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Apixaban provides larger medical cost savings than other NOACs
WASHINGTON – Apixaban yields the great medical cost savings of the three novel oral anticoagulants available as alternatives to warfarin for stroke prevention in patients with nonvalvular atrial fibrillation, according to a new comparative analysis.
This analysis differed from prior cost savings studies, which relied upon relative risk reductions for stroke and major bleeding events obtained directly from the pivotal phase III clinical trials conducted for each of the novel oral anticoagulants (NOACs).
Instead, the new analysis used as the comparator arm real-world event rates in warfarin-treated patients in a large national health insurance claims database. This was done because of the high likelihood that event rates in warfarin-treated controls in the clinical trials may be considerably lower than in everyday practice, since the trials were carried out in a selected patient population, with exclusion of the elderly and others at higher risk of adverse events, Michael Stokes explained at the annual meeting of the American College of Cardiology.
The investigators used the 21% relative risk reductions for both stroke and major bleeding with the use of apixaban (Eliquis), compared with warfarin in the ARISTOTLE trial (N. Engl. J. Med. 2011;365:981-92), and applied those relative risk reductions to 23,525 managed care patients with atrial fibrillation on warfarin for stroke prevention in the Medco claims database. They found that the use of apixaban instead of warfarin would result in an estimated 1.1 fewer strokes and 2.1 fewer major bleeding events excluding intracranial hemorrhage per 100 person-years of follow-up in a real-world population, said Mr. Stokes of Evidera, a health care consulting firm in Montreal.
In contrast, applying the relative risk figures for dabigatran (Pradaxa) obtained from the RE-LY trial (N. Engl. J. Med. 2009;361:1139-51) yielded estimates of 1.9 fewer strokes but 0.7 additional major bleeding events per 100 person-years, compared with warfarin in everyday practice. For rivaroxaban (Xarelto), the data from the ROCKET-AF trial (N. Engl. J. Med. 2011;365:883-91) pointed to 0.8 fewer strokes than with warfarin, but 1.4 more major bleeding events, he continued.
For the key outcome of total medical costs saved through avoidance of stroke or major bleeding through the use of a NOAC rather than warfarin, the estimates were $1,245/year for a patient on apixaban and $555 for dabigatran. In contrast, rivaroxaban was not associated with a savings, but rather with an increase in medical costs of $144 per patient per year.
These are figures that take some of the sting out of the high prescription costs for the NOACs. The savings estimates relied upon incremental 1-year medical cost figures of $44,792/stroke and $35,829/major bleeding event, excluding intracranial hemorrhage, which were obtained from another study (Stroke 2011;42:112-8).
Since patients on warfarin for stroke prevention in the Medco database were older and thus higher risk than those in the NOAC pivotal trials were, the total medical cost savings for each NOAC were larger in the new analysis. In one earlier analysis that relied upon reference rates from the clinical trials, the total medical cost savings estimate for each NOAC, compared with warfarin, was $485 per patient per year for apixaban, $179 for dabigatran, and $89 for rivaroxaban (J. Med. Econ. 2012;15:776-85).
Mr. Stokes’s analysis was carried out by Evidera with research funding from Bristol-Myers Squibb and Pfizer, which jointly developed apixaban.
WASHINGTON – Apixaban yields the great medical cost savings of the three novel oral anticoagulants available as alternatives to warfarin for stroke prevention in patients with nonvalvular atrial fibrillation, according to a new comparative analysis.
This analysis differed from prior cost savings studies, which relied upon relative risk reductions for stroke and major bleeding events obtained directly from the pivotal phase III clinical trials conducted for each of the novel oral anticoagulants (NOACs).
Instead, the new analysis used as the comparator arm real-world event rates in warfarin-treated patients in a large national health insurance claims database. This was done because of the high likelihood that event rates in warfarin-treated controls in the clinical trials may be considerably lower than in everyday practice, since the trials were carried out in a selected patient population, with exclusion of the elderly and others at higher risk of adverse events, Michael Stokes explained at the annual meeting of the American College of Cardiology.
The investigators used the 21% relative risk reductions for both stroke and major bleeding with the use of apixaban (Eliquis), compared with warfarin in the ARISTOTLE trial (N. Engl. J. Med. 2011;365:981-92), and applied those relative risk reductions to 23,525 managed care patients with atrial fibrillation on warfarin for stroke prevention in the Medco claims database. They found that the use of apixaban instead of warfarin would result in an estimated 1.1 fewer strokes and 2.1 fewer major bleeding events excluding intracranial hemorrhage per 100 person-years of follow-up in a real-world population, said Mr. Stokes of Evidera, a health care consulting firm in Montreal.
In contrast, applying the relative risk figures for dabigatran (Pradaxa) obtained from the RE-LY trial (N. Engl. J. Med. 2009;361:1139-51) yielded estimates of 1.9 fewer strokes but 0.7 additional major bleeding events per 100 person-years, compared with warfarin in everyday practice. For rivaroxaban (Xarelto), the data from the ROCKET-AF trial (N. Engl. J. Med. 2011;365:883-91) pointed to 0.8 fewer strokes than with warfarin, but 1.4 more major bleeding events, he continued.
For the key outcome of total medical costs saved through avoidance of stroke or major bleeding through the use of a NOAC rather than warfarin, the estimates were $1,245/year for a patient on apixaban and $555 for dabigatran. In contrast, rivaroxaban was not associated with a savings, but rather with an increase in medical costs of $144 per patient per year.
These are figures that take some of the sting out of the high prescription costs for the NOACs. The savings estimates relied upon incremental 1-year medical cost figures of $44,792/stroke and $35,829/major bleeding event, excluding intracranial hemorrhage, which were obtained from another study (Stroke 2011;42:112-8).
Since patients on warfarin for stroke prevention in the Medco database were older and thus higher risk than those in the NOAC pivotal trials were, the total medical cost savings for each NOAC were larger in the new analysis. In one earlier analysis that relied upon reference rates from the clinical trials, the total medical cost savings estimate for each NOAC, compared with warfarin, was $485 per patient per year for apixaban, $179 for dabigatran, and $89 for rivaroxaban (J. Med. Econ. 2012;15:776-85).
Mr. Stokes’s analysis was carried out by Evidera with research funding from Bristol-Myers Squibb and Pfizer, which jointly developed apixaban.
WASHINGTON – Apixaban yields the great medical cost savings of the three novel oral anticoagulants available as alternatives to warfarin for stroke prevention in patients with nonvalvular atrial fibrillation, according to a new comparative analysis.
This analysis differed from prior cost savings studies, which relied upon relative risk reductions for stroke and major bleeding events obtained directly from the pivotal phase III clinical trials conducted for each of the novel oral anticoagulants (NOACs).
Instead, the new analysis used as the comparator arm real-world event rates in warfarin-treated patients in a large national health insurance claims database. This was done because of the high likelihood that event rates in warfarin-treated controls in the clinical trials may be considerably lower than in everyday practice, since the trials were carried out in a selected patient population, with exclusion of the elderly and others at higher risk of adverse events, Michael Stokes explained at the annual meeting of the American College of Cardiology.
The investigators used the 21% relative risk reductions for both stroke and major bleeding with the use of apixaban (Eliquis), compared with warfarin in the ARISTOTLE trial (N. Engl. J. Med. 2011;365:981-92), and applied those relative risk reductions to 23,525 managed care patients with atrial fibrillation on warfarin for stroke prevention in the Medco claims database. They found that the use of apixaban instead of warfarin would result in an estimated 1.1 fewer strokes and 2.1 fewer major bleeding events excluding intracranial hemorrhage per 100 person-years of follow-up in a real-world population, said Mr. Stokes of Evidera, a health care consulting firm in Montreal.
In contrast, applying the relative risk figures for dabigatran (Pradaxa) obtained from the RE-LY trial (N. Engl. J. Med. 2009;361:1139-51) yielded estimates of 1.9 fewer strokes but 0.7 additional major bleeding events per 100 person-years, compared with warfarin in everyday practice. For rivaroxaban (Xarelto), the data from the ROCKET-AF trial (N. Engl. J. Med. 2011;365:883-91) pointed to 0.8 fewer strokes than with warfarin, but 1.4 more major bleeding events, he continued.
For the key outcome of total medical costs saved through avoidance of stroke or major bleeding through the use of a NOAC rather than warfarin, the estimates were $1,245/year for a patient on apixaban and $555 for dabigatran. In contrast, rivaroxaban was not associated with a savings, but rather with an increase in medical costs of $144 per patient per year.
These are figures that take some of the sting out of the high prescription costs for the NOACs. The savings estimates relied upon incremental 1-year medical cost figures of $44,792/stroke and $35,829/major bleeding event, excluding intracranial hemorrhage, which were obtained from another study (Stroke 2011;42:112-8).
Since patients on warfarin for stroke prevention in the Medco database were older and thus higher risk than those in the NOAC pivotal trials were, the total medical cost savings for each NOAC were larger in the new analysis. In one earlier analysis that relied upon reference rates from the clinical trials, the total medical cost savings estimate for each NOAC, compared with warfarin, was $485 per patient per year for apixaban, $179 for dabigatran, and $89 for rivaroxaban (J. Med. Econ. 2012;15:776-85).
Mr. Stokes’s analysis was carried out by Evidera with research funding from Bristol-Myers Squibb and Pfizer, which jointly developed apixaban.
AT ACC 14
Major finding: Using apixaban instead of warfarin for stroke prevention in AF would result in an estimated medical cost savings of $1,245 per patient/year through reduced risks of stroke and major bleeding. Dabigatran would save an estimated $555/year, while rivaroxaban would result in a $144 increase in medical costs.
Data source: This was a cost-savings analysis that used data from the pivotal clinical trials of the novel anticoagulants in combination with real-world reference data on warfarin event rates obtained from a large health insurance claims database.
Disclosures: This medical costs savings analysis was conducted by Evidera, a research firm, with funding from Bristol-Myers Squibb and Pfizer. The presenter is an Evidera employee.
Intraoperative steroids found to increase MI risk in cardiac surgery patients
WASHINGTON – Administering methylprednisolone to patients undergoing cardiac surgery with cardiopulmonary bypass did not reduce the risks of death or major morbidity at 30 days, but was associated with an increased risk of early postoperative myocardial infarction, in a randomized controlled trial of about 7,500 high-risk surgical patients.
Based on the results of the study, the Steroids in Cardiac Surgery (SIRS) trial, "methylprednisolone should not be administered prophylactically to high-risk patients undergoing cardiac surgery" with cardiopulmonary bypass, Dr. Richard Whitlock said at the annual meeting of the American College of Cardiology.
SIRS, a randomized controlled study, evaluated the effects of prophylactic steroids in patients undergoing cardiac surgery with cardiopulmonary bypass in 18 countries in North and South America, Europe, the Middle East, and Asia. The study addressed whether the use of prophylactic steroids can attenuate the "intense inflammatory response" that occurs with cardiopulmonary bypass and is associated with adverse outcomes, said Dr. Whitlock, a cardiac surgeon at McMaster University, Hamilton, Ont., and lead investigator in the study.
Whether this approach results in improved outcomes has been unclear, he said. A recent meta-analysis of 44 small studies suggested that steroids have clinical benefits in this setting, and this use of methylprednisolone is standard practice in many European countries. And although it is not used as extensively in the United States, it is still standard care at some U.S. centers, he noted.
In SIRS, patients were randomized to 500 mg methylprednisolone, administered intravenously during surgery (3,755 patients) or placebo (3,752). Patients were considered high risk; their mean age was 67 years, two-thirds were male, and their mean EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 7.1. Only one patient, who was in the treatment group, was lost to follow-up.
There were no significant differences between the two groups in the two primary endpoints: total mortality at 30 days and the combined endpoint of total mortality, stroke, MI, renal failure, or respiratory failure within 30 days. The results were consistent across different subgroups, including sex, diabetes status, age, EuroSCORE, type of surgery and duration of cardiopulmonary bypass.
However, significantly more patients in the treatment group had an MI – mostly early – after surgery (500 vs. 408 in the placebo group), an increased risk of 22%, which was statistically significant.
The use of methylprednisolone was not associated with an altered risk of other stroke, new renal failure, or respiratory failure, or other outcomes measured, including transfusion requirements, new-onset atrial fibrillation, length of ICU or hospital stay, surgical site infections, delirium, or GI complications, Dr. Whitlock said.
When asked about a possible mechanism behind the SIRS results, Dr. Whitlock said that one possible explanation could be that since one of the important early recovery strategies after myocardial injury is movement of glucose into cells, and insulin requirements increase in the steroid-treated patients, "it is possible that we’re inducing insulin resistance: Thereby, glucose is not entering the myocyte for the recovery phase after the ischemic insult." While that is plausible, he added, "we really don’t have the answer. What is important is the signal is clear, it’s clear across all subgroups, and it is a prognostically important increase."
Dr. Amit Khera, director of the preventive cardiology program at UT Southwestern Medical Center, Dallas, commented that SIRS was a definitive study, and this use of methylprednisolone, at least at higher doses, "should not be a strategy we should pursue."
The SIRS trial was conducted by the Population Health Research Institute at the Hamilton Health Sciences and McMaster University during 2007-2014 and was funded with grants from the Canadian Institutes for Health Research and the Canadian Network and Centre for Trials Internationally. Dr. Whitlock said he had no relevant financial disclosures.
WASHINGTON – Administering methylprednisolone to patients undergoing cardiac surgery with cardiopulmonary bypass did not reduce the risks of death or major morbidity at 30 days, but was associated with an increased risk of early postoperative myocardial infarction, in a randomized controlled trial of about 7,500 high-risk surgical patients.
Based on the results of the study, the Steroids in Cardiac Surgery (SIRS) trial, "methylprednisolone should not be administered prophylactically to high-risk patients undergoing cardiac surgery" with cardiopulmonary bypass, Dr. Richard Whitlock said at the annual meeting of the American College of Cardiology.
SIRS, a randomized controlled study, evaluated the effects of prophylactic steroids in patients undergoing cardiac surgery with cardiopulmonary bypass in 18 countries in North and South America, Europe, the Middle East, and Asia. The study addressed whether the use of prophylactic steroids can attenuate the "intense inflammatory response" that occurs with cardiopulmonary bypass and is associated with adverse outcomes, said Dr. Whitlock, a cardiac surgeon at McMaster University, Hamilton, Ont., and lead investigator in the study.
Whether this approach results in improved outcomes has been unclear, he said. A recent meta-analysis of 44 small studies suggested that steroids have clinical benefits in this setting, and this use of methylprednisolone is standard practice in many European countries. And although it is not used as extensively in the United States, it is still standard care at some U.S. centers, he noted.
In SIRS, patients were randomized to 500 mg methylprednisolone, administered intravenously during surgery (3,755 patients) or placebo (3,752). Patients were considered high risk; their mean age was 67 years, two-thirds were male, and their mean EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 7.1. Only one patient, who was in the treatment group, was lost to follow-up.
There were no significant differences between the two groups in the two primary endpoints: total mortality at 30 days and the combined endpoint of total mortality, stroke, MI, renal failure, or respiratory failure within 30 days. The results were consistent across different subgroups, including sex, diabetes status, age, EuroSCORE, type of surgery and duration of cardiopulmonary bypass.
However, significantly more patients in the treatment group had an MI – mostly early – after surgery (500 vs. 408 in the placebo group), an increased risk of 22%, which was statistically significant.
The use of methylprednisolone was not associated with an altered risk of other stroke, new renal failure, or respiratory failure, or other outcomes measured, including transfusion requirements, new-onset atrial fibrillation, length of ICU or hospital stay, surgical site infections, delirium, or GI complications, Dr. Whitlock said.
When asked about a possible mechanism behind the SIRS results, Dr. Whitlock said that one possible explanation could be that since one of the important early recovery strategies after myocardial injury is movement of glucose into cells, and insulin requirements increase in the steroid-treated patients, "it is possible that we’re inducing insulin resistance: Thereby, glucose is not entering the myocyte for the recovery phase after the ischemic insult." While that is plausible, he added, "we really don’t have the answer. What is important is the signal is clear, it’s clear across all subgroups, and it is a prognostically important increase."
Dr. Amit Khera, director of the preventive cardiology program at UT Southwestern Medical Center, Dallas, commented that SIRS was a definitive study, and this use of methylprednisolone, at least at higher doses, "should not be a strategy we should pursue."
The SIRS trial was conducted by the Population Health Research Institute at the Hamilton Health Sciences and McMaster University during 2007-2014 and was funded with grants from the Canadian Institutes for Health Research and the Canadian Network and Centre for Trials Internationally. Dr. Whitlock said he had no relevant financial disclosures.
WASHINGTON – Administering methylprednisolone to patients undergoing cardiac surgery with cardiopulmonary bypass did not reduce the risks of death or major morbidity at 30 days, but was associated with an increased risk of early postoperative myocardial infarction, in a randomized controlled trial of about 7,500 high-risk surgical patients.
Based on the results of the study, the Steroids in Cardiac Surgery (SIRS) trial, "methylprednisolone should not be administered prophylactically to high-risk patients undergoing cardiac surgery" with cardiopulmonary bypass, Dr. Richard Whitlock said at the annual meeting of the American College of Cardiology.
SIRS, a randomized controlled study, evaluated the effects of prophylactic steroids in patients undergoing cardiac surgery with cardiopulmonary bypass in 18 countries in North and South America, Europe, the Middle East, and Asia. The study addressed whether the use of prophylactic steroids can attenuate the "intense inflammatory response" that occurs with cardiopulmonary bypass and is associated with adverse outcomes, said Dr. Whitlock, a cardiac surgeon at McMaster University, Hamilton, Ont., and lead investigator in the study.
Whether this approach results in improved outcomes has been unclear, he said. A recent meta-analysis of 44 small studies suggested that steroids have clinical benefits in this setting, and this use of methylprednisolone is standard practice in many European countries. And although it is not used as extensively in the United States, it is still standard care at some U.S. centers, he noted.
In SIRS, patients were randomized to 500 mg methylprednisolone, administered intravenously during surgery (3,755 patients) or placebo (3,752). Patients were considered high risk; their mean age was 67 years, two-thirds were male, and their mean EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 7.1. Only one patient, who was in the treatment group, was lost to follow-up.
There were no significant differences between the two groups in the two primary endpoints: total mortality at 30 days and the combined endpoint of total mortality, stroke, MI, renal failure, or respiratory failure within 30 days. The results were consistent across different subgroups, including sex, diabetes status, age, EuroSCORE, type of surgery and duration of cardiopulmonary bypass.
However, significantly more patients in the treatment group had an MI – mostly early – after surgery (500 vs. 408 in the placebo group), an increased risk of 22%, which was statistically significant.
The use of methylprednisolone was not associated with an altered risk of other stroke, new renal failure, or respiratory failure, or other outcomes measured, including transfusion requirements, new-onset atrial fibrillation, length of ICU or hospital stay, surgical site infections, delirium, or GI complications, Dr. Whitlock said.
When asked about a possible mechanism behind the SIRS results, Dr. Whitlock said that one possible explanation could be that since one of the important early recovery strategies after myocardial injury is movement of glucose into cells, and insulin requirements increase in the steroid-treated patients, "it is possible that we’re inducing insulin resistance: Thereby, glucose is not entering the myocyte for the recovery phase after the ischemic insult." While that is plausible, he added, "we really don’t have the answer. What is important is the signal is clear, it’s clear across all subgroups, and it is a prognostically important increase."
Dr. Amit Khera, director of the preventive cardiology program at UT Southwestern Medical Center, Dallas, commented that SIRS was a definitive study, and this use of methylprednisolone, at least at higher doses, "should not be a strategy we should pursue."
The SIRS trial was conducted by the Population Health Research Institute at the Hamilton Health Sciences and McMaster University during 2007-2014 and was funded with grants from the Canadian Institutes for Health Research and the Canadian Network and Centre for Trials Internationally. Dr. Whitlock said he had no relevant financial disclosures.
AT ACC 14
Major finding: Intraoperative methylprednisolone had no prophylactic effect in reducing mortality or serious morbidity, but was associated with a 22% increased risk of early postoperative MI, in high-risk patients undergoing cardiac surgery with cardiopulmonary bypass.
Data source: The SIRS trial, a randomized, controlled international study that compared 30-day all-cause mortality and a composite endpoint in more than 7,500 high risk patients undergoing cardiac surgery with cardiopulmonary bypass randomized to receive an intravenous dose of methylprednisolone or placebo.
Disclosures: SIRS was funded with grants from the Canadian Institutes for Health Research and the Canadian Network and Centre for Trials Internationally. Dr. Whitlock said he had no relevant financial disclosures.
Bariatric surgery’s benefit persists in type 2 diabetes
WASHINGTON – Bariatric surgery combined with intensive medical therapy had a significantly greater impact on glycemic control, compared with medical therapy alone, in a 3-year study of overweight and obese people with uncontrolled type 2 diabetes – providing evidence supporting the durability of the beneficial effects of surgery beyond 1 year.
In the study of 137 patients, who all received intensive medical therapy, 37.5% of patients who had a gastric bypass and 24.5% of those who had a sleeve-gastrectomy had achieved the primary endpoint, a hemoglobin A1c of 6% or lower, 3 years after surgery, compared with 5% of those who had received medical therapy alone, Dr. Sangeeta Kashyap said on March 31 at the annual meeting of the American College of Cardiology.
"Many surgical patients achieved this control without the use of any diabetic medications, particularly insulin; metabolic syndrome components improved, and quality of life was enhanced," said Dr. Kashyap, an endocrinologist at the Cleveland Clinic, where the study was conducted.
In addition, about two-thirds (65%) of those in the surgery groups met the American Diabetes Association HbA1c goal of 7% or less, compared with 40% of those in the medical group, she added.
These are the 3-year results of the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. The 1-year results of STAMPEDE are among the data that have shown intensive medical therapy and surgery can result in the remission of type 2 diabetes, but the durability of these effects have been unclear.
STAMPEDE is an investigator-initiated study that enrolled 150 overweight or obese middle-aged adults who had had type 2 diabetes for an average of 8.3 years and HbA1c levels above 7% (mean baseline level was 9.3%) and a body mass index of 27-43 kg/m2 (mean baseline BMI was 36); their mean age was 48 years, two-thirds were white, 68% were women, and 43% required insulin. One-third had a BMI under 35, below the current National Institutes of Health guideline for bariatric surgery.
After randomization to intensive medical therapy alone or a Roux-en-Y gastric bypass or sleeve gastrectomy plus intensive medical therapy, treatment was adjusted every 3 months for the first 2 years, then every 6 months, aiming for a HbA1c of 6% or less. The results were based on the 137 patients who completed 3 years of follow-up.
Significantly more patients in the surgery groups achieved the primary endpoint at 3 years without diabetes medications: 35.4% in the bypass group and 20.4% in the sleeve group, compared with none of those on medical therapy. "Virtually all" of those in the gastric bypass group met the primary endpoint without the use of insulin, Dr. Kashyap noted.
Relapses of glycemic control, defined as those who met the primary endpoint at 12 months but not at 3 years, occurred in the bypass group (24%) but were higher in the sleeve group (50%) and in the medical therapy group (80%).
Other benefits identified at 3 years included improved measures of HDL and triglycerides in the surgery group, compared with the medical therapy group. There were no differences in changes in blood pressure or in LDL levels; or, at 2 years, no differences between carotid intimal medial thickness measures in the three groups. But there was a substantial decrease in the medications used for blood pressure and cholesterol in the surgery groups: At 3 years, about 40% of the patients in the two surgery groups were not taking any cardiovascular medications, vs. only 2% of those in the medical therapy group.
Those in the two surgery groups also had more favorable effects on secondary endpoints that included body weight, use of glucose-lowering medications, and quality of life, compared with the intensive medical therapy group. Those in the bypass group showed improvements in five of eight quality of life measures, including physical function and less body pain, and those in the sleeve gastrectomy group has improvements in two of the eight measures, compared with no improvements among those on medical therapy.
Dr. Kashyap said that being able to take fewer medications per day and mobility and physical function improvements in the significant number of patients with osteoarthritis contributed to the improved quality of life in the surgery patients.
There were no procedure-related deaths, and other than four patients in the surgery groups who required additional surgery in the first year, none needed surgery after that time, and there were no deaths or life-threatening complications in the three groups of patients.
Dr. Kashyap pointed out that bariatric surgery is considered optimal for people who are heavier than a proportion of the patients in this study, but in the study, people who might not normally be considered for bariatric surgery experienced significant benefits. Often an underused intervention in medicine, bariatric surgery "should be considered a treatment option for patients with uncontrolled type 2 diabetes with moderate to severe obesity," Dr. Kashyap concluded.
The size of the study was one of the limitations, and larger studies are needed to determine if this approach is associated with benefits on cardiovascular events and complications, she added.
The 3-year STAMPEDE results were published concurrently with the presentation in the New England Journal of Medicine (doi:10.1056/NEJMoa1401329).
The investigator-initiated study received funding from Ethicon, the Cleveland Clinic, LifeScan, and the National Institutes of Health. Dr. Kashyap had no disclosures.
WASHINGTON – Bariatric surgery combined with intensive medical therapy had a significantly greater impact on glycemic control, compared with medical therapy alone, in a 3-year study of overweight and obese people with uncontrolled type 2 diabetes – providing evidence supporting the durability of the beneficial effects of surgery beyond 1 year.
In the study of 137 patients, who all received intensive medical therapy, 37.5% of patients who had a gastric bypass and 24.5% of those who had a sleeve-gastrectomy had achieved the primary endpoint, a hemoglobin A1c of 6% or lower, 3 years after surgery, compared with 5% of those who had received medical therapy alone, Dr. Sangeeta Kashyap said on March 31 at the annual meeting of the American College of Cardiology.
"Many surgical patients achieved this control without the use of any diabetic medications, particularly insulin; metabolic syndrome components improved, and quality of life was enhanced," said Dr. Kashyap, an endocrinologist at the Cleveland Clinic, where the study was conducted.
In addition, about two-thirds (65%) of those in the surgery groups met the American Diabetes Association HbA1c goal of 7% or less, compared with 40% of those in the medical group, she added.
These are the 3-year results of the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. The 1-year results of STAMPEDE are among the data that have shown intensive medical therapy and surgery can result in the remission of type 2 diabetes, but the durability of these effects have been unclear.
STAMPEDE is an investigator-initiated study that enrolled 150 overweight or obese middle-aged adults who had had type 2 diabetes for an average of 8.3 years and HbA1c levels above 7% (mean baseline level was 9.3%) and a body mass index of 27-43 kg/m2 (mean baseline BMI was 36); their mean age was 48 years, two-thirds were white, 68% were women, and 43% required insulin. One-third had a BMI under 35, below the current National Institutes of Health guideline for bariatric surgery.
After randomization to intensive medical therapy alone or a Roux-en-Y gastric bypass or sleeve gastrectomy plus intensive medical therapy, treatment was adjusted every 3 months for the first 2 years, then every 6 months, aiming for a HbA1c of 6% or less. The results were based on the 137 patients who completed 3 years of follow-up.
Significantly more patients in the surgery groups achieved the primary endpoint at 3 years without diabetes medications: 35.4% in the bypass group and 20.4% in the sleeve group, compared with none of those on medical therapy. "Virtually all" of those in the gastric bypass group met the primary endpoint without the use of insulin, Dr. Kashyap noted.
Relapses of glycemic control, defined as those who met the primary endpoint at 12 months but not at 3 years, occurred in the bypass group (24%) but were higher in the sleeve group (50%) and in the medical therapy group (80%).
Other benefits identified at 3 years included improved measures of HDL and triglycerides in the surgery group, compared with the medical therapy group. There were no differences in changes in blood pressure or in LDL levels; or, at 2 years, no differences between carotid intimal medial thickness measures in the three groups. But there was a substantial decrease in the medications used for blood pressure and cholesterol in the surgery groups: At 3 years, about 40% of the patients in the two surgery groups were not taking any cardiovascular medications, vs. only 2% of those in the medical therapy group.
Those in the two surgery groups also had more favorable effects on secondary endpoints that included body weight, use of glucose-lowering medications, and quality of life, compared with the intensive medical therapy group. Those in the bypass group showed improvements in five of eight quality of life measures, including physical function and less body pain, and those in the sleeve gastrectomy group has improvements in two of the eight measures, compared with no improvements among those on medical therapy.
Dr. Kashyap said that being able to take fewer medications per day and mobility and physical function improvements in the significant number of patients with osteoarthritis contributed to the improved quality of life in the surgery patients.
There were no procedure-related deaths, and other than four patients in the surgery groups who required additional surgery in the first year, none needed surgery after that time, and there were no deaths or life-threatening complications in the three groups of patients.
Dr. Kashyap pointed out that bariatric surgery is considered optimal for people who are heavier than a proportion of the patients in this study, but in the study, people who might not normally be considered for bariatric surgery experienced significant benefits. Often an underused intervention in medicine, bariatric surgery "should be considered a treatment option for patients with uncontrolled type 2 diabetes with moderate to severe obesity," Dr. Kashyap concluded.
The size of the study was one of the limitations, and larger studies are needed to determine if this approach is associated with benefits on cardiovascular events and complications, she added.
The 3-year STAMPEDE results were published concurrently with the presentation in the New England Journal of Medicine (doi:10.1056/NEJMoa1401329).
The investigator-initiated study received funding from Ethicon, the Cleveland Clinic, LifeScan, and the National Institutes of Health. Dr. Kashyap had no disclosures.
WASHINGTON – Bariatric surgery combined with intensive medical therapy had a significantly greater impact on glycemic control, compared with medical therapy alone, in a 3-year study of overweight and obese people with uncontrolled type 2 diabetes – providing evidence supporting the durability of the beneficial effects of surgery beyond 1 year.
In the study of 137 patients, who all received intensive medical therapy, 37.5% of patients who had a gastric bypass and 24.5% of those who had a sleeve-gastrectomy had achieved the primary endpoint, a hemoglobin A1c of 6% or lower, 3 years after surgery, compared with 5% of those who had received medical therapy alone, Dr. Sangeeta Kashyap said on March 31 at the annual meeting of the American College of Cardiology.
"Many surgical patients achieved this control without the use of any diabetic medications, particularly insulin; metabolic syndrome components improved, and quality of life was enhanced," said Dr. Kashyap, an endocrinologist at the Cleveland Clinic, where the study was conducted.
In addition, about two-thirds (65%) of those in the surgery groups met the American Diabetes Association HbA1c goal of 7% or less, compared with 40% of those in the medical group, she added.
These are the 3-year results of the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. The 1-year results of STAMPEDE are among the data that have shown intensive medical therapy and surgery can result in the remission of type 2 diabetes, but the durability of these effects have been unclear.
STAMPEDE is an investigator-initiated study that enrolled 150 overweight or obese middle-aged adults who had had type 2 diabetes for an average of 8.3 years and HbA1c levels above 7% (mean baseline level was 9.3%) and a body mass index of 27-43 kg/m2 (mean baseline BMI was 36); their mean age was 48 years, two-thirds were white, 68% were women, and 43% required insulin. One-third had a BMI under 35, below the current National Institutes of Health guideline for bariatric surgery.
After randomization to intensive medical therapy alone or a Roux-en-Y gastric bypass or sleeve gastrectomy plus intensive medical therapy, treatment was adjusted every 3 months for the first 2 years, then every 6 months, aiming for a HbA1c of 6% or less. The results were based on the 137 patients who completed 3 years of follow-up.
Significantly more patients in the surgery groups achieved the primary endpoint at 3 years without diabetes medications: 35.4% in the bypass group and 20.4% in the sleeve group, compared with none of those on medical therapy. "Virtually all" of those in the gastric bypass group met the primary endpoint without the use of insulin, Dr. Kashyap noted.
Relapses of glycemic control, defined as those who met the primary endpoint at 12 months but not at 3 years, occurred in the bypass group (24%) but were higher in the sleeve group (50%) and in the medical therapy group (80%).
Other benefits identified at 3 years included improved measures of HDL and triglycerides in the surgery group, compared with the medical therapy group. There were no differences in changes in blood pressure or in LDL levels; or, at 2 years, no differences between carotid intimal medial thickness measures in the three groups. But there was a substantial decrease in the medications used for blood pressure and cholesterol in the surgery groups: At 3 years, about 40% of the patients in the two surgery groups were not taking any cardiovascular medications, vs. only 2% of those in the medical therapy group.
Those in the two surgery groups also had more favorable effects on secondary endpoints that included body weight, use of glucose-lowering medications, and quality of life, compared with the intensive medical therapy group. Those in the bypass group showed improvements in five of eight quality of life measures, including physical function and less body pain, and those in the sleeve gastrectomy group has improvements in two of the eight measures, compared with no improvements among those on medical therapy.
Dr. Kashyap said that being able to take fewer medications per day and mobility and physical function improvements in the significant number of patients with osteoarthritis contributed to the improved quality of life in the surgery patients.
There were no procedure-related deaths, and other than four patients in the surgery groups who required additional surgery in the first year, none needed surgery after that time, and there were no deaths or life-threatening complications in the three groups of patients.
Dr. Kashyap pointed out that bariatric surgery is considered optimal for people who are heavier than a proportion of the patients in this study, but in the study, people who might not normally be considered for bariatric surgery experienced significant benefits. Often an underused intervention in medicine, bariatric surgery "should be considered a treatment option for patients with uncontrolled type 2 diabetes with moderate to severe obesity," Dr. Kashyap concluded.
The size of the study was one of the limitations, and larger studies are needed to determine if this approach is associated with benefits on cardiovascular events and complications, she added.
The 3-year STAMPEDE results were published concurrently with the presentation in the New England Journal of Medicine (doi:10.1056/NEJMoa1401329).
The investigator-initiated study received funding from Ethicon, the Cleveland Clinic, LifeScan, and the National Institutes of Health. Dr. Kashyap had no disclosures.
AT ACC 14
Major finding: Significantly more patients treated with one of two types of bariatric surgery achieved the HbA1c target (37.5% and 24.5%) after 3 years, compared with those on medical therapy alone (5%).
Data source: The STAMPEDE trial, which compared the effects of bariatric surgery plus intensive medical therapy to medical therapy alone in 137 people with type 2 diabetes out to 3 years.
Disclosures: The investigator-initiated study received funding from Ethicon, the Cleveland Clinic, LifeScan, and the National Institutes of Health. Dr. Kashyap had no disclosures.
Evolocumab betters ezetimibe for lowering LDL in statin-intolerant patients
WASHINGTON – Evolocumab, an investigational fully human monoclonal antibody, was associated with markedly greater LDL cholesterol reductions than ezetimibe in a phase III clinical trial of statin-intolerant patients.
"Robust LDL lowering and good tolerability make evolocumab a promising therapy for addressing the large unmet clinical need in high-risk hypercholesterolemic patients with statin intolerance," Dr. Erik S.G. Stroes said in presenting results of the phase III trial, known as GAUSS-2, at the annual meeting of the American College of Cardiology.
Evolocumab is an injected product that inhibits PCSK9 (proprotein convertase subtilisin/kexin type 9). Ezetimibe is the only well-tolerated and approved alternative available for LDL cholesterol lowering in patients who can’t take a statin.
Recent real-world patient surveys suggest the rate of statin intolerance is 10%-20%, much more common than was initially apparent from the highly selective landmark statin clinical trials, observed Dr. Stroes, professor and chair of the department of vascular medicine at the Academic Medical Center, Amsterdam.
GAUSS-2 (the second study of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects) was a 12-week, double-blind, phase III clinical trial that included 307 participants. All had a history of intolerance to at least two statins. The majority of GAUSS-2 participants had previously discontinued three or more statins, nearly always because of muscle aches and pains, and almost one-quarter had unsuccessfully tried four or more statins.
The mean baseline LDL cholesterol level was 193 mg/dL. Subjects were randomized 2:2:1:1 to one of four treatment arms: subcutaneously injected evolocumab at 140 mg, given biweekly plus an oral placebo; evolocumab 420 mg, given monthly plus placebo; or 10 mg/day of oral ezetimibe plus a placebo injection given either biweekly or monthly.
The primary endpoint was the percentage change in LDL cholesterol levels from baseline through week 12. The two evolocumab dosing regimens proved clinically equivalent, with mean LDL cholesterol reductions of 53% and 56%, in contrast to the 15% and 18% reductions in the two ezetimibe arms.
As in the other four phase III evolocumab trials presented at ACC 14, the PCSK9 inhibitor was well tolerated with 96% of patients randomized to evolocumab in GAUSS-2 completing the 12-week study. Given that 100% of GAUSS-2 participants had a history of intolerable muscle-related side effects during multiple prior rounds of statin therapy, it’s noteworthy that the incidence of myalgia in the evolocumab group was 8%, even lower than the 18% rate in the ezetimibe group, Dr. Stroes commented.
At the same late-breaking clinical trials session at which Dr. Stroes presented GAUSS-2, Dr. Jennifer G. Robinson presented the results of LAPLACE-2, a randomized, double-blind, 12-week, phase III trial in which investigators looked at the lipid-lowering effects of evolocumab in conjunction with various doses of atorvastatin, rosuvastatin, and simvastatin. LAPLACE-2 (LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy) featured a complex study design in which roughly 1,900 patients with elevated LDL cholesterol levels were randomized to 1 of 24 treatment arms.
At week 12, the percent reduction in LDL cholesterol from baseline in the various evolocumab arms ranged from 55% to 76%. An LDL cholesterol level of less than 70 mg/dL was achieved in 86%-94% of patients on evolocumab and moderate-intensity statin therapy, such as atorvastatin at 10 mg/day and in 3%-95% of those on evolocumab and high-intensity statin therapy, such as atorvastatin at 80 mg/day or simvastatin at 40 mg/day.
At week 12, the mean LDL cholesterol level in patients on evolocumab plus high-intensity statin therapy was 35-38 mg/dL. In those on a moderate-intensity statin regimen, the mean LDL cholesterol level was 38-45 mg/dL, reported Dr. Robinson, professor of epidemiology and of medicine and director of the prevention intervention center at the University of Iowa, Iowa City.
With five evolocumab phase III clinical trials presented at ACC 14 showing a consistent pattern of large-scale LDL cholesterol lowering and a side effect profile essentially that of placebo, the crucial question now becomes whether achieving LDL cholesterol levels in the 35-45 mg/dL range will translate into a large reduction in cardiovascular events. All eyes have turned to the ongoing FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, in which 22,500 patients with clinical atherosclerotic cardiovascular disease are being randomized to evolocumab or placebo in combination with moderate- or high-intensity statin therapy with cardiovascular event rates as the key endpoints. Results are expected in 2018.
In the meantime, Dr. Robinson said, it’s possible that prior to the FOURIER results, the Food and Drug Administration will approve evolocumab with an indication for LDL cholesterol lowering. After all, ezetimibe was approved on the strength of far more modest lipid lowering, and in the absence of supporting outcome data. But if evolocumab were to receive marketing approval in advance of the event rate data, she added, the proper way for physicians to use it would be only in the patient groups with significant clinical unmet needs who were the focus of the phase III trials: those with statin intolerance (GAUSS-2), familial hypercholesterolemia and other genetic dyslipidemias (RUTHERFORD-2), or people whose cardiovascular risk status warrants high-intensity statin therapy but who can only tolerate moderate-intensity therapy (LAPLACE-2).
Dr. Stroes concurred. "We are absolutely not in competition with statins; we have to start with statins," he emphasized. "What I hope is that while we’re waiting for the outcome study, that we’ll be able to continue treating these patients in open-label extension studies, because they don’t have an alternative."
Discussant Dr. Joseph S. Alpert called the evolocumab results "very dramatic. Like everybody else, I’m waiting to see the outcome data. My prediction is that it’s going to be a positive trial," said Dr. Alpert, professor of medicine and director of the coronary care unit at University of Arizona Medical Center, Tucson.
If that proves to be the case, he added, it would probably result in a return to the ‘treat to target/know your LDL number’ approach that the ACC/American Heart Association guidelines turned away from last year in an enormously controversial move.
Simultaneous with Dr. Stroes’s presentation of GAUSS-2, the study was published online (J. Am. Coll. Cardiol. 2014 [doi:10.1016/j.jacc.2014.03.019]).
Dr. Stroes and Dr. Robinson serve as consultants to Amgen, which sponsored the studies.
WASHINGTON – Evolocumab, an investigational fully human monoclonal antibody, was associated with markedly greater LDL cholesterol reductions than ezetimibe in a phase III clinical trial of statin-intolerant patients.
"Robust LDL lowering and good tolerability make evolocumab a promising therapy for addressing the large unmet clinical need in high-risk hypercholesterolemic patients with statin intolerance," Dr. Erik S.G. Stroes said in presenting results of the phase III trial, known as GAUSS-2, at the annual meeting of the American College of Cardiology.
Evolocumab is an injected product that inhibits PCSK9 (proprotein convertase subtilisin/kexin type 9). Ezetimibe is the only well-tolerated and approved alternative available for LDL cholesterol lowering in patients who can’t take a statin.
Recent real-world patient surveys suggest the rate of statin intolerance is 10%-20%, much more common than was initially apparent from the highly selective landmark statin clinical trials, observed Dr. Stroes, professor and chair of the department of vascular medicine at the Academic Medical Center, Amsterdam.
GAUSS-2 (the second study of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects) was a 12-week, double-blind, phase III clinical trial that included 307 participants. All had a history of intolerance to at least two statins. The majority of GAUSS-2 participants had previously discontinued three or more statins, nearly always because of muscle aches and pains, and almost one-quarter had unsuccessfully tried four or more statins.
The mean baseline LDL cholesterol level was 193 mg/dL. Subjects were randomized 2:2:1:1 to one of four treatment arms: subcutaneously injected evolocumab at 140 mg, given biweekly plus an oral placebo; evolocumab 420 mg, given monthly plus placebo; or 10 mg/day of oral ezetimibe plus a placebo injection given either biweekly or monthly.
The primary endpoint was the percentage change in LDL cholesterol levels from baseline through week 12. The two evolocumab dosing regimens proved clinically equivalent, with mean LDL cholesterol reductions of 53% and 56%, in contrast to the 15% and 18% reductions in the two ezetimibe arms.
As in the other four phase III evolocumab trials presented at ACC 14, the PCSK9 inhibitor was well tolerated with 96% of patients randomized to evolocumab in GAUSS-2 completing the 12-week study. Given that 100% of GAUSS-2 participants had a history of intolerable muscle-related side effects during multiple prior rounds of statin therapy, it’s noteworthy that the incidence of myalgia in the evolocumab group was 8%, even lower than the 18% rate in the ezetimibe group, Dr. Stroes commented.
At the same late-breaking clinical trials session at which Dr. Stroes presented GAUSS-2, Dr. Jennifer G. Robinson presented the results of LAPLACE-2, a randomized, double-blind, 12-week, phase III trial in which investigators looked at the lipid-lowering effects of evolocumab in conjunction with various doses of atorvastatin, rosuvastatin, and simvastatin. LAPLACE-2 (LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy) featured a complex study design in which roughly 1,900 patients with elevated LDL cholesterol levels were randomized to 1 of 24 treatment arms.
At week 12, the percent reduction in LDL cholesterol from baseline in the various evolocumab arms ranged from 55% to 76%. An LDL cholesterol level of less than 70 mg/dL was achieved in 86%-94% of patients on evolocumab and moderate-intensity statin therapy, such as atorvastatin at 10 mg/day and in 3%-95% of those on evolocumab and high-intensity statin therapy, such as atorvastatin at 80 mg/day or simvastatin at 40 mg/day.
At week 12, the mean LDL cholesterol level in patients on evolocumab plus high-intensity statin therapy was 35-38 mg/dL. In those on a moderate-intensity statin regimen, the mean LDL cholesterol level was 38-45 mg/dL, reported Dr. Robinson, professor of epidemiology and of medicine and director of the prevention intervention center at the University of Iowa, Iowa City.
With five evolocumab phase III clinical trials presented at ACC 14 showing a consistent pattern of large-scale LDL cholesterol lowering and a side effect profile essentially that of placebo, the crucial question now becomes whether achieving LDL cholesterol levels in the 35-45 mg/dL range will translate into a large reduction in cardiovascular events. All eyes have turned to the ongoing FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, in which 22,500 patients with clinical atherosclerotic cardiovascular disease are being randomized to evolocumab or placebo in combination with moderate- or high-intensity statin therapy with cardiovascular event rates as the key endpoints. Results are expected in 2018.
In the meantime, Dr. Robinson said, it’s possible that prior to the FOURIER results, the Food and Drug Administration will approve evolocumab with an indication for LDL cholesterol lowering. After all, ezetimibe was approved on the strength of far more modest lipid lowering, and in the absence of supporting outcome data. But if evolocumab were to receive marketing approval in advance of the event rate data, she added, the proper way for physicians to use it would be only in the patient groups with significant clinical unmet needs who were the focus of the phase III trials: those with statin intolerance (GAUSS-2), familial hypercholesterolemia and other genetic dyslipidemias (RUTHERFORD-2), or people whose cardiovascular risk status warrants high-intensity statin therapy but who can only tolerate moderate-intensity therapy (LAPLACE-2).
Dr. Stroes concurred. "We are absolutely not in competition with statins; we have to start with statins," he emphasized. "What I hope is that while we’re waiting for the outcome study, that we’ll be able to continue treating these patients in open-label extension studies, because they don’t have an alternative."
Discussant Dr. Joseph S. Alpert called the evolocumab results "very dramatic. Like everybody else, I’m waiting to see the outcome data. My prediction is that it’s going to be a positive trial," said Dr. Alpert, professor of medicine and director of the coronary care unit at University of Arizona Medical Center, Tucson.
If that proves to be the case, he added, it would probably result in a return to the ‘treat to target/know your LDL number’ approach that the ACC/American Heart Association guidelines turned away from last year in an enormously controversial move.
Simultaneous with Dr. Stroes’s presentation of GAUSS-2, the study was published online (J. Am. Coll. Cardiol. 2014 [doi:10.1016/j.jacc.2014.03.019]).
Dr. Stroes and Dr. Robinson serve as consultants to Amgen, which sponsored the studies.
WASHINGTON – Evolocumab, an investigational fully human monoclonal antibody, was associated with markedly greater LDL cholesterol reductions than ezetimibe in a phase III clinical trial of statin-intolerant patients.
"Robust LDL lowering and good tolerability make evolocumab a promising therapy for addressing the large unmet clinical need in high-risk hypercholesterolemic patients with statin intolerance," Dr. Erik S.G. Stroes said in presenting results of the phase III trial, known as GAUSS-2, at the annual meeting of the American College of Cardiology.
Evolocumab is an injected product that inhibits PCSK9 (proprotein convertase subtilisin/kexin type 9). Ezetimibe is the only well-tolerated and approved alternative available for LDL cholesterol lowering in patients who can’t take a statin.
Recent real-world patient surveys suggest the rate of statin intolerance is 10%-20%, much more common than was initially apparent from the highly selective landmark statin clinical trials, observed Dr. Stroes, professor and chair of the department of vascular medicine at the Academic Medical Center, Amsterdam.
GAUSS-2 (the second study of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects) was a 12-week, double-blind, phase III clinical trial that included 307 participants. All had a history of intolerance to at least two statins. The majority of GAUSS-2 participants had previously discontinued three or more statins, nearly always because of muscle aches and pains, and almost one-quarter had unsuccessfully tried four or more statins.
The mean baseline LDL cholesterol level was 193 mg/dL. Subjects were randomized 2:2:1:1 to one of four treatment arms: subcutaneously injected evolocumab at 140 mg, given biweekly plus an oral placebo; evolocumab 420 mg, given monthly plus placebo; or 10 mg/day of oral ezetimibe plus a placebo injection given either biweekly or monthly.
The primary endpoint was the percentage change in LDL cholesterol levels from baseline through week 12. The two evolocumab dosing regimens proved clinically equivalent, with mean LDL cholesterol reductions of 53% and 56%, in contrast to the 15% and 18% reductions in the two ezetimibe arms.
As in the other four phase III evolocumab trials presented at ACC 14, the PCSK9 inhibitor was well tolerated with 96% of patients randomized to evolocumab in GAUSS-2 completing the 12-week study. Given that 100% of GAUSS-2 participants had a history of intolerable muscle-related side effects during multiple prior rounds of statin therapy, it’s noteworthy that the incidence of myalgia in the evolocumab group was 8%, even lower than the 18% rate in the ezetimibe group, Dr. Stroes commented.
At the same late-breaking clinical trials session at which Dr. Stroes presented GAUSS-2, Dr. Jennifer G. Robinson presented the results of LAPLACE-2, a randomized, double-blind, 12-week, phase III trial in which investigators looked at the lipid-lowering effects of evolocumab in conjunction with various doses of atorvastatin, rosuvastatin, and simvastatin. LAPLACE-2 (LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy) featured a complex study design in which roughly 1,900 patients with elevated LDL cholesterol levels were randomized to 1 of 24 treatment arms.
At week 12, the percent reduction in LDL cholesterol from baseline in the various evolocumab arms ranged from 55% to 76%. An LDL cholesterol level of less than 70 mg/dL was achieved in 86%-94% of patients on evolocumab and moderate-intensity statin therapy, such as atorvastatin at 10 mg/day and in 3%-95% of those on evolocumab and high-intensity statin therapy, such as atorvastatin at 80 mg/day or simvastatin at 40 mg/day.
At week 12, the mean LDL cholesterol level in patients on evolocumab plus high-intensity statin therapy was 35-38 mg/dL. In those on a moderate-intensity statin regimen, the mean LDL cholesterol level was 38-45 mg/dL, reported Dr. Robinson, professor of epidemiology and of medicine and director of the prevention intervention center at the University of Iowa, Iowa City.
With five evolocumab phase III clinical trials presented at ACC 14 showing a consistent pattern of large-scale LDL cholesterol lowering and a side effect profile essentially that of placebo, the crucial question now becomes whether achieving LDL cholesterol levels in the 35-45 mg/dL range will translate into a large reduction in cardiovascular events. All eyes have turned to the ongoing FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, in which 22,500 patients with clinical atherosclerotic cardiovascular disease are being randomized to evolocumab or placebo in combination with moderate- or high-intensity statin therapy with cardiovascular event rates as the key endpoints. Results are expected in 2018.
In the meantime, Dr. Robinson said, it’s possible that prior to the FOURIER results, the Food and Drug Administration will approve evolocumab with an indication for LDL cholesterol lowering. After all, ezetimibe was approved on the strength of far more modest lipid lowering, and in the absence of supporting outcome data. But if evolocumab were to receive marketing approval in advance of the event rate data, she added, the proper way for physicians to use it would be only in the patient groups with significant clinical unmet needs who were the focus of the phase III trials: those with statin intolerance (GAUSS-2), familial hypercholesterolemia and other genetic dyslipidemias (RUTHERFORD-2), or people whose cardiovascular risk status warrants high-intensity statin therapy but who can only tolerate moderate-intensity therapy (LAPLACE-2).
Dr. Stroes concurred. "We are absolutely not in competition with statins; we have to start with statins," he emphasized. "What I hope is that while we’re waiting for the outcome study, that we’ll be able to continue treating these patients in open-label extension studies, because they don’t have an alternative."
Discussant Dr. Joseph S. Alpert called the evolocumab results "very dramatic. Like everybody else, I’m waiting to see the outcome data. My prediction is that it’s going to be a positive trial," said Dr. Alpert, professor of medicine and director of the coronary care unit at University of Arizona Medical Center, Tucson.
If that proves to be the case, he added, it would probably result in a return to the ‘treat to target/know your LDL number’ approach that the ACC/American Heart Association guidelines turned away from last year in an enormously controversial move.
Simultaneous with Dr. Stroes’s presentation of GAUSS-2, the study was published online (J. Am. Coll. Cardiol. 2014 [doi:10.1016/j.jacc.2014.03.019]).
Dr. Stroes and Dr. Robinson serve as consultants to Amgen, which sponsored the studies.
AT ACC 14
Major finding: Statin-intolerant patients with hypercholesterolemia experienced mean 53%-56% reductions in LDL cholesterol in response to 12 weeks on evolocumab, an investigational fully human monoclonal antibody, compared with 15%-18% decreases with ezetimibe.
Data source: This was a phase III, randomized, double-blind clinical trial in which 307 patients with a history of intolerance to two or more different statins were randomized to evolocumab or ezetimibe for 12 weeks.
Disclosures: The study was funded by Amgen. The presenter has served as a consultant to the company.
VIDEO: Novel drug misses mark for MI prevention, but shows promise
WASHINGTON – In the large STABILITY trial, darapladib did not significantly reduce the primary endpoint of cardiovascular death, MI, or stroke in patients with stable coronary disease.
The novel selective oral inhibitor of lipoprotein-associated phospholipase A has been shown to reduce the enzyme by 60%. The aim of this study was to reduce it within coronary plaque.
Despite the negative outcome, investigator Dr. Harvey D. White told us in an interview at the annual meeting of the American College of Cardiology that there is more to learn about darapladib, as a secondary endpoint of reducing cardiovascular death, MI, and urgent revascularization was nominally significant.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
WASHINGTON – In the large STABILITY trial, darapladib did not significantly reduce the primary endpoint of cardiovascular death, MI, or stroke in patients with stable coronary disease.
The novel selective oral inhibitor of lipoprotein-associated phospholipase A has been shown to reduce the enzyme by 60%. The aim of this study was to reduce it within coronary plaque.
Despite the negative outcome, investigator Dr. Harvey D. White told us in an interview at the annual meeting of the American College of Cardiology that there is more to learn about darapladib, as a secondary endpoint of reducing cardiovascular death, MI, and urgent revascularization was nominally significant.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
WASHINGTON – In the large STABILITY trial, darapladib did not significantly reduce the primary endpoint of cardiovascular death, MI, or stroke in patients with stable coronary disease.
The novel selective oral inhibitor of lipoprotein-associated phospholipase A has been shown to reduce the enzyme by 60%. The aim of this study was to reduce it within coronary plaque.
Despite the negative outcome, investigator Dr. Harvey D. White told us in an interview at the annual meeting of the American College of Cardiology that there is more to learn about darapladib, as a secondary endpoint of reducing cardiovascular death, MI, and urgent revascularization was nominally significant.
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 ACC 14
Colchicine called first-line pericarditis treatment
WASHINGTON – Adding colchicine to standard anti-inflammatory treatment for patients with recurrent pericarditis led to significantly fewer subsequent recurrences than did standard treatment alone in a randomized trial with 240 patients.
The findings cement colchicine as a first-line treatment for pericarditis patients who need drug treatment, Dr. Massimo Imazio said at the annual meeting of the American College of Cardiology. "Taken together with results from other randomized controlled trials, these findings suggest that colchicine should probably be regarded as a first-line treatment for either acute or recurrent pericarditis in the absence of contraindications."
Concurrent with Dr. Imazio’s report at the meeting, the results of the study were published online. (Lancet 2014 [doi:10.1016/S0140-6736(13)62709-9]).
The CORP 2 (Colchicine for Recurrent Pericarditis 2) trial was conducted at four centers in Italy during 2005-2012 and enrolled 240 adults with an episode of pericarditis and a documented prior pericarditis episode that had been followed by a symptom-free interval of at least 6 weeks.
For the study, Dr. Imazio and his associates randomized patients to received colchicine, either at 0.5 mg b.i.d. or once daily in patients weighing 70 kg or less, with no loading dose to avoid potential gastrointestinal adverse effects. Patients also received standard anti-inflammatory treatment with aspirin, ibuprofen, or indomethacin, and select patients could receive corticosteroid treatment. Treatment was continued for 6 months. Patients averaged 49 years of age; more than 80% had idiopathic pericarditis with the rest divided nearly equally between cardiac injury syndrome and connective tissue disease. Enrollment excluded patients with bacterial or neoplastic etiologies for their pericarditis.
Pericarditis occurred in 22% of patients treated with colchicine and 43% of those on placebo during an average follow-up of 20 months, a statistically significant difference for the study’s primary endpoint, reported Dr. Imazio, a cardiologist at Maria Vittoria Hospital in Torino, Italy. This benefit translated into a number needed to treat of five patients to prevent one pericarditis recurrence during 18 months of follow-up, he said. Colchicine was as effective in patients previously treated with the drug as in colchicine-naive patients, and was equally effective in all of the etiologies studied.
The dosage of colchicine used was well tolerated with no excess adverse effects or treatment discontinuations compared with placebo and no serious adverse effects. Overall, colchicine cut recurrence rates by about half based on a meta-analysis of these results along with those from six prior reports from randomized controlled trials of colchicine in a total of 1,275 patients with either a first episode or recurrent pericarditis, Dr. Imazio said. The meta-analysis also showed a consistent safety profile, with no excess adverse events or need for treatment withdrawal. The 6-month duration of treatment was selected arbitrarily; a future study could evaluate the drug for a longer treatment period, he added.
A concern with colchicine is that it morphed a few years ago from a cheap generic drug to a rebranded trade drug, Colcrys, with a large rise in price. Takeda, the company that now solely markets colchicine in the United States, had no role in the CORP 2 study.
Dr. Imazio said that he had no relevant financial disclosures.
On Twitter @mitchelzoler
These results are a major and important advance. Patients with recurrent pericarditis often require treatment with a corticosteroid that is effective, but patients frequently relapse when you try to taper the dose. It can be a very difficult down titration, and persistent corticosteroid treatment can cause salt retention and hypertension.
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Mitchel L. Zoler/Frontline Medical News
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In my practice colchicine is the drug of choice for patients with either a first episode or a recurrence of pericarditis. The dosing schedule used in the current study avoided the adverse effects that had been seen in prior studies with colchicine.
Colchicine is better than standard anti-inflammatory drugs, but it is not widely used for pericarditis in the United States, in part because the price has risen dramatically in recent years. But even at its current price, I use colchicine for all pericarditis patients, except those with a mild, brief episode that can be treated with aspirin alone. Patients with persistent and recurrent pericarditis can have persistent pain and can really suffer. Pericarditis is difficult to treat, but colchicine markedly helps. It ought to be used more than it currently is, although it has no labeling for this indication.
Dr. Allan S. Jaffe is a cardiologist and professor of medicine at the Mayo Clinic in Rochester, Minn. He said that he has been a consultant to or received honoraria from 10 drug or device companies but has no relationship with Takeda, the company that markets colchicine. He made these remarks in an interview and as a discussant for the report at the meeting.
These results are a major and important advance. Patients with recurrent pericarditis often require treatment with a corticosteroid that is effective, but patients frequently relapse when you try to taper the dose. It can be a very difficult down titration, and persistent corticosteroid treatment can cause salt retention and hypertension.
|
Mitchel L. Zoler/Frontline Medical News
|
In my practice colchicine is the drug of choice for patients with either a first episode or a recurrence of pericarditis. The dosing schedule used in the current study avoided the adverse effects that had been seen in prior studies with colchicine.
Colchicine is better than standard anti-inflammatory drugs, but it is not widely used for pericarditis in the United States, in part because the price has risen dramatically in recent years. But even at its current price, I use colchicine for all pericarditis patients, except those with a mild, brief episode that can be treated with aspirin alone. Patients with persistent and recurrent pericarditis can have persistent pain and can really suffer. Pericarditis is difficult to treat, but colchicine markedly helps. It ought to be used more than it currently is, although it has no labeling for this indication.
Dr. Allan S. Jaffe is a cardiologist and professor of medicine at the Mayo Clinic in Rochester, Minn. He said that he has been a consultant to or received honoraria from 10 drug or device companies but has no relationship with Takeda, the company that markets colchicine. He made these remarks in an interview and as a discussant for the report at the meeting.
These results are a major and important advance. Patients with recurrent pericarditis often require treatment with a corticosteroid that is effective, but patients frequently relapse when you try to taper the dose. It can be a very difficult down titration, and persistent corticosteroid treatment can cause salt retention and hypertension.
|
Mitchel L. Zoler/Frontline Medical News
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In my practice colchicine is the drug of choice for patients with either a first episode or a recurrence of pericarditis. The dosing schedule used in the current study avoided the adverse effects that had been seen in prior studies with colchicine.
Colchicine is better than standard anti-inflammatory drugs, but it is not widely used for pericarditis in the United States, in part because the price has risen dramatically in recent years. But even at its current price, I use colchicine for all pericarditis patients, except those with a mild, brief episode that can be treated with aspirin alone. Patients with persistent and recurrent pericarditis can have persistent pain and can really suffer. Pericarditis is difficult to treat, but colchicine markedly helps. It ought to be used more than it currently is, although it has no labeling for this indication.
Dr. Allan S. Jaffe is a cardiologist and professor of medicine at the Mayo Clinic in Rochester, Minn. He said that he has been a consultant to or received honoraria from 10 drug or device companies but has no relationship with Takeda, the company that markets colchicine. He made these remarks in an interview and as a discussant for the report at the meeting.
WASHINGTON – Adding colchicine to standard anti-inflammatory treatment for patients with recurrent pericarditis led to significantly fewer subsequent recurrences than did standard treatment alone in a randomized trial with 240 patients.
The findings cement colchicine as a first-line treatment for pericarditis patients who need drug treatment, Dr. Massimo Imazio said at the annual meeting of the American College of Cardiology. "Taken together with results from other randomized controlled trials, these findings suggest that colchicine should probably be regarded as a first-line treatment for either acute or recurrent pericarditis in the absence of contraindications."
Concurrent with Dr. Imazio’s report at the meeting, the results of the study were published online. (Lancet 2014 [doi:10.1016/S0140-6736(13)62709-9]).
The CORP 2 (Colchicine for Recurrent Pericarditis 2) trial was conducted at four centers in Italy during 2005-2012 and enrolled 240 adults with an episode of pericarditis and a documented prior pericarditis episode that had been followed by a symptom-free interval of at least 6 weeks.
For the study, Dr. Imazio and his associates randomized patients to received colchicine, either at 0.5 mg b.i.d. or once daily in patients weighing 70 kg or less, with no loading dose to avoid potential gastrointestinal adverse effects. Patients also received standard anti-inflammatory treatment with aspirin, ibuprofen, or indomethacin, and select patients could receive corticosteroid treatment. Treatment was continued for 6 months. Patients averaged 49 years of age; more than 80% had idiopathic pericarditis with the rest divided nearly equally between cardiac injury syndrome and connective tissue disease. Enrollment excluded patients with bacterial or neoplastic etiologies for their pericarditis.
Pericarditis occurred in 22% of patients treated with colchicine and 43% of those on placebo during an average follow-up of 20 months, a statistically significant difference for the study’s primary endpoint, reported Dr. Imazio, a cardiologist at Maria Vittoria Hospital in Torino, Italy. This benefit translated into a number needed to treat of five patients to prevent one pericarditis recurrence during 18 months of follow-up, he said. Colchicine was as effective in patients previously treated with the drug as in colchicine-naive patients, and was equally effective in all of the etiologies studied.
The dosage of colchicine used was well tolerated with no excess adverse effects or treatment discontinuations compared with placebo and no serious adverse effects. Overall, colchicine cut recurrence rates by about half based on a meta-analysis of these results along with those from six prior reports from randomized controlled trials of colchicine in a total of 1,275 patients with either a first episode or recurrent pericarditis, Dr. Imazio said. The meta-analysis also showed a consistent safety profile, with no excess adverse events or need for treatment withdrawal. The 6-month duration of treatment was selected arbitrarily; a future study could evaluate the drug for a longer treatment period, he added.
A concern with colchicine is that it morphed a few years ago from a cheap generic drug to a rebranded trade drug, Colcrys, with a large rise in price. Takeda, the company that now solely markets colchicine in the United States, had no role in the CORP 2 study.
Dr. Imazio said that he had no relevant financial disclosures.
On Twitter @mitchelzoler
WASHINGTON – Adding colchicine to standard anti-inflammatory treatment for patients with recurrent pericarditis led to significantly fewer subsequent recurrences than did standard treatment alone in a randomized trial with 240 patients.
The findings cement colchicine as a first-line treatment for pericarditis patients who need drug treatment, Dr. Massimo Imazio said at the annual meeting of the American College of Cardiology. "Taken together with results from other randomized controlled trials, these findings suggest that colchicine should probably be regarded as a first-line treatment for either acute or recurrent pericarditis in the absence of contraindications."
Concurrent with Dr. Imazio’s report at the meeting, the results of the study were published online. (Lancet 2014 [doi:10.1016/S0140-6736(13)62709-9]).
The CORP 2 (Colchicine for Recurrent Pericarditis 2) trial was conducted at four centers in Italy during 2005-2012 and enrolled 240 adults with an episode of pericarditis and a documented prior pericarditis episode that had been followed by a symptom-free interval of at least 6 weeks.
For the study, Dr. Imazio and his associates randomized patients to received colchicine, either at 0.5 mg b.i.d. or once daily in patients weighing 70 kg or less, with no loading dose to avoid potential gastrointestinal adverse effects. Patients also received standard anti-inflammatory treatment with aspirin, ibuprofen, or indomethacin, and select patients could receive corticosteroid treatment. Treatment was continued for 6 months. Patients averaged 49 years of age; more than 80% had idiopathic pericarditis with the rest divided nearly equally between cardiac injury syndrome and connective tissue disease. Enrollment excluded patients with bacterial or neoplastic etiologies for their pericarditis.
Pericarditis occurred in 22% of patients treated with colchicine and 43% of those on placebo during an average follow-up of 20 months, a statistically significant difference for the study’s primary endpoint, reported Dr. Imazio, a cardiologist at Maria Vittoria Hospital in Torino, Italy. This benefit translated into a number needed to treat of five patients to prevent one pericarditis recurrence during 18 months of follow-up, he said. Colchicine was as effective in patients previously treated with the drug as in colchicine-naive patients, and was equally effective in all of the etiologies studied.
The dosage of colchicine used was well tolerated with no excess adverse effects or treatment discontinuations compared with placebo and no serious adverse effects. Overall, colchicine cut recurrence rates by about half based on a meta-analysis of these results along with those from six prior reports from randomized controlled trials of colchicine in a total of 1,275 patients with either a first episode or recurrent pericarditis, Dr. Imazio said. The meta-analysis also showed a consistent safety profile, with no excess adverse events or need for treatment withdrawal. The 6-month duration of treatment was selected arbitrarily; a future study could evaluate the drug for a longer treatment period, he added.
A concern with colchicine is that it morphed a few years ago from a cheap generic drug to a rebranded trade drug, Colcrys, with a large rise in price. Takeda, the company that now solely markets colchicine in the United States, had no role in the CORP 2 study.
Dr. Imazio said that he had no relevant financial disclosures.
On Twitter @mitchelzoler
AT ACC 14
Major finding: Patients with recurrent pericarditis treated with colchicine had a 22% recurrence rate compared with a 43% rate in control patients.
Data source: A randomized placebo-controlled trial with 240 patients enrolled at four centers in Italy.
Disclosures: Dr. Imazio said he had no relevant financial disclosures. Takeda, the sole company marketing colchicine (Colcrys) in the United States, played no role in the CORP 2 study. Dr. Jaffe said that he has been a consultant to or received honoraria from 10 drug or device companies, but he has no relationship with Takeda.
Risk of two types of polymer stents seen as comparable
Biodegradable biolimus-eluting stents are as safe and effective as durable everolimus-eluting stents at 2 years’ follow-up, with no significant differences seen in rates of target lesion revascularization, mortality, or myocardial infarction.
The findings come from NEXT (NOBORI Biolimus-Eluting vs. XIENCE/PROMUS Everolimus-Eluting Stent Trial), a 3-year randomized trial led by Dr. Masahiro Natsuaki of Saiseikai Fukuoka (Japan) General Hospital. They were presented March 31 at the annual meeting of the American College of Cardiology and published simultaneously in JAMA (doi:10.1001/jama.2014.3584).
NEXT aims to determine the noninferiority of the biodegradable polymer biolimus-eluting stent (BP-BES) to the durable polymer everolimus-eluting stent (DP-EES) as measured by target lesion revascularization and whether BP-DES carries a risk for excess mortality or MI compared with DP-EES, as shorter studies and meta-analyses have suggested.
Dr. Natsuaki and colleagues randomized 3,235 patients from nearly 100 treatment centers to BP-BES (n = 1,617) or DP-EES (n = 1,618), with 98% of all patients completing follow-up.
Mortality and MI were comparable for both stents (7.8% for BP-BES vs. 7.7% for DP-EES; noninferiority, P = .003), and the need for target lesion revascularization was also comparable for both stents (6.2% vs. 6%; noninferiority, P less than .001).
Dr. Natsuaki and colleagues noted that "2 years is not long enough to confirm the long-term safety of BP-BES, and the study was underpowered for the interim analysis. Follow-up at 3 years will be important."
NEXT is the first randomized trial to report outcomes longer than 1 year, Dr. Natsuaki said, which could be why these results differ from those of previous studies. In addition, previous meta-analyses pooled "several different biodegradable drug-eluting stents as a class, different risk profiles of enrolled patients across trials, and the wide variation in the ages of the trials, with changes in clinical practices such as duration of dual antiplatelet therapy." In NEXT, dual antiplatelet therapy continued in 69% of BP-BES patients and 70% of DP-EES patients at 2 years.
The researchers said that patients with MI were underrepresented in their sample and that "event rates were less than expected."
NEXT was sponsored by Terumo Japan, the maker of the biodegradable stents used in the study. Two investigators disclosed that they serve as advisers for Terumo Japan and Abbott Vascular Japan, maker of the durable polymer stents used.
Biodegradable biolimus-eluting stents are as safe and effective as durable everolimus-eluting stents at 2 years’ follow-up, with no significant differences seen in rates of target lesion revascularization, mortality, or myocardial infarction.
The findings come from NEXT (NOBORI Biolimus-Eluting vs. XIENCE/PROMUS Everolimus-Eluting Stent Trial), a 3-year randomized trial led by Dr. Masahiro Natsuaki of Saiseikai Fukuoka (Japan) General Hospital. They were presented March 31 at the annual meeting of the American College of Cardiology and published simultaneously in JAMA (doi:10.1001/jama.2014.3584).
NEXT aims to determine the noninferiority of the biodegradable polymer biolimus-eluting stent (BP-BES) to the durable polymer everolimus-eluting stent (DP-EES) as measured by target lesion revascularization and whether BP-DES carries a risk for excess mortality or MI compared with DP-EES, as shorter studies and meta-analyses have suggested.
Dr. Natsuaki and colleagues randomized 3,235 patients from nearly 100 treatment centers to BP-BES (n = 1,617) or DP-EES (n = 1,618), with 98% of all patients completing follow-up.
Mortality and MI were comparable for both stents (7.8% for BP-BES vs. 7.7% for DP-EES; noninferiority, P = .003), and the need for target lesion revascularization was also comparable for both stents (6.2% vs. 6%; noninferiority, P less than .001).
Dr. Natsuaki and colleagues noted that "2 years is not long enough to confirm the long-term safety of BP-BES, and the study was underpowered for the interim analysis. Follow-up at 3 years will be important."
NEXT is the first randomized trial to report outcomes longer than 1 year, Dr. Natsuaki said, which could be why these results differ from those of previous studies. In addition, previous meta-analyses pooled "several different biodegradable drug-eluting stents as a class, different risk profiles of enrolled patients across trials, and the wide variation in the ages of the trials, with changes in clinical practices such as duration of dual antiplatelet therapy." In NEXT, dual antiplatelet therapy continued in 69% of BP-BES patients and 70% of DP-EES patients at 2 years.
The researchers said that patients with MI were underrepresented in their sample and that "event rates were less than expected."
NEXT was sponsored by Terumo Japan, the maker of the biodegradable stents used in the study. Two investigators disclosed that they serve as advisers for Terumo Japan and Abbott Vascular Japan, maker of the durable polymer stents used.
Biodegradable biolimus-eluting stents are as safe and effective as durable everolimus-eluting stents at 2 years’ follow-up, with no significant differences seen in rates of target lesion revascularization, mortality, or myocardial infarction.
The findings come from NEXT (NOBORI Biolimus-Eluting vs. XIENCE/PROMUS Everolimus-Eluting Stent Trial), a 3-year randomized trial led by Dr. Masahiro Natsuaki of Saiseikai Fukuoka (Japan) General Hospital. They were presented March 31 at the annual meeting of the American College of Cardiology and published simultaneously in JAMA (doi:10.1001/jama.2014.3584).
NEXT aims to determine the noninferiority of the biodegradable polymer biolimus-eluting stent (BP-BES) to the durable polymer everolimus-eluting stent (DP-EES) as measured by target lesion revascularization and whether BP-DES carries a risk for excess mortality or MI compared with DP-EES, as shorter studies and meta-analyses have suggested.
Dr. Natsuaki and colleagues randomized 3,235 patients from nearly 100 treatment centers to BP-BES (n = 1,617) or DP-EES (n = 1,618), with 98% of all patients completing follow-up.
Mortality and MI were comparable for both stents (7.8% for BP-BES vs. 7.7% for DP-EES; noninferiority, P = .003), and the need for target lesion revascularization was also comparable for both stents (6.2% vs. 6%; noninferiority, P less than .001).
Dr. Natsuaki and colleagues noted that "2 years is not long enough to confirm the long-term safety of BP-BES, and the study was underpowered for the interim analysis. Follow-up at 3 years will be important."
NEXT is the first randomized trial to report outcomes longer than 1 year, Dr. Natsuaki said, which could be why these results differ from those of previous studies. In addition, previous meta-analyses pooled "several different biodegradable drug-eluting stents as a class, different risk profiles of enrolled patients across trials, and the wide variation in the ages of the trials, with changes in clinical practices such as duration of dual antiplatelet therapy." In NEXT, dual antiplatelet therapy continued in 69% of BP-BES patients and 70% of DP-EES patients at 2 years.
The researchers said that patients with MI were underrepresented in their sample and that "event rates were less than expected."
NEXT was sponsored by Terumo Japan, the maker of the biodegradable stents used in the study. Two investigators disclosed that they serve as advisers for Terumo Japan and Abbott Vascular Japan, maker of the durable polymer stents used.
FROM ACC 14
Major finding: Mortality and myocardial infarction were comparable for BP-BES (7.8%) vs. DP-EES (7.7%); noninferiority, P = .003), as was the need for target lesion revascularization (6.2% vs. 6%; noninferiority, P less than .001).
Data source: The NOBORI Biolimus-Eluting vs. XIENCE/PROMUS Everolimus-Eluting Stent Trial, a randomized trial of 3,235 patients.
Disclosures: NEXT was sponsored by Terumo Japan, the maker of BP-BES. Two investigators disclosed that they serve as advisers for Terumo Japan and Abbott Vascular Japan, maker of DP-EES.
Neither perioperative aspirin nor clonidine prevents MI
Neither perioperative aspirin therapy nor perioperative clonidine prevented death or MI in patients undergoing noncardiac surgery who were at risk for major vascular complications, according to data reported at the annual meeting of the American College of Cardiology.
Far from being protective, both preventive strategies exerted harmful effects: Aspirin raised the risk of major bleeding, and clonidine increased the risks of clinically important hypotension, bradycardia, and nonfatal MI, said Dr. P. J. Devereaux of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton (Ont.) General Hospital, and his associates in the POISE-2 (Perioperative Ischemic Evaluation 2) clinical trial.
The POISE-2 findings were simultaneously reported online in the New England Journal of Medicine 2014 March 31 [doi:10/1056.
NEJMoa1401105] and [doi:10/1056.
NEJMoa1401106]).
MI is the most common major vascular complication related to noncardiac surgery, and perioperative aspirin is thought to prevent it by inhibiting thrombus formation. At present, one-third of patients at risk for vascular complications receive perioperative aspirin even though the risks and benefits of this preventive strategy are uncertain.
Similarly, small trials have indicated that the antihypertensive agent clonidine, an alpha2 adrenergic agonist, reduces the risk of myocardial ischemia without inducing hemodynamic instability when given to at-risk patients undergoing noncardiac surgery, which in turn may prevent MI and death. Clonidine has additional analgesic, anxiolytic, antishivering, and anti-inflammatory effects that may be helpful.
The POISE-2 trial was designed to determine whether either of these approaches was more effective than placebo at preventing the composite endpoint of MI or death within 30 days of surgery.
A total of 10,010 patients were enrolled at 135 hospitals in 23 countries, stratified by whether they were already taking daily aspirin prophylaxis, and randomly assigned in a double-blind fashion to receive either perioperative aspirin (4,998 subjects) or placebo (5,012 subjects), and to receive either perioperative clonidine (5,009 subjects) or placebo (5,001 subjects). The mean age of these participants was 68.6 years, and 52.8% were men. Most were at risk because of their history of vascular disease; advanced age; need for dialysis; smoking status; or comorbid diabetes, heart failure, transient ischemic attack, or hypertension.
The types of surgery they underwent included general, orthopedic, urologic, gynecologic, vascular, and thoracic procedures.
The primary outcome of death or MI occurred in 7% of the aspirin group and 7.1% of the placebo group, a nonsignificant difference. The risks of other adverse outcomes, including stroke, cardiac revascularization, pulmonary embolism, acute kidney injury, and deep vein thrombosis, also were not significantly different between the two groups.
Median length of hospital stay and length of ICU and CCU stays also were not significantly different between patients who received aspirin and those who received placebo. However, aspirin raised the risk of major bleeding (4.6%), compared with placebo (3.8%), for a hazard ratio of 1.23. The most common sites of bleeding were the surgical site and the GI tract.
These effects were consistent across all subgroups of patients. In particular, they were the same whether the patients were already taking daily prophylactic aspirin therapy.
Clonidine also did not prevent death or MI within 30 days, compared with placebo; the rates were 7.3% and 6.8%, respectively. The risks of other adverse outcomes also were not significantly different between the two groups, nor were lengths of hospital, ICU, or CCU stays. However, clonidine raised the risk of clinically important hypotension (47.6% vs. 37.1%), clinically important bradycardia (12% vs. 8.1%), and nonfatal cardiac arrest (0.3% vs. 0.1%).
These effects were consistent across all subgroups of patients. In particular, clonidine was no more beneficial than was placebo in patients who underwent vascular surgery, a subgroup in whom previous, smaller studies found the drug to protect against both MI and mortality.
POISE-2 was not designed to determine why aspirin wasn’t effective at preventing perioperative MI, but Dr. Devereaux and his associates offered three possible explanations. First, MI was associated with major bleeding, and aspirin raises the risk of this complication. "It is possible that aspirin prevented some perioperative MI through thrombus inhibition [but] caused some MIs through bleeding and the subsequent mismatch between the supply of and the demand for myocardial oxygen, thus resulting in the overall neutral effect in our study," they said.
Second, the heart rate findings couldn’t statistically rule out a possible moderate beneficial effect of aspirin therapy. And third, it is possible that coronary-artery thrombus isn’t the dominant mechanism of perioperative MI, and aspirin’s antithrombotic effect didn’t address this unknown dominant mechanism.
Similarly, it is not known why clonidine failed to be protective, but the investigators offered two possible reasons. First, the drug induced hypotension, which raises the risk of perioperative MI. And second, it also induced bradycardia, which may be a proxy for an overall adverse effect on heart rate control; this also can increase the risk of perioperative MI, they said.
The POISE-2 trial was supported by the Canadian Institutes of Health Research, the National Health and Medical Research Council of Australia, and the Spanish Ministry of Health and Social Policy. Bayer Pharma provided the aspirin used in the study, and Boehringer Ingelheim provided the clonidine and some funding. Dr. Devereaux reported ties to Abbott, Bayer Pharma, Boehringer Ingelheim, Covidien, Roche, and Stryker and; some of his associates reported ties to several industry sources.
Myriad, and sometimes opposing, mechanisms contribute to perioperative MI, including excess bleeding, dramatic fluid shifts, unrelenting tachycardia, myocardial stress with fixed coronary obstruction, profound hypo- or hypertension, coronary plaque rupture, and coronary spasm, said Dr. Prashant Vaishnava and Dr. Kim A. Eagle.
So it shouldn’t be surprising that a medical therapy aimed at one of these mechanisms may actually augment a different mechanism, and end up raising MI risk. "Aspirin may reduce coronary thrombosis at the expense of excess bleeding; clonidine may reduce hypertensive swings only to be countered by clinically important hypotension," they noted.
On balance, the POISE-2 results provide cogent evidence against the use of either perioperative aspirin or clonidine.
Dr. Vaishnava and Dr. Eagle are at the Samuel and Jean A. Frankel Cardiovascular Center at the University of Michigan Health System, Ann Arbor. They reported no potential conflicts of interest. These remarks were taken from their editorial accompanying the POISE-2 trial reports (New Engl. J. Med. 2014 March 31 [doi:10.1056/NEJMe1402976]).
Myriad, and sometimes opposing, mechanisms contribute to perioperative MI, including excess bleeding, dramatic fluid shifts, unrelenting tachycardia, myocardial stress with fixed coronary obstruction, profound hypo- or hypertension, coronary plaque rupture, and coronary spasm, said Dr. Prashant Vaishnava and Dr. Kim A. Eagle.
So it shouldn’t be surprising that a medical therapy aimed at one of these mechanisms may actually augment a different mechanism, and end up raising MI risk. "Aspirin may reduce coronary thrombosis at the expense of excess bleeding; clonidine may reduce hypertensive swings only to be countered by clinically important hypotension," they noted.
On balance, the POISE-2 results provide cogent evidence against the use of either perioperative aspirin or clonidine.
Dr. Vaishnava and Dr. Eagle are at the Samuel and Jean A. Frankel Cardiovascular Center at the University of Michigan Health System, Ann Arbor. They reported no potential conflicts of interest. These remarks were taken from their editorial accompanying the POISE-2 trial reports (New Engl. J. Med. 2014 March 31 [doi:10.1056/NEJMe1402976]).
Myriad, and sometimes opposing, mechanisms contribute to perioperative MI, including excess bleeding, dramatic fluid shifts, unrelenting tachycardia, myocardial stress with fixed coronary obstruction, profound hypo- or hypertension, coronary plaque rupture, and coronary spasm, said Dr. Prashant Vaishnava and Dr. Kim A. Eagle.
So it shouldn’t be surprising that a medical therapy aimed at one of these mechanisms may actually augment a different mechanism, and end up raising MI risk. "Aspirin may reduce coronary thrombosis at the expense of excess bleeding; clonidine may reduce hypertensive swings only to be countered by clinically important hypotension," they noted.
On balance, the POISE-2 results provide cogent evidence against the use of either perioperative aspirin or clonidine.
Dr. Vaishnava and Dr. Eagle are at the Samuel and Jean A. Frankel Cardiovascular Center at the University of Michigan Health System, Ann Arbor. They reported no potential conflicts of interest. These remarks were taken from their editorial accompanying the POISE-2 trial reports (New Engl. J. Med. 2014 March 31 [doi:10.1056/NEJMe1402976]).
Neither perioperative aspirin therapy nor perioperative clonidine prevented death or MI in patients undergoing noncardiac surgery who were at risk for major vascular complications, according to data reported at the annual meeting of the American College of Cardiology.
Far from being protective, both preventive strategies exerted harmful effects: Aspirin raised the risk of major bleeding, and clonidine increased the risks of clinically important hypotension, bradycardia, and nonfatal MI, said Dr. P. J. Devereaux of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton (Ont.) General Hospital, and his associates in the POISE-2 (Perioperative Ischemic Evaluation 2) clinical trial.
The POISE-2 findings were simultaneously reported online in the New England Journal of Medicine 2014 March 31 [doi:10/1056.
NEJMoa1401105] and [doi:10/1056.
NEJMoa1401106]).
MI is the most common major vascular complication related to noncardiac surgery, and perioperative aspirin is thought to prevent it by inhibiting thrombus formation. At present, one-third of patients at risk for vascular complications receive perioperative aspirin even though the risks and benefits of this preventive strategy are uncertain.
Similarly, small trials have indicated that the antihypertensive agent clonidine, an alpha2 adrenergic agonist, reduces the risk of myocardial ischemia without inducing hemodynamic instability when given to at-risk patients undergoing noncardiac surgery, which in turn may prevent MI and death. Clonidine has additional analgesic, anxiolytic, antishivering, and anti-inflammatory effects that may be helpful.
The POISE-2 trial was designed to determine whether either of these approaches was more effective than placebo at preventing the composite endpoint of MI or death within 30 days of surgery.
A total of 10,010 patients were enrolled at 135 hospitals in 23 countries, stratified by whether they were already taking daily aspirin prophylaxis, and randomly assigned in a double-blind fashion to receive either perioperative aspirin (4,998 subjects) or placebo (5,012 subjects), and to receive either perioperative clonidine (5,009 subjects) or placebo (5,001 subjects). The mean age of these participants was 68.6 years, and 52.8% were men. Most were at risk because of their history of vascular disease; advanced age; need for dialysis; smoking status; or comorbid diabetes, heart failure, transient ischemic attack, or hypertension.
The types of surgery they underwent included general, orthopedic, urologic, gynecologic, vascular, and thoracic procedures.
The primary outcome of death or MI occurred in 7% of the aspirin group and 7.1% of the placebo group, a nonsignificant difference. The risks of other adverse outcomes, including stroke, cardiac revascularization, pulmonary embolism, acute kidney injury, and deep vein thrombosis, also were not significantly different between the two groups.
Median length of hospital stay and length of ICU and CCU stays also were not significantly different between patients who received aspirin and those who received placebo. However, aspirin raised the risk of major bleeding (4.6%), compared with placebo (3.8%), for a hazard ratio of 1.23. The most common sites of bleeding were the surgical site and the GI tract.
These effects were consistent across all subgroups of patients. In particular, they were the same whether the patients were already taking daily prophylactic aspirin therapy.
Clonidine also did not prevent death or MI within 30 days, compared with placebo; the rates were 7.3% and 6.8%, respectively. The risks of other adverse outcomes also were not significantly different between the two groups, nor were lengths of hospital, ICU, or CCU stays. However, clonidine raised the risk of clinically important hypotension (47.6% vs. 37.1%), clinically important bradycardia (12% vs. 8.1%), and nonfatal cardiac arrest (0.3% vs. 0.1%).
These effects were consistent across all subgroups of patients. In particular, clonidine was no more beneficial than was placebo in patients who underwent vascular surgery, a subgroup in whom previous, smaller studies found the drug to protect against both MI and mortality.
POISE-2 was not designed to determine why aspirin wasn’t effective at preventing perioperative MI, but Dr. Devereaux and his associates offered three possible explanations. First, MI was associated with major bleeding, and aspirin raises the risk of this complication. "It is possible that aspirin prevented some perioperative MI through thrombus inhibition [but] caused some MIs through bleeding and the subsequent mismatch between the supply of and the demand for myocardial oxygen, thus resulting in the overall neutral effect in our study," they said.
Second, the heart rate findings couldn’t statistically rule out a possible moderate beneficial effect of aspirin therapy. And third, it is possible that coronary-artery thrombus isn’t the dominant mechanism of perioperative MI, and aspirin’s antithrombotic effect didn’t address this unknown dominant mechanism.
Similarly, it is not known why clonidine failed to be protective, but the investigators offered two possible reasons. First, the drug induced hypotension, which raises the risk of perioperative MI. And second, it also induced bradycardia, which may be a proxy for an overall adverse effect on heart rate control; this also can increase the risk of perioperative MI, they said.
The POISE-2 trial was supported by the Canadian Institutes of Health Research, the National Health and Medical Research Council of Australia, and the Spanish Ministry of Health and Social Policy. Bayer Pharma provided the aspirin used in the study, and Boehringer Ingelheim provided the clonidine and some funding. Dr. Devereaux reported ties to Abbott, Bayer Pharma, Boehringer Ingelheim, Covidien, Roche, and Stryker and; some of his associates reported ties to several industry sources.
Neither perioperative aspirin therapy nor perioperative clonidine prevented death or MI in patients undergoing noncardiac surgery who were at risk for major vascular complications, according to data reported at the annual meeting of the American College of Cardiology.
Far from being protective, both preventive strategies exerted harmful effects: Aspirin raised the risk of major bleeding, and clonidine increased the risks of clinically important hypotension, bradycardia, and nonfatal MI, said Dr. P. J. Devereaux of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton (Ont.) General Hospital, and his associates in the POISE-2 (Perioperative Ischemic Evaluation 2) clinical trial.
The POISE-2 findings were simultaneously reported online in the New England Journal of Medicine 2014 March 31 [doi:10/1056.
NEJMoa1401105] and [doi:10/1056.
NEJMoa1401106]).
MI is the most common major vascular complication related to noncardiac surgery, and perioperative aspirin is thought to prevent it by inhibiting thrombus formation. At present, one-third of patients at risk for vascular complications receive perioperative aspirin even though the risks and benefits of this preventive strategy are uncertain.
Similarly, small trials have indicated that the antihypertensive agent clonidine, an alpha2 adrenergic agonist, reduces the risk of myocardial ischemia without inducing hemodynamic instability when given to at-risk patients undergoing noncardiac surgery, which in turn may prevent MI and death. Clonidine has additional analgesic, anxiolytic, antishivering, and anti-inflammatory effects that may be helpful.
The POISE-2 trial was designed to determine whether either of these approaches was more effective than placebo at preventing the composite endpoint of MI or death within 30 days of surgery.
A total of 10,010 patients were enrolled at 135 hospitals in 23 countries, stratified by whether they were already taking daily aspirin prophylaxis, and randomly assigned in a double-blind fashion to receive either perioperative aspirin (4,998 subjects) or placebo (5,012 subjects), and to receive either perioperative clonidine (5,009 subjects) or placebo (5,001 subjects). The mean age of these participants was 68.6 years, and 52.8% were men. Most were at risk because of their history of vascular disease; advanced age; need for dialysis; smoking status; or comorbid diabetes, heart failure, transient ischemic attack, or hypertension.
The types of surgery they underwent included general, orthopedic, urologic, gynecologic, vascular, and thoracic procedures.
The primary outcome of death or MI occurred in 7% of the aspirin group and 7.1% of the placebo group, a nonsignificant difference. The risks of other adverse outcomes, including stroke, cardiac revascularization, pulmonary embolism, acute kidney injury, and deep vein thrombosis, also were not significantly different between the two groups.
Median length of hospital stay and length of ICU and CCU stays also were not significantly different between patients who received aspirin and those who received placebo. However, aspirin raised the risk of major bleeding (4.6%), compared with placebo (3.8%), for a hazard ratio of 1.23. The most common sites of bleeding were the surgical site and the GI tract.
These effects were consistent across all subgroups of patients. In particular, they were the same whether the patients were already taking daily prophylactic aspirin therapy.
Clonidine also did not prevent death or MI within 30 days, compared with placebo; the rates were 7.3% and 6.8%, respectively. The risks of other adverse outcomes also were not significantly different between the two groups, nor were lengths of hospital, ICU, or CCU stays. However, clonidine raised the risk of clinically important hypotension (47.6% vs. 37.1%), clinically important bradycardia (12% vs. 8.1%), and nonfatal cardiac arrest (0.3% vs. 0.1%).
These effects were consistent across all subgroups of patients. In particular, clonidine was no more beneficial than was placebo in patients who underwent vascular surgery, a subgroup in whom previous, smaller studies found the drug to protect against both MI and mortality.
POISE-2 was not designed to determine why aspirin wasn’t effective at preventing perioperative MI, but Dr. Devereaux and his associates offered three possible explanations. First, MI was associated with major bleeding, and aspirin raises the risk of this complication. "It is possible that aspirin prevented some perioperative MI through thrombus inhibition [but] caused some MIs through bleeding and the subsequent mismatch between the supply of and the demand for myocardial oxygen, thus resulting in the overall neutral effect in our study," they said.
Second, the heart rate findings couldn’t statistically rule out a possible moderate beneficial effect of aspirin therapy. And third, it is possible that coronary-artery thrombus isn’t the dominant mechanism of perioperative MI, and aspirin’s antithrombotic effect didn’t address this unknown dominant mechanism.
Similarly, it is not known why clonidine failed to be protective, but the investigators offered two possible reasons. First, the drug induced hypotension, which raises the risk of perioperative MI. And second, it also induced bradycardia, which may be a proxy for an overall adverse effect on heart rate control; this also can increase the risk of perioperative MI, they said.
The POISE-2 trial was supported by the Canadian Institutes of Health Research, the National Health and Medical Research Council of Australia, and the Spanish Ministry of Health and Social Policy. Bayer Pharma provided the aspirin used in the study, and Boehringer Ingelheim provided the clonidine and some funding. Dr. Devereaux reported ties to Abbott, Bayer Pharma, Boehringer Ingelheim, Covidien, Roche, and Stryker and; some of his associates reported ties to several industry sources.
FROM ACC 14
Major finding: The primary outcome of death or MI occurred in 7% of the aspirin group and 7.1% of the placebo group, a nonsignificant difference; it also occurred in 7.3% of the clonidine group and 6.8% of the placebo group, also a nonsignificant difference.
Data source: A randomized, blinded clinical trial evaluating perioperative aspirin vs. placebo and perioperative clonidine vs. placebo in 10,010 patients undergoing noncardiac surgery who were at risk for major vascular complications.
Disclosures: The POISE-2 trial was supported by the Canadian Institutes of Health Research, the National Health and Medical Research Council of Australia, and the Spanish Ministry of Health and Social Policy. Bayer Pharma provided the aspirin used in the study and Boehringer Ingelheim provided the clonidine and some funding. Dr. Devereaux reported ties to Abbott, Bayer Pharma, Boehringer Ingelheim, Covidien, Roche, and Stryker and; some of his associates reported ties to several industry sources.
No improvements in left ventricular function with metformin after myocardial infarction
Treatment with metformin failed to show any positive effects on left ventricular function in diabetes-free patients who presented with ST-segment elevation MI, according to the results of a double-blind, placebo-controlled study.
The study in 380 patients undergoing primary percutaneous coronary intervention – 191 of whom were given metformin and 189 of whom were given placebo – found no significant effects of twice-daily metformin (500 mg) on left ventricular ejection fraction (LVEF) after 4 months of treatment, and there was no significant difference in the incidence of major cardiac events between the two groups, Dr. Chris P. H. Lexis said at the annual meeting of the American College of Cardiology.
Specifically, at 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% in the metformin group, compared with 54.8% in the placebo group. NT-proBNP concentration was 167 ng/L in the metformin group and 167 ng/L in the placebo group. Major adverse cardiovascular events were observed in six patients (3.1%) in the metformin group and in two patients (1.1%) in the placebo group. Creatinine concentration (79 micromol/L vs. 79 micromol/L) and glycated hemoglobin (5.9% vs. 5.9%) were not significantly different between both groups. No cases of lactic acidosis were observed, according to the investigators.
Up to half of patients who experience an ST-segment elevation MI (STEMI) develop left ventricular dysfunction, which is the strongest predictor of adverse outcomes, such as heart failure.
Findings from previous animal studies had suggested that metformin may have favorable effects on ventricular function, possibly through enhanced phosphorylation of AMP-activated protein kinase causing changes in intracellular pathways and altering mitochondrial function, in turn resulting in improved systolic and diastolic function.
"Data from experimental studies have suggested that administration of metformin before and during ischemia reperfusion might affect these protective pathways and preserve left ventricular function, independent of glycometabolic state," according to Dr. Lexis of the University of Groningen, the Netherlands, and his associates, in a paper simultaneously published online in JAMA (2014 March 31 [doi:10.1001/jama.2014.3315]).
"Moreover, in observational studies of patients with acute myocardial infarction, concurrent treatment with metformin was associated with lower peak values of CK [creatine kinase], myocardial band of CK, and troponins and with improved survival after STEMI in patients with type 2 diabetes, compared with other antihyperglycemic strategies."
percutaneous coronary intervention, PCI, LVEF, ACC, American College of Cardiology, Dr. Chris P. H. Lexis
Treatment with metformin failed to show any positive effects on left ventricular function in diabetes-free patients who presented with ST-segment elevation MI, according to the results of a double-blind, placebo-controlled study.
The study in 380 patients undergoing primary percutaneous coronary intervention – 191 of whom were given metformin and 189 of whom were given placebo – found no significant effects of twice-daily metformin (500 mg) on left ventricular ejection fraction (LVEF) after 4 months of treatment, and there was no significant difference in the incidence of major cardiac events between the two groups, Dr. Chris P. H. Lexis said at the annual meeting of the American College of Cardiology.
Specifically, at 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% in the metformin group, compared with 54.8% in the placebo group. NT-proBNP concentration was 167 ng/L in the metformin group and 167 ng/L in the placebo group. Major adverse cardiovascular events were observed in six patients (3.1%) in the metformin group and in two patients (1.1%) in the placebo group. Creatinine concentration (79 micromol/L vs. 79 micromol/L) and glycated hemoglobin (5.9% vs. 5.9%) were not significantly different between both groups. No cases of lactic acidosis were observed, according to the investigators.
Up to half of patients who experience an ST-segment elevation MI (STEMI) develop left ventricular dysfunction, which is the strongest predictor of adverse outcomes, such as heart failure.
Findings from previous animal studies had suggested that metformin may have favorable effects on ventricular function, possibly through enhanced phosphorylation of AMP-activated protein kinase causing changes in intracellular pathways and altering mitochondrial function, in turn resulting in improved systolic and diastolic function.
"Data from experimental studies have suggested that administration of metformin before and during ischemia reperfusion might affect these protective pathways and preserve left ventricular function, independent of glycometabolic state," according to Dr. Lexis of the University of Groningen, the Netherlands, and his associates, in a paper simultaneously published online in JAMA (2014 March 31 [doi:10.1001/jama.2014.3315]).
"Moreover, in observational studies of patients with acute myocardial infarction, concurrent treatment with metformin was associated with lower peak values of CK [creatine kinase], myocardial band of CK, and troponins and with improved survival after STEMI in patients with type 2 diabetes, compared with other antihyperglycemic strategies."
Treatment with metformin failed to show any positive effects on left ventricular function in diabetes-free patients who presented with ST-segment elevation MI, according to the results of a double-blind, placebo-controlled study.
The study in 380 patients undergoing primary percutaneous coronary intervention – 191 of whom were given metformin and 189 of whom were given placebo – found no significant effects of twice-daily metformin (500 mg) on left ventricular ejection fraction (LVEF) after 4 months of treatment, and there was no significant difference in the incidence of major cardiac events between the two groups, Dr. Chris P. H. Lexis said at the annual meeting of the American College of Cardiology.
Specifically, at 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% in the metformin group, compared with 54.8% in the placebo group. NT-proBNP concentration was 167 ng/L in the metformin group and 167 ng/L in the placebo group. Major adverse cardiovascular events were observed in six patients (3.1%) in the metformin group and in two patients (1.1%) in the placebo group. Creatinine concentration (79 micromol/L vs. 79 micromol/L) and glycated hemoglobin (5.9% vs. 5.9%) were not significantly different between both groups. No cases of lactic acidosis were observed, according to the investigators.
Up to half of patients who experience an ST-segment elevation MI (STEMI) develop left ventricular dysfunction, which is the strongest predictor of adverse outcomes, such as heart failure.
Findings from previous animal studies had suggested that metformin may have favorable effects on ventricular function, possibly through enhanced phosphorylation of AMP-activated protein kinase causing changes in intracellular pathways and altering mitochondrial function, in turn resulting in improved systolic and diastolic function.
"Data from experimental studies have suggested that administration of metformin before and during ischemia reperfusion might affect these protective pathways and preserve left ventricular function, independent of glycometabolic state," according to Dr. Lexis of the University of Groningen, the Netherlands, and his associates, in a paper simultaneously published online in JAMA (2014 March 31 [doi:10.1001/jama.2014.3315]).
"Moreover, in observational studies of patients with acute myocardial infarction, concurrent treatment with metformin was associated with lower peak values of CK [creatine kinase], myocardial band of CK, and troponins and with improved survival after STEMI in patients with type 2 diabetes, compared with other antihyperglycemic strategies."
percutaneous coronary intervention, PCI, LVEF, ACC, American College of Cardiology, Dr. Chris P. H. Lexis
percutaneous coronary intervention, PCI, LVEF, ACC, American College of Cardiology, Dr. Chris P. H. Lexis
FROM ACC 14
Major finding: Treatment with metformin after STEMI had no significant impact on LVEF or on the incidence of major cardiac events in nondiabetic patients undergoing primary percutaneous coronary intervention.
Data source: A randomized, double-blind, placebo controlled trial in 380 patients undergoing primary percutaneous coronary intervention after STEMI.
Disclosures: The study was supported by a grant from ZonMw, the Netherlands Organization for Health Research and Development. Some authors reported research grants, consultancies, speakers fees, and travel fees from various pharmaceutical companies.
Patients with LBBB get bigger long-term survival bang from CRT-D
WASHINGTON – Early treatment with cardiac-resynchronization therapy with a defibrillator showed a significant survival benefit in patients with mild heart failure, left ventricular dysfunction, and left bundle-branch block, but no benefit was seen among those who did not have bundle-branch block.
In this long-term follow-up analysis of the MADIT-CRT trial, there was a trend toward increased all-cause mortality among those who did not have left bundle-branch block, said Dr. Ilan Goldenberg of the Israeli Association for Cardiovascular Trials and Tel Aviv (Israel) University at the annual meeting of the American College of Cardiology. MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy) followed 1,692 surviving patients for a median of 5.6 years, as the first phase, and 854 patients enrolled in registries in the United States and elsewhere, as the second phase, and the data were merged. The primary endpoint was death from any cause.
The results indicate that in patients with mild heart failure (HF) symptoms, left ventricular dysfunction, and left bundle-branch block (LBBB), "early intervention with cardiac resynchronization therapy is associated with a significant long-term survival benefit, whereas currently, there is no evidence for any clinical benefit associated with cardiac resynchronization therapy in mild heart failure patients" without LBBB, he concluded.
In the original study, treatment with a cardiac resynchronization therapy–defibrillator (CRT-D) was associated with a significant 34% reduction in the risk of nonfatal HF events or all-cause mortality over a median 2.4 years follow-up. But the effect of the device on risk of all-cause mortality was neutral, possibly because of the short-term follow-up, so whether treatment could affect long-term survival in this population was unclear, he pointed out. Benefit in the original trial appeared to be restricted to patients with LBBB, he added.
In the long-term study, 7 years after enrollment, cumulative all-cause mortality in those with LBBB was 18% among those patients treated with CRT-D, compared with 29% among those who received defibrillator therapy alone, a statistically significant difference that represented a 41% reduced risk. The separation in event rates appeared after 1 year and continued for 7 years. Based on this difference in survival, nine patients would need to be treated with CRT-D to save one life over 7 years, Dr. Goldenberg said. The survival benefit was present regardless of age, sex, HF functional class I or II, baseline ejection fractions or cardiac volume, or QRS duration.
In patients with LBBB, treatment was also associated with a "pronounced" risk reduction of 62% in heart failure events, with benefits that started to appear after enrollment and continued through follow-up, and a significant 55% reduction in the combined endpoint of heart failure and death.
"In contrast, among patients without LBBB, we see that even after multivariate adjustment, there was no evidence for any clinical benefit associated with cardiac resynchronization therapy, with even a trend to a 57% increased risk of all-cause mortality" in patients without LBBB. In contrast, in patients who did not have left bundle-branch block, "there was no evidence for any clinical benefit associated with cardiac resynchronization therapy during long-term follow-up," for all-cause mortality and for nonfatal HF events, Dr. Goldenberg said.
The earlier results were published in 2009 (N. Engl. J. Med. 2009;361:1329-38).
The current study was published simultaneously with its presentation in the New England Journal of Medicine (2014, March 30 [doi:10.1056/NEJMoa1401426]).
The study was funded by unrestricted research grants from Boston Scientific to the University of Rochester, N.Y., and the Israeli Association for Cardiovascular Trials. Dr. Goldenberg disclosed having received grant support from Boston Scientific outside of this study.
MADIT-CRT trial, Dr. Ilan Goldenberg, ACC, American College of Cardiology
WASHINGTON – Early treatment with cardiac-resynchronization therapy with a defibrillator showed a significant survival benefit in patients with mild heart failure, left ventricular dysfunction, and left bundle-branch block, but no benefit was seen among those who did not have bundle-branch block.
In this long-term follow-up analysis of the MADIT-CRT trial, there was a trend toward increased all-cause mortality among those who did not have left bundle-branch block, said Dr. Ilan Goldenberg of the Israeli Association for Cardiovascular Trials and Tel Aviv (Israel) University at the annual meeting of the American College of Cardiology. MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy) followed 1,692 surviving patients for a median of 5.6 years, as the first phase, and 854 patients enrolled in registries in the United States and elsewhere, as the second phase, and the data were merged. The primary endpoint was death from any cause.
The results indicate that in patients with mild heart failure (HF) symptoms, left ventricular dysfunction, and left bundle-branch block (LBBB), "early intervention with cardiac resynchronization therapy is associated with a significant long-term survival benefit, whereas currently, there is no evidence for any clinical benefit associated with cardiac resynchronization therapy in mild heart failure patients" without LBBB, he concluded.
In the original study, treatment with a cardiac resynchronization therapy–defibrillator (CRT-D) was associated with a significant 34% reduction in the risk of nonfatal HF events or all-cause mortality over a median 2.4 years follow-up. But the effect of the device on risk of all-cause mortality was neutral, possibly because of the short-term follow-up, so whether treatment could affect long-term survival in this population was unclear, he pointed out. Benefit in the original trial appeared to be restricted to patients with LBBB, he added.
In the long-term study, 7 years after enrollment, cumulative all-cause mortality in those with LBBB was 18% among those patients treated with CRT-D, compared with 29% among those who received defibrillator therapy alone, a statistically significant difference that represented a 41% reduced risk. The separation in event rates appeared after 1 year and continued for 7 years. Based on this difference in survival, nine patients would need to be treated with CRT-D to save one life over 7 years, Dr. Goldenberg said. The survival benefit was present regardless of age, sex, HF functional class I or II, baseline ejection fractions or cardiac volume, or QRS duration.
In patients with LBBB, treatment was also associated with a "pronounced" risk reduction of 62% in heart failure events, with benefits that started to appear after enrollment and continued through follow-up, and a significant 55% reduction in the combined endpoint of heart failure and death.
"In contrast, among patients without LBBB, we see that even after multivariate adjustment, there was no evidence for any clinical benefit associated with cardiac resynchronization therapy, with even a trend to a 57% increased risk of all-cause mortality" in patients without LBBB. In contrast, in patients who did not have left bundle-branch block, "there was no evidence for any clinical benefit associated with cardiac resynchronization therapy during long-term follow-up," for all-cause mortality and for nonfatal HF events, Dr. Goldenberg said.
The earlier results were published in 2009 (N. Engl. J. Med. 2009;361:1329-38).
The current study was published simultaneously with its presentation in the New England Journal of Medicine (2014, March 30 [doi:10.1056/NEJMoa1401426]).
The study was funded by unrestricted research grants from Boston Scientific to the University of Rochester, N.Y., and the Israeli Association for Cardiovascular Trials. Dr. Goldenberg disclosed having received grant support from Boston Scientific outside of this study.
WASHINGTON – Early treatment with cardiac-resynchronization therapy with a defibrillator showed a significant survival benefit in patients with mild heart failure, left ventricular dysfunction, and left bundle-branch block, but no benefit was seen among those who did not have bundle-branch block.
In this long-term follow-up analysis of the MADIT-CRT trial, there was a trend toward increased all-cause mortality among those who did not have left bundle-branch block, said Dr. Ilan Goldenberg of the Israeli Association for Cardiovascular Trials and Tel Aviv (Israel) University at the annual meeting of the American College of Cardiology. MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy) followed 1,692 surviving patients for a median of 5.6 years, as the first phase, and 854 patients enrolled in registries in the United States and elsewhere, as the second phase, and the data were merged. The primary endpoint was death from any cause.
The results indicate that in patients with mild heart failure (HF) symptoms, left ventricular dysfunction, and left bundle-branch block (LBBB), "early intervention with cardiac resynchronization therapy is associated with a significant long-term survival benefit, whereas currently, there is no evidence for any clinical benefit associated with cardiac resynchronization therapy in mild heart failure patients" without LBBB, he concluded.
In the original study, treatment with a cardiac resynchronization therapy–defibrillator (CRT-D) was associated with a significant 34% reduction in the risk of nonfatal HF events or all-cause mortality over a median 2.4 years follow-up. But the effect of the device on risk of all-cause mortality was neutral, possibly because of the short-term follow-up, so whether treatment could affect long-term survival in this population was unclear, he pointed out. Benefit in the original trial appeared to be restricted to patients with LBBB, he added.
In the long-term study, 7 years after enrollment, cumulative all-cause mortality in those with LBBB was 18% among those patients treated with CRT-D, compared with 29% among those who received defibrillator therapy alone, a statistically significant difference that represented a 41% reduced risk. The separation in event rates appeared after 1 year and continued for 7 years. Based on this difference in survival, nine patients would need to be treated with CRT-D to save one life over 7 years, Dr. Goldenberg said. The survival benefit was present regardless of age, sex, HF functional class I or II, baseline ejection fractions or cardiac volume, or QRS duration.
In patients with LBBB, treatment was also associated with a "pronounced" risk reduction of 62% in heart failure events, with benefits that started to appear after enrollment and continued through follow-up, and a significant 55% reduction in the combined endpoint of heart failure and death.
"In contrast, among patients without LBBB, we see that even after multivariate adjustment, there was no evidence for any clinical benefit associated with cardiac resynchronization therapy, with even a trend to a 57% increased risk of all-cause mortality" in patients without LBBB. In contrast, in patients who did not have left bundle-branch block, "there was no evidence for any clinical benefit associated with cardiac resynchronization therapy during long-term follow-up," for all-cause mortality and for nonfatal HF events, Dr. Goldenberg said.
The earlier results were published in 2009 (N. Engl. J. Med. 2009;361:1329-38).
The current study was published simultaneously with its presentation in the New England Journal of Medicine (2014, March 30 [doi:10.1056/NEJMoa1401426]).
The study was funded by unrestricted research grants from Boston Scientific to the University of Rochester, N.Y., and the Israeli Association for Cardiovascular Trials. Dr. Goldenberg disclosed having received grant support from Boston Scientific outside of this study.
MADIT-CRT trial, Dr. Ilan Goldenberg, ACC, American College of Cardiology
MADIT-CRT trial, Dr. Ilan Goldenberg, ACC, American College of Cardiology
AT ACC 14
Major finding: All-cause mortality over 7 years in patients with mild heart failure, left ventricular dysfunction, and left bundle-branch block was 18% in those treated with CRT-D vs. 29% in those treated with a defibrillator alone, a significant benefit that was not seen in those patients who did not have LBBB.
Data source: A long-term follow-up of more than 1,600 patients enrolled in MADIT-CRT, comparing treatment with CRT-D to treatment with a defibrillator alone.
Disclosure: The study was funded by unrestricted research grants from Boston Scientific to the University of Rochester, New York, and the Israeli Association for Cardiovascular Trials. Dr. Goldenberg disclosed having received grant support from Boston Scientific outside of this study.