secondary endpoints analyzed. However, we cannot rule out a detrimental effect of rosuvastatin," the investigators wrote.
The results, combined with previous smaller randomized trials of other statins, suggest no benefits from starting or continuing statin therapy for sepsis-associated ARDS, Dr. Truwit said.
"The finding in observational studies that previous statin use provides a benefit may reflect better access to health care among patients who use statins than among those who do not, with a shorter time to the initiation of antibiotic therapy at the onset of symptoms of infection in statin users," according to the journal article.
The National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research funded the STATCOPE trial. The investigators reported financial associations with dozens of companies, including five of Dr. Criner’s coinvestigators who had financial associations with Merck, which makes simvastatin. The SAILS trial was sponsored by the NHLBI and by AstraZeneca, which makes rosuvastatin. Dr. Truwit reported having no financial disclosures. Three of his coinvestigators reported financial ties to AstraZeneca, and four reported associations with a total of 14 other companies.
On Twitter @sherryboschert
SAN DIEGO – Two separate prospective, multicenter trials of statins stopped early when interim results showed they did not help – and potentially harmed – patients with moderate to severe chronic obstructive pulmonary disease or sepsis-associated acute respiratory distress syndrome.
The findings contradict previous observational data suggesting that the potential anti-inflammatory effects of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA) might benefit patients with these two diseases.
Statins did not significantly reduce rates of exacerbation of chronic obstructive pulmonary disease (COPD) or the time to first exacerbation in a study of 885 patients with moderate-to-severe COPD who were at high risk for exacerbations and who did not require statins for other indications. Patients in the STATCOPE trial (Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD) received a daily oral dose of either 40 mg simvastatin or placebo for 12-36 months.
The simvastatin group had a mean of 1.36 exacerbations/person-year, compared with 1.39/person-year in the placebo group. The median number of days to the first exacerbation was 223 on simvastatin and 231 on placebo, differences that were not significant, Dr. Gerard J. Criner and his associates reported at an international conference of the American Thoracic Society.
The results were published online by the New England Journal of Medicine (2014 May 18 [doi:10.1056/NEJMoa1403086]).
Among the 885 patients for whom follow-up information was available, 1,982 acute COPD exacerbations occurred, 965 in 430 patients on simvastatin and 1,017 exacerbations in 447 patients on placebo, said Dr. Criner, professor of medicine and director of the medical intensive care unit and the ventilator rehabilitation unit at Temple University, Philadelphia.
Overall, 34% of patients had three or more exacerbations of COPD, with similar numbers in each group – 141 in the simvastatin group and 155 in the placebo groups. The proportions of patients who received glucocorticoid therapy or antibiotics for exacerbations did not differ significantly between groups.
The simvastatin group had a significantly higher rate of nonfatal serious adverse events involving the GI tract (mainly nausea and bloating from simvastatin) in 30 patients (0.05 events/person-year), compared with events in 17 patients on placebo (0.02 events/person-year). Rates of other nonfatal adverse events were similar between groups, with pneumonia and other respiratory and cardiovascular events most common. Twenty-eight patients on simvastatin and 30 on placebo died.
Asked why he thinks the STATCOPE trial’s negative results didn’t confirm previous positive findings from observational studies including thousands of patients, Dr. Criner speculated that excluding patients with indications for statins may have removed patients with cardiovascular risks who were included in other studies. "I think a lot of the problems we’re seeing for exacerbations in COPD might be related to cardiovascular events in patients who aren’t appropriately treated with statins, who should be," he said.
Rosuvastatin sags in SAILS trial
In the separate double-blind SAILS trial (Statins for Acutely Injured Lungs [ARDS] From Sepsis), enteral rosuvastatin did not decrease mortality, compared with placebo, in 745 patients with sepsis-associated acute respiratory distress syndrome (ARDS). Dr. Jonathon D. Truwit and his associates are scheduled to report the results at the meeting on Tuesday. The findings also appeared online in the New England Journal of Medicine (2014 May 18 [doi:10.1056/NEJMoa1401520]).
Researchers found that 28.5% of patients on rosuvastatin and 25% on placebo died before hospital discharge or within 60 days if the patient was still in a health care facility, reported Dr. Truwit, professor of medicine at the Medical College of Wisconsin, Madison.
Patients in the rosuvastatin group received a loading dose of 40 mg followed by daily maintenance doses of 20 mg (or 10 mg for patients with a morning serum creatinine level of 2.8 mg/dL or more who were not receiving renal replacement therapy. Treatment continued until the third day of discharge from the ICU, hospital discharge, or death, whichever came first.
Both the rosuvastatin and placebo groups had a mean of 15 ventilator-free days.
Results also did not differ significantly between groups for the 339 patients who were in shock at the start of the study or for 109 patients who had used statins before the study and who underwent a 48-hour washout period before randomization.
Patients on rosuvastatin had a mean of 10.1 days free of renal failure and 10.8 days free of hepatic failure within the first 14 days, both significantly fewer compared with patients on placebo (11 and 11.8 days, respectively). "These differences in organ-failure-free days were small, and their significance may be spurious owing to the number of secondary endpoints analyzed. However, we cannot rule out a detrimental effect of rosuvastatin," the investigators wrote.
The results, combined with previous smaller randomized trials of other statins, suggest no benefits from starting or continuing statin therapy for sepsis-associated ARDS, Dr. Truwit said.
"The finding in observational studies that previous statin use provides a benefit may reflect better access to health care among patients who use statins than among those who do not, with a shorter time to the initiation of antibiotic therapy at the onset of symptoms of infection in statin users," according to the journal article.
The National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research funded the STATCOPE trial. The investigators reported financial associations with dozens of companies, including five of Dr. Criner’s coinvestigators who had financial associations with Merck, which makes simvastatin. The SAILS trial was sponsored by the NHLBI and by AstraZeneca, which makes rosuvastatin. Dr. Truwit reported having no financial disclosures. Three of his coinvestigators reported financial ties to AstraZeneca, and four reported associations with a total of 14 other companies.
On Twitter @sherryboschert
AT ATS 2014
Key clinical point: Statins did not help, and possibly harmed, patients with moderate to severe COPD or sepsis-associated acute respiratory distress syndrome who did not require statins for other indications.
Major finding: The mean rate of COPD exacerbations was 1.36 in the simvastatin group and 1.39 in the placebo group, not significantly different.
Data source: STATCOPE, a multicenter prospective randomized, placebo-controlled trial of daily oral simvastatin 40 mg or placebo in 885 patients with COPD at high risk for exacerbations.
Disclosures: The National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research funded the STATCOPE trial. Several coinvestigators reported financial associations with dozens of companies, including with Merck, which makes simvastatin.
