Rheumatoid Arthritis

WASHINGTON – The lipid changes induced by tocilizumab do not translate into an increased risk of heart attack or stroke in patients with rheumatoid arthritis, a 5-year postmarketing study has determined.

Patients taking the drug experienced quick and dramatic increases in low-density lipoprotein cholesterol: 12% in just 4 weeks. But when compared against patients taking etanercept, they showed no significant increases in stroke, heart attack, heart failure hospitalization, or cardiac death, Jon Giles, MD, said at the annual meeting of the American College of Rheumatology.

Tocilizumab’s profound effects on lipids have been confirmed in all of its pivotal trials, with average across-the-board increases of 17%-25% in total cholesterol, low-and high-density cholesterol, and triglycerides. ENTRACTE is the first trial, however, to compare its cardiovascular safety profile to that of another RA medication.

The study comprised 3,080 patients with active, seropositive RA from 353 centers across 31 countries. The mean age of the patients was 61 years. All patients had at least one cardiovascular risk factor, including current smoking (30%), hypertension (71%), or diabetes (18%). About a quarter were already taking a statin, and about 5% had a history of heart attack, stroke, or coronary revascularization.

They were randomized to open-label tocilizumab 8 mg/kg infused every 4 weeks or etanercept 50 mg injected weekly. The mean follow-up reported was 3.5 years, but some patients had full 5-year data. “This was plenty of time to see early atherothrombotic complications if they were going to develop,” Dr. Giles said.

The primary endpoint was a composite of major cardiovascular outcomes including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included individual components of the primary endpoint, as well as all-cause mortality, heart failure hospitalization, fatal and nonfatal myocardial infarction and stroke, and lipid levels.

By week 4, LDL-cholesterol levels had risen by almost 12% in the tocilizumab group. This moderated somewhat, but stayed elevated, reaching 9% above baseline by week 144. In contrast, LDL-cholesterol in the etanercept group was virtually unchanged throughout the study.

In the intent-to-treat analysis, there were 161 occurrences of the composite outcome: 83 in the tocilizumab group and 78 in the etanercept group (hazard ratio, 1.05). This was not a significant difference. The event rate was 1.70 per 100 person-years in the etanercept group and 1.82 in the tocilizumab group – also not significantly different.

The individual secondary endpoints were almost identical in each group: cardiovascular death, 35 with etanercept vs. 36 with tocilizumab; nonfatal MI, 31 vs. 28; nonfatal stroke, 15 vs. 24; and all-cause mortality, 64 in each group. A multivariate regression analysis showed no significantly increased risks associated with tocilizumab in any of the secondary endpoints. The rates and types of adverse events were also similar.

Because this was a safety study, the investigators were interested in the uncertainty in their estimate of risk, Dr. Giles said in an interview.

“The study was designed to exclude at most an 80% increase in cardiovascular events for the patients treated with tocilizumab, compared with etanercept. What we determined was that we could exclude with 95% certainty that if a much larger sample of similar patients was studied, the risk of such events in the tocilizumab group would not exceed a 43% higher rate at the extreme. Notably, the degree of uncertainty included the possibility that the event rate could be lower in the tocilizumab group, compared with those treated with etanercept.”

Dr. Giles reported receiving consulting fees from Genentech, which markets tocilizumab. All other authors also disclosed financial relationships with Genentech or its parent company, Roche. Four authors were employees of Roche/Genentech.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – The lipid changes induced by tocilizumab do not translate into an increased risk of heart attack or stroke in patients with rheumatoid arthritis, a 5-year postmarketing study has determined.

Patients taking the drug experienced quick and dramatic increases in low-density lipoprotein cholesterol: 12% in just 4 weeks. But when compared against patients taking etanercept, they showed no significant increases in stroke, heart attack, heart failure hospitalization, or cardiac death, Jon Giles, MD, said at the annual meeting of the American College of Rheumatology.

Tocilizumab’s profound effects on lipids have been confirmed in all of its pivotal trials, with average across-the-board increases of 17%-25% in total cholesterol, low-and high-density cholesterol, and triglycerides. ENTRACTE is the first trial, however, to compare its cardiovascular safety profile to that of another RA medication.

The study comprised 3,080 patients with active, seropositive RA from 353 centers across 31 countries. The mean age of the patients was 61 years. All patients had at least one cardiovascular risk factor, including current smoking (30%), hypertension (71%), or diabetes (18%). About a quarter were already taking a statin, and about 5% had a history of heart attack, stroke, or coronary revascularization.

They were randomized to open-label tocilizumab 8 mg/kg infused every 4 weeks or etanercept 50 mg injected weekly. The mean follow-up reported was 3.5 years, but some patients had full 5-year data. “This was plenty of time to see early atherothrombotic complications if they were going to develop,” Dr. Giles said.

The primary endpoint was a composite of major cardiovascular outcomes including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included individual components of the primary endpoint, as well as all-cause mortality, heart failure hospitalization, fatal and nonfatal myocardial infarction and stroke, and lipid levels.

By week 4, LDL-cholesterol levels had risen by almost 12% in the tocilizumab group. This moderated somewhat, but stayed elevated, reaching 9% above baseline by week 144. In contrast, LDL-cholesterol in the etanercept group was virtually unchanged throughout the study.

In the intent-to-treat analysis, there were 161 occurrences of the composite outcome: 83 in the tocilizumab group and 78 in the etanercept group (hazard ratio, 1.05). This was not a significant difference. The event rate was 1.70 per 100 person-years in the etanercept group and 1.82 in the tocilizumab group – also not significantly different.

The individual secondary endpoints were almost identical in each group: cardiovascular death, 35 with etanercept vs. 36 with tocilizumab; nonfatal MI, 31 vs. 28; nonfatal stroke, 15 vs. 24; and all-cause mortality, 64 in each group. A multivariate regression analysis showed no significantly increased risks associated with tocilizumab in any of the secondary endpoints. The rates and types of adverse events were also similar.

Because this was a safety study, the investigators were interested in the uncertainty in their estimate of risk, Dr. Giles said in an interview.

“The study was designed to exclude at most an 80% increase in cardiovascular events for the patients treated with tocilizumab, compared with etanercept. What we determined was that we could exclude with 95% certainty that if a much larger sample of similar patients was studied, the risk of such events in the tocilizumab group would not exceed a 43% higher rate at the extreme. Notably, the degree of uncertainty included the possibility that the event rate could be lower in the tocilizumab group, compared with those treated with etanercept.”

Dr. Giles reported receiving consulting fees from Genentech, which markets tocilizumab. All other authors also disclosed financial relationships with Genentech or its parent company, Roche. Four authors were employees of Roche/Genentech.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – The lipid changes induced by tocilizumab do not translate into an increased risk of heart attack or stroke in patients with rheumatoid arthritis, a 5-year postmarketing study has determined.

Patients taking the drug experienced quick and dramatic increases in low-density lipoprotein cholesterol: 12% in just 4 weeks. But when compared against patients taking etanercept, they showed no significant increases in stroke, heart attack, heart failure hospitalization, or cardiac death, Jon Giles, MD, said at the annual meeting of the American College of Rheumatology.

Tocilizumab’s profound effects on lipids have been confirmed in all of its pivotal trials, with average across-the-board increases of 17%-25% in total cholesterol, low-and high-density cholesterol, and triglycerides. ENTRACTE is the first trial, however, to compare its cardiovascular safety profile to that of another RA medication.

The study comprised 3,080 patients with active, seropositive RA from 353 centers across 31 countries. The mean age of the patients was 61 years. All patients had at least one cardiovascular risk factor, including current smoking (30%), hypertension (71%), or diabetes (18%). About a quarter were already taking a statin, and about 5% had a history of heart attack, stroke, or coronary revascularization.

They were randomized to open-label tocilizumab 8 mg/kg infused every 4 weeks or etanercept 50 mg injected weekly. The mean follow-up reported was 3.5 years, but some patients had full 5-year data. “This was plenty of time to see early atherothrombotic complications if they were going to develop,” Dr. Giles said.

The primary endpoint was a composite of major cardiovascular outcomes including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included individual components of the primary endpoint, as well as all-cause mortality, heart failure hospitalization, fatal and nonfatal myocardial infarction and stroke, and lipid levels.

By week 4, LDL-cholesterol levels had risen by almost 12% in the tocilizumab group. This moderated somewhat, but stayed elevated, reaching 9% above baseline by week 144. In contrast, LDL-cholesterol in the etanercept group was virtually unchanged throughout the study.

In the intent-to-treat analysis, there were 161 occurrences of the composite outcome: 83 in the tocilizumab group and 78 in the etanercept group (hazard ratio, 1.05). This was not a significant difference. The event rate was 1.70 per 100 person-years in the etanercept group and 1.82 in the tocilizumab group – also not significantly different.

The individual secondary endpoints were almost identical in each group: cardiovascular death, 35 with etanercept vs. 36 with tocilizumab; nonfatal MI, 31 vs. 28; nonfatal stroke, 15 vs. 24; and all-cause mortality, 64 in each group. A multivariate regression analysis showed no significantly increased risks associated with tocilizumab in any of the secondary endpoints. The rates and types of adverse events were also similar.

Because this was a safety study, the investigators were interested in the uncertainty in their estimate of risk, Dr. Giles said in an interview.

“The study was designed to exclude at most an 80% increase in cardiovascular events for the patients treated with tocilizumab, compared with etanercept. What we determined was that we could exclude with 95% certainty that if a much larger sample of similar patients was studied, the risk of such events in the tocilizumab group would not exceed a 43% higher rate at the extreme. Notably, the degree of uncertainty included the possibility that the event rate could be lower in the tocilizumab group, compared with those treated with etanercept.”

Dr. Giles reported receiving consulting fees from Genentech, which markets tocilizumab. All other authors also disclosed financial relationships with Genentech or its parent company, Roche. Four authors were employees of Roche/Genentech.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – Prenatal exposure to tumor necrosis factor–inhibiting drugs does not significantly increase the risk of a serious antenatal infection in infants born to women taking the drugs for rheumatoid arthritis, according to a large database study.

Researchers from McGill University, Montreal, and the University of Alabama at Birmingham who conducted the study did find a higher rate of serious infections among infants born to users of a tumor necrosis factor inhibitor (TNFi), especially among those exposed to infliximab, but after adjustment for maternal age and other antirheumatic drugs, the risk was not statistically significant.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – Prenatal exposure to tumor necrosis factor–inhibiting drugs does not significantly increase the risk of a serious antenatal infection in infants born to women taking the drugs for rheumatoid arthritis, according to a large database study.

Researchers from McGill University, Montreal, and the University of Alabama at Birmingham who conducted the study did find a higher rate of serious infections among infants born to users of a tumor necrosis factor inhibitor (TNFi), especially among those exposed to infliximab, but after adjustment for maternal age and other antirheumatic drugs, the risk was not statistically significant.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – Prenatal exposure to tumor necrosis factor–inhibiting drugs does not significantly increase the risk of a serious antenatal infection in infants born to women taking the drugs for rheumatoid arthritis, according to a large database study.

Researchers from McGill University, Montreal, and the University of Alabama at Birmingham who conducted the study did find a higher rate of serious infections among infants born to users of a tumor necrosis factor inhibitor (TNFi), especially among those exposed to infliximab, but after adjustment for maternal age and other antirheumatic drugs, the risk was not statistically significant.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

An experimental biological agent, GP2015, demonstrated equivalent efficacy and comparable safety to etanercept for moderate to severe plaque psoriasis in a manufacturer-sponsored study, according to a report published online in the British Journal of Dermatology.

These findings should contribute to the confirmation of GP2015 as an etanercept (Enbrel) biosimilar for this patient population. Proposed biosimilars such as GP2015 are follow-on versions of authorized biological products, and regulatory authorities require that they demonstrate similarity with a large body of physiochemical and clinical data before they can be confirmed as biosimilars, said Christopher Griffiths, MD, of the Dermatology Centre, Salford Royal Hospital, University of Manchester (England), and his associates.

To contribute such data, Dr. Griffiths and his associates studied the efficacy and safety of GP2015 compared with etanercept, a tumor necrosis factor blocker, in the 2-year EGALITY trial. They assessed 531 adults at 74 medical centers in 11 European countries and South Africa, all of whom had active but stable chronic plaque psoriasis affecting 10% or more of their body surface area and Psoriasis Area and Severity Index (PASI) scores of 10 or more.

The study participants were randomly assigned in approximately equal numbers in a double-blind fashion to self administer GP2015 or etanercept subcutaneously, twice weekly for 12 weeks. Those who achieved at least a 50% improvement in PASI score were then randomized to continue the same treatment once weekly or to undergo a series of three treatment “switches” between GP2015 and etanercept at 6-week intervals until week 30. During an extension phase of the study, participants could then continue to receive the same treatment they had ended on, until week 52.

The primary efficacy endpoint – the percentage of patients who showed at least a 75% improvement from baseline in PASI score (PASI 75) at 12 weeks – was 73.4% with GP2015 and 75.7% with etanercept, which demonstrated therapeutic equivalence. A secondary efficacy end point – mean change in PASI score from baseline to week 12 – also was similar between the two study drugs. In all treatment groups, both PASI mean scores and change in PASI scores over time were comparable between the two study groups, regardless of switching between the two agents. In addition, in all groups, PASI 75 and PASI 90 scores increased gradually over time until week 30, and then remained stable through week 52, the investigators said (Br J Dermatol. 2016. doi: 10.1111/bjd.15152).

The proportion of patients with at least one treatment-emergent adverse event was similar in the GP2015 and etanercept groups who did not switch agents (59.8% and 57.3%, respectively), and was also similar among those who did switch agents between GP2015 (61%) and etanercept (59.4%).

The rates of serious adverse events and of adverse events that led to withdrawal from the study were similar across all treatment groups. Immunogenicity of GP2015 was similar to etanercept.

However, the rate of “adverse events of special interest” – those referred to in special warnings and precautions on the etanercept label – was markedly higher for continued GP2015 than for continued etanercept (11.0% vs. 4.7%) and for switched GP2015 than for switched etanercept (11.0% vs. 5.2%). One patient who took etanercept throughout the trial developed malignant melanoma.

The results of the study “confirm biosimilarity that was established with all previous analytical comparisons to the reference product in that equivalent efficacy was demonstrated as well as similar safety and immunogenicity of GP2015” with etanercept, “in a highly sensitive, generally immune-competent population,” the authors concluded.

The study was funded by Hexal AG, a Sandoz company, which was involved in the study design, data collection and analysis, and manuscript preparation. Dr. Griffiths reported ties to AbbVie, BMS. Galderma, Janssen, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz, and UCB Pharma, and his associates reported ties to numerous industry sources.

An experimental biological agent, GP2015, demonstrated equivalent efficacy and comparable safety to etanercept for moderate to severe plaque psoriasis in a manufacturer-sponsored study, according to a report published online in the British Journal of Dermatology.

These findings should contribute to the confirmation of GP2015 as an etanercept (Enbrel) biosimilar for this patient population. Proposed biosimilars such as GP2015 are follow-on versions of authorized biological products, and regulatory authorities require that they demonstrate similarity with a large body of physiochemical and clinical data before they can be confirmed as biosimilars, said Christopher Griffiths, MD, of the Dermatology Centre, Salford Royal Hospital, University of Manchester (England), and his associates.

To contribute such data, Dr. Griffiths and his associates studied the efficacy and safety of GP2015 compared with etanercept, a tumor necrosis factor blocker, in the 2-year EGALITY trial. They assessed 531 adults at 74 medical centers in 11 European countries and South Africa, all of whom had active but stable chronic plaque psoriasis affecting 10% or more of their body surface area and Psoriasis Area and Severity Index (PASI) scores of 10 or more.

The study participants were randomly assigned in approximately equal numbers in a double-blind fashion to self administer GP2015 or etanercept subcutaneously, twice weekly for 12 weeks. Those who achieved at least a 50% improvement in PASI score were then randomized to continue the same treatment once weekly or to undergo a series of three treatment “switches” between GP2015 and etanercept at 6-week intervals until week 30. During an extension phase of the study, participants could then continue to receive the same treatment they had ended on, until week 52.

The primary efficacy endpoint – the percentage of patients who showed at least a 75% improvement from baseline in PASI score (PASI 75) at 12 weeks – was 73.4% with GP2015 and 75.7% with etanercept, which demonstrated therapeutic equivalence. A secondary efficacy end point – mean change in PASI score from baseline to week 12 – also was similar between the two study drugs. In all treatment groups, both PASI mean scores and change in PASI scores over time were comparable between the two study groups, regardless of switching between the two agents. In addition, in all groups, PASI 75 and PASI 90 scores increased gradually over time until week 30, and then remained stable through week 52, the investigators said (Br J Dermatol. 2016. doi: 10.1111/bjd.15152).

The proportion of patients with at least one treatment-emergent adverse event was similar in the GP2015 and etanercept groups who did not switch agents (59.8% and 57.3%, respectively), and was also similar among those who did switch agents between GP2015 (61%) and etanercept (59.4%).

The rates of serious adverse events and of adverse events that led to withdrawal from the study were similar across all treatment groups. Immunogenicity of GP2015 was similar to etanercept.

However, the rate of “adverse events of special interest” – those referred to in special warnings and precautions on the etanercept label – was markedly higher for continued GP2015 than for continued etanercept (11.0% vs. 4.7%) and for switched GP2015 than for switched etanercept (11.0% vs. 5.2%). One patient who took etanercept throughout the trial developed malignant melanoma.

The results of the study “confirm biosimilarity that was established with all previous analytical comparisons to the reference product in that equivalent efficacy was demonstrated as well as similar safety and immunogenicity of GP2015” with etanercept, “in a highly sensitive, generally immune-competent population,” the authors concluded.

The study was funded by Hexal AG, a Sandoz company, which was involved in the study design, data collection and analysis, and manuscript preparation. Dr. Griffiths reported ties to AbbVie, BMS. Galderma, Janssen, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz, and UCB Pharma, and his associates reported ties to numerous industry sources.

An experimental biological agent, GP2015, demonstrated equivalent efficacy and comparable safety to etanercept for moderate to severe plaque psoriasis in a manufacturer-sponsored study, according to a report published online in the British Journal of Dermatology.

These findings should contribute to the confirmation of GP2015 as an etanercept (Enbrel) biosimilar for this patient population. Proposed biosimilars such as GP2015 are follow-on versions of authorized biological products, and regulatory authorities require that they demonstrate similarity with a large body of physiochemical and clinical data before they can be confirmed as biosimilars, said Christopher Griffiths, MD, of the Dermatology Centre, Salford Royal Hospital, University of Manchester (England), and his associates.

To contribute such data, Dr. Griffiths and his associates studied the efficacy and safety of GP2015 compared with etanercept, a tumor necrosis factor blocker, in the 2-year EGALITY trial. They assessed 531 adults at 74 medical centers in 11 European countries and South Africa, all of whom had active but stable chronic plaque psoriasis affecting 10% or more of their body surface area and Psoriasis Area and Severity Index (PASI) scores of 10 or more.

The study participants were randomly assigned in approximately equal numbers in a double-blind fashion to self administer GP2015 or etanercept subcutaneously, twice weekly for 12 weeks. Those who achieved at least a 50% improvement in PASI score were then randomized to continue the same treatment once weekly or to undergo a series of three treatment “switches” between GP2015 and etanercept at 6-week intervals until week 30. During an extension phase of the study, participants could then continue to receive the same treatment they had ended on, until week 52.

The primary efficacy endpoint – the percentage of patients who showed at least a 75% improvement from baseline in PASI score (PASI 75) at 12 weeks – was 73.4% with GP2015 and 75.7% with etanercept, which demonstrated therapeutic equivalence. A secondary efficacy end point – mean change in PASI score from baseline to week 12 – also was similar between the two study drugs. In all treatment groups, both PASI mean scores and change in PASI scores over time were comparable between the two study groups, regardless of switching between the two agents. In addition, in all groups, PASI 75 and PASI 90 scores increased gradually over time until week 30, and then remained stable through week 52, the investigators said (Br J Dermatol. 2016. doi: 10.1111/bjd.15152).

The proportion of patients with at least one treatment-emergent adverse event was similar in the GP2015 and etanercept groups who did not switch agents (59.8% and 57.3%, respectively), and was also similar among those who did switch agents between GP2015 (61%) and etanercept (59.4%).

The rates of serious adverse events and of adverse events that led to withdrawal from the study were similar across all treatment groups. Immunogenicity of GP2015 was similar to etanercept.

However, the rate of “adverse events of special interest” – those referred to in special warnings and precautions on the etanercept label – was markedly higher for continued GP2015 than for continued etanercept (11.0% vs. 4.7%) and for switched GP2015 than for switched etanercept (11.0% vs. 5.2%). One patient who took etanercept throughout the trial developed malignant melanoma.

The results of the study “confirm biosimilarity that was established with all previous analytical comparisons to the reference product in that equivalent efficacy was demonstrated as well as similar safety and immunogenicity of GP2015” with etanercept, “in a highly sensitive, generally immune-competent population,” the authors concluded.

The study was funded by Hexal AG, a Sandoz company, which was involved in the study design, data collection and analysis, and manuscript preparation. Dr. Griffiths reported ties to AbbVie, BMS. Galderma, Janssen, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz, and UCB Pharma, and his associates reported ties to numerous industry sources.

WASHINGTON – Certolizumab pegol is not transmitted into human breast milk in any clinically meaningful level, a postmarketing pharmacokinetic study has determined.

While there were individual differences in how much of the TNF inhibitor did cross into milk, none of the 17 women in the study transmitted more than 0.076 mcg/mL in any sample, Megan Clowse, MD, said at the annual meeting of the American College of Rheumatology.

“This is well below even 1% of the expected plasma concentration of a therapeutic dose,” said Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C. “Additionally, the mean relative infant dose was 0.125% – also far below the cutoff of less than 10% of the adult dose, the level generally thought to be of little concern for infant well-being.”

©Jupiterimages/Thinkstock

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – Certolizumab pegol is not transmitted into human breast milk in any clinically meaningful level, a postmarketing pharmacokinetic study has determined.

While there were individual differences in how much of the TNF inhibitor did cross into milk, none of the 17 women in the study transmitted more than 0.076 mcg/mL in any sample, Megan Clowse, MD, said at the annual meeting of the American College of Rheumatology.

“This is well below even 1% of the expected plasma concentration of a therapeutic dose,” said Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C. “Additionally, the mean relative infant dose was 0.125% – also far below the cutoff of less than 10% of the adult dose, the level generally thought to be of little concern for infant well-being.”

©Jupiterimages/Thinkstock

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – Certolizumab pegol is not transmitted into human breast milk in any clinically meaningful level, a postmarketing pharmacokinetic study has determined.

While there were individual differences in how much of the TNF inhibitor did cross into milk, none of the 17 women in the study transmitted more than 0.076 mcg/mL in any sample, Megan Clowse, MD, said at the annual meeting of the American College of Rheumatology.

“This is well below even 1% of the expected plasma concentration of a therapeutic dose,” said Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C. “Additionally, the mean relative infant dose was 0.125% – also far below the cutoff of less than 10% of the adult dose, the level generally thought to be of little concern for infant well-being.”

©Jupiterimages/Thinkstock

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – Data from the first randomized trial of switching from an originator biologic to a biosimilar of the originator indicate that the infliximab biosimilar Remsima is no different from the infliximab originator Remicade in the rate of disease worsening over 1 year across a combination of all its approved indications.

The outcomes of the Norwegian, double-blind, noninferiority trial, called NOR-SWITCH, indicate similar rates of disease worsening across patients switched to Remsima and those who stayed on Remicade. However, exploratory group analyses conducted on the different disease subgroups in the trial (Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriasis, and psoriatic arthritis) showed a potentially concerning level of disease worsening among Crohn’s disease patients on Remsima with a confidence interval that nearly fell entirely within the range favoring Remicade.

In the United States, Remsima, also known as CT-P13, is marketed by Pfizer as Inflectra.

WASHINGTON – Data from the first randomized trial of switching from an originator biologic to a biosimilar of the originator indicate that the infliximab biosimilar Remsima is no different from the infliximab originator Remicade in the rate of disease worsening over 1 year across a combination of all its approved indications.

The outcomes of the Norwegian, double-blind, noninferiority trial, called NOR-SWITCH, indicate similar rates of disease worsening across patients switched to Remsima and those who stayed on Remicade. However, exploratory group analyses conducted on the different disease subgroups in the trial (Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriasis, and psoriatic arthritis) showed a potentially concerning level of disease worsening among Crohn’s disease patients on Remsima with a confidence interval that nearly fell entirely within the range favoring Remicade.

In the United States, Remsima, also known as CT-P13, is marketed by Pfizer as Inflectra.

WASHINGTON – Data from the first randomized trial of switching from an originator biologic to a biosimilar of the originator indicate that the infliximab biosimilar Remsima is no different from the infliximab originator Remicade in the rate of disease worsening over 1 year across a combination of all its approved indications.

The outcomes of the Norwegian, double-blind, noninferiority trial, called NOR-SWITCH, indicate similar rates of disease worsening across patients switched to Remsima and those who stayed on Remicade. However, exploratory group analyses conducted on the different disease subgroups in the trial (Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriasis, and psoriatic arthritis) showed a potentially concerning level of disease worsening among Crohn’s disease patients on Remsima with a confidence interval that nearly fell entirely within the range favoring Remicade.

In the United States, Remsima, also known as CT-P13, is marketed by Pfizer as Inflectra.

WASHINGTON – Biologic agents should be stopped prior to elective total knee or hip arthroplasty in patients with rheumatic diseases, according to a draft guideline developed by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.

The guideline, which address the perioperative management of antirheumatic medications in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), or lupus who are undergoing such surgery, is currently under review, Dr. Susan Goodman, MD, coprincipal investigator, reported at the annual meeting of the American College of Rheumatology.

The draft guideline was created because “guidance was needed for common clinical situations, even where data were sparse. We didn’t want to configure treatment mandates – that’s not what these are,” Dr. Goodman of Cornell University, New York, said.

The recommendations are conditional, she said, meaning that the benefits probably outweigh the harms, that the recommendations apply to most but not all patients, and that future research may lead to changes.

“They’re also preference sensitive,” she said, explaining that patients’ values and preferences should be carefully considered, as they might differ from those of the patient panel consulted during guideline development; the panel expressed greater concern about the risk of infection following surgery than about perioperative flares resulting from medication discontinuation.

Based on agreement by at least 80% of a voting panel which considered available evidence in the context of their clinical experience along with the input from the patient panel, the draft guideline states that:

• Current doses of methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine should be continued in patients with rheumatic diseases undergoing elective hip and knee replacement. This recommendation is based on an extensive literature review that showed the infection rate is decreased in patients who continue these medications, Dr. Goodman said.

• All biologics should be withheld prior to surgery in patients with inflammatory arthritis, and surgery should be planned for the end of the dosing cycle. This matter wasn’t specifically addressed in the literature; however, numerous randomized controlled trials outside of the surgical setting demonstrate an increased risk of infection associated with their use, she noted.

“All of the biologic medications were found to be associated with an increased risk of infection,” she said. “Because of this and the level of importance patients place on minimizing infection risk, we’ve recommended that biologics be withheld prior to surgery.”

• Tofacitinib, which was considered in a separate oral, targeted therapy category, should be withheld for at least 7 days prior to surgery in patients with RA, spondyloarthritis, and JIA. Data from systematic reviews and meta-analyses showed an increased risk of infection with tofacitinib, although more research is needed in order to “firm up” this recommendation, Dr. Goodman said.

• In lupus patients, rituximab and belimumab should be withheld prior to surgery, and surgery should be planned for the end of the dosing period.

“Again, this was not answered in the literature. We depended on observational studies that we reviewed that did show that patients with severe active lupus were at much higher risk for adverse events. But since rituximab isn’t approved by the [Food and Drug Administration] for use in lupus, and belimumab isn’t approved for use in severe lupus – and those seem to be the high-risk patients – we thought withholding them was more prudent,” she said.

• Patients with severe lupus should continue on current doses of methotrexate, mycophenolic acid, azathioprine, mizoribine, cyclosporine, and tacrolimus through surgery. This recommendation is based on indirect data from experience in organ transplant patients.

• All medications should be discontinued in patients whose lupus is not severe.

“Our recommendation is to withhold for 7 days to 2-5 days after surgery in the absence of any wound healing complications or any other complications,” she said, noting that the literature does not directly address this; the recommendation is based on indirect evidence in patients with either active infection or who are at risk for infection.

“We thought that careful monitoring of the patient would permit us to identify flare and intervene quickly. … and that, for mild cases of lupus, the morbidity associated with infection might not be greater than the morbidity associated with the disease flare,” she said.

• Biologics should be restarted once surgical wounds show evidence of healing and there is no clinical evidence of infection. The literature does not directly address this; the recommendation is based on the rationale for use of these medications in patients with either active infection or risk for infection.

• Current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with RA, lupus, or inflammatory arthritis. A meta-analysis and systematic review of randomized controlled trial data and observational data showed no hemodynamic difference between daily doses and stress doses.

“In addition, there are abundant observational data demonstrating an increase in infection in patients on chronic steroids greater than 15 mg, and we thought that part of the optimization of the patient would be getting them on the lowest possible steroid dose,” she said, stressing that this refers only to adults receiving glucocorticoids for their rheumatic disease, and not to those with a history of JIA who may have received steroids during development, or to those receiving glucocorticoids for primary, adrenal, or hypothalamic disease.

According to Dr. Goodman, the time is right for the introduction of these recommendations, because the increased use of disease-modifying drugs and biologics means that most patients coming in for these surgeries will be taking these medications.

Further, despite the widespread use of the medications, the rate of total knee and hip arthroplasty surgeries among patients with rheumatic diseases is about the same as it was 20 or 30 years ago – and their risk for devastating complications, including infections, remains high, she said, noting that appropriate medication management provides an opportunity to mitigate risk.

Coprincipal investigator, Bryan Springer, MD, further emphasized the importance of the guideline, noting that the 5-year survival among rheumatic disease patients who develop certain perioperative complications is lower than for many common cancers, and that the literature offers little guidance on managing medications in the perioperative period.

“We now have a document that’s based on the available evidence, and also based on expert opinion, to help us manage these patients much more thoroughly in the perioperative period,” Dr. Springer, an orthopedic surgeon in Charlotte, N.C., said during a press briefing on the guideline.

Dr. Springer highlighted the value of the unique collaboration between the ACR and the AAHKS, calling the effort a win both for patients, and for “collaborative efforts, collaborative research, which we just really don’t do enough of,” he said. “I hope this is a huge step towards that direction.”

This guideline development process was funded by the ACR and AAHKS.

sworcester@frontlinemedcom.com

WASHINGTON – Biologic agents should be stopped prior to elective total knee or hip arthroplasty in patients with rheumatic diseases, according to a draft guideline developed by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.

The guideline, which address the perioperative management of antirheumatic medications in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), or lupus who are undergoing such surgery, is currently under review, Dr. Susan Goodman, MD, coprincipal investigator, reported at the annual meeting of the American College of Rheumatology.

The draft guideline was created because “guidance was needed for common clinical situations, even where data were sparse. We didn’t want to configure treatment mandates – that’s not what these are,” Dr. Goodman of Cornell University, New York, said.

The recommendations are conditional, she said, meaning that the benefits probably outweigh the harms, that the recommendations apply to most but not all patients, and that future research may lead to changes.

“They’re also preference sensitive,” she said, explaining that patients’ values and preferences should be carefully considered, as they might differ from those of the patient panel consulted during guideline development; the panel expressed greater concern about the risk of infection following surgery than about perioperative flares resulting from medication discontinuation.

Based on agreement by at least 80% of a voting panel which considered available evidence in the context of their clinical experience along with the input from the patient panel, the draft guideline states that:

• Current doses of methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine should be continued in patients with rheumatic diseases undergoing elective hip and knee replacement. This recommendation is based on an extensive literature review that showed the infection rate is decreased in patients who continue these medications, Dr. Goodman said.

• All biologics should be withheld prior to surgery in patients with inflammatory arthritis, and surgery should be planned for the end of the dosing cycle. This matter wasn’t specifically addressed in the literature; however, numerous randomized controlled trials outside of the surgical setting demonstrate an increased risk of infection associated with their use, she noted.

“All of the biologic medications were found to be associated with an increased risk of infection,” she said. “Because of this and the level of importance patients place on minimizing infection risk, we’ve recommended that biologics be withheld prior to surgery.”

• Tofacitinib, which was considered in a separate oral, targeted therapy category, should be withheld for at least 7 days prior to surgery in patients with RA, spondyloarthritis, and JIA. Data from systematic reviews and meta-analyses showed an increased risk of infection with tofacitinib, although more research is needed in order to “firm up” this recommendation, Dr. Goodman said.

• In lupus patients, rituximab and belimumab should be withheld prior to surgery, and surgery should be planned for the end of the dosing period.

“Again, this was not answered in the literature. We depended on observational studies that we reviewed that did show that patients with severe active lupus were at much higher risk for adverse events. But since rituximab isn’t approved by the [Food and Drug Administration] for use in lupus, and belimumab isn’t approved for use in severe lupus – and those seem to be the high-risk patients – we thought withholding them was more prudent,” she said.

• Patients with severe lupus should continue on current doses of methotrexate, mycophenolic acid, azathioprine, mizoribine, cyclosporine, and tacrolimus through surgery. This recommendation is based on indirect data from experience in organ transplant patients.

• All medications should be discontinued in patients whose lupus is not severe.

“Our recommendation is to withhold for 7 days to 2-5 days after surgery in the absence of any wound healing complications or any other complications,” she said, noting that the literature does not directly address this; the recommendation is based on indirect evidence in patients with either active infection or who are at risk for infection.

“We thought that careful monitoring of the patient would permit us to identify flare and intervene quickly. … and that, for mild cases of lupus, the morbidity associated with infection might not be greater than the morbidity associated with the disease flare,” she said.

• Biologics should be restarted once surgical wounds show evidence of healing and there is no clinical evidence of infection. The literature does not directly address this; the recommendation is based on the rationale for use of these medications in patients with either active infection or risk for infection.

• Current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with RA, lupus, or inflammatory arthritis. A meta-analysis and systematic review of randomized controlled trial data and observational data showed no hemodynamic difference between daily doses and stress doses.

“In addition, there are abundant observational data demonstrating an increase in infection in patients on chronic steroids greater than 15 mg, and we thought that part of the optimization of the patient would be getting them on the lowest possible steroid dose,” she said, stressing that this refers only to adults receiving glucocorticoids for their rheumatic disease, and not to those with a history of JIA who may have received steroids during development, or to those receiving glucocorticoids for primary, adrenal, or hypothalamic disease.

According to Dr. Goodman, the time is right for the introduction of these recommendations, because the increased use of disease-modifying drugs and biologics means that most patients coming in for these surgeries will be taking these medications.

Further, despite the widespread use of the medications, the rate of total knee and hip arthroplasty surgeries among patients with rheumatic diseases is about the same as it was 20 or 30 years ago – and their risk for devastating complications, including infections, remains high, she said, noting that appropriate medication management provides an opportunity to mitigate risk.

Coprincipal investigator, Bryan Springer, MD, further emphasized the importance of the guideline, noting that the 5-year survival among rheumatic disease patients who develop certain perioperative complications is lower than for many common cancers, and that the literature offers little guidance on managing medications in the perioperative period.

“We now have a document that’s based on the available evidence, and also based on expert opinion, to help us manage these patients much more thoroughly in the perioperative period,” Dr. Springer, an orthopedic surgeon in Charlotte, N.C., said during a press briefing on the guideline.

Dr. Springer highlighted the value of the unique collaboration between the ACR and the AAHKS, calling the effort a win both for patients, and for “collaborative efforts, collaborative research, which we just really don’t do enough of,” he said. “I hope this is a huge step towards that direction.”

This guideline development process was funded by the ACR and AAHKS.

sworcester@frontlinemedcom.com

WASHINGTON – Biologic agents should be stopped prior to elective total knee or hip arthroplasty in patients with rheumatic diseases, according to a draft guideline developed by the American College of Rheumatology and the American Association of Hip and Knee Surgeons.

The guideline, which address the perioperative management of antirheumatic medications in patients with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, juvenile idiopathic arthritis (JIA), or lupus who are undergoing such surgery, is currently under review, Dr. Susan Goodman, MD, coprincipal investigator, reported at the annual meeting of the American College of Rheumatology.

The draft guideline was created because “guidance was needed for common clinical situations, even where data were sparse. We didn’t want to configure treatment mandates – that’s not what these are,” Dr. Goodman of Cornell University, New York, said.

The recommendations are conditional, she said, meaning that the benefits probably outweigh the harms, that the recommendations apply to most but not all patients, and that future research may lead to changes.

“They’re also preference sensitive,” she said, explaining that patients’ values and preferences should be carefully considered, as they might differ from those of the patient panel consulted during guideline development; the panel expressed greater concern about the risk of infection following surgery than about perioperative flares resulting from medication discontinuation.

Based on agreement by at least 80% of a voting panel which considered available evidence in the context of their clinical experience along with the input from the patient panel, the draft guideline states that:

• Current doses of methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine should be continued in patients with rheumatic diseases undergoing elective hip and knee replacement. This recommendation is based on an extensive literature review that showed the infection rate is decreased in patients who continue these medications, Dr. Goodman said.

• All biologics should be withheld prior to surgery in patients with inflammatory arthritis, and surgery should be planned for the end of the dosing cycle. This matter wasn’t specifically addressed in the literature; however, numerous randomized controlled trials outside of the surgical setting demonstrate an increased risk of infection associated with their use, she noted.

“All of the biologic medications were found to be associated with an increased risk of infection,” she said. “Because of this and the level of importance patients place on minimizing infection risk, we’ve recommended that biologics be withheld prior to surgery.”

• Tofacitinib, which was considered in a separate oral, targeted therapy category, should be withheld for at least 7 days prior to surgery in patients with RA, spondyloarthritis, and JIA. Data from systematic reviews and meta-analyses showed an increased risk of infection with tofacitinib, although more research is needed in order to “firm up” this recommendation, Dr. Goodman said.

• In lupus patients, rituximab and belimumab should be withheld prior to surgery, and surgery should be planned for the end of the dosing period.

“Again, this was not answered in the literature. We depended on observational studies that we reviewed that did show that patients with severe active lupus were at much higher risk for adverse events. But since rituximab isn’t approved by the [Food and Drug Administration] for use in lupus, and belimumab isn’t approved for use in severe lupus – and those seem to be the high-risk patients – we thought withholding them was more prudent,” she said.

• Patients with severe lupus should continue on current doses of methotrexate, mycophenolic acid, azathioprine, mizoribine, cyclosporine, and tacrolimus through surgery. This recommendation is based on indirect data from experience in organ transplant patients.

• All medications should be discontinued in patients whose lupus is not severe.

“Our recommendation is to withhold for 7 days to 2-5 days after surgery in the absence of any wound healing complications or any other complications,” she said, noting that the literature does not directly address this; the recommendation is based on indirect evidence in patients with either active infection or who are at risk for infection.

“We thought that careful monitoring of the patient would permit us to identify flare and intervene quickly. … and that, for mild cases of lupus, the morbidity associated with infection might not be greater than the morbidity associated with the disease flare,” she said.

• Biologics should be restarted once surgical wounds show evidence of healing and there is no clinical evidence of infection. The literature does not directly address this; the recommendation is based on the rationale for use of these medications in patients with either active infection or risk for infection.

• Current daily doses of glucocorticoids, rather than supraphysiologic doses, should be continued in adults with RA, lupus, or inflammatory arthritis. A meta-analysis and systematic review of randomized controlled trial data and observational data showed no hemodynamic difference between daily doses and stress doses.

“In addition, there are abundant observational data demonstrating an increase in infection in patients on chronic steroids greater than 15 mg, and we thought that part of the optimization of the patient would be getting them on the lowest possible steroid dose,” she said, stressing that this refers only to adults receiving glucocorticoids for their rheumatic disease, and not to those with a history of JIA who may have received steroids during development, or to those receiving glucocorticoids for primary, adrenal, or hypothalamic disease.

According to Dr. Goodman, the time is right for the introduction of these recommendations, because the increased use of disease-modifying drugs and biologics means that most patients coming in for these surgeries will be taking these medications.

Further, despite the widespread use of the medications, the rate of total knee and hip arthroplasty surgeries among patients with rheumatic diseases is about the same as it was 20 or 30 years ago – and their risk for devastating complications, including infections, remains high, she said, noting that appropriate medication management provides an opportunity to mitigate risk.

Coprincipal investigator, Bryan Springer, MD, further emphasized the importance of the guideline, noting that the 5-year survival among rheumatic disease patients who develop certain perioperative complications is lower than for many common cancers, and that the literature offers little guidance on managing medications in the perioperative period.

“We now have a document that’s based on the available evidence, and also based on expert opinion, to help us manage these patients much more thoroughly in the perioperative period,” Dr. Springer, an orthopedic surgeon in Charlotte, N.C., said during a press briefing on the guideline.

Dr. Springer highlighted the value of the unique collaboration between the ACR and the AAHKS, calling the effort a win both for patients, and for “collaborative efforts, collaborative research, which we just really don’t do enough of,” he said. “I hope this is a huge step towards that direction.”

This guideline development process was funded by the ACR and AAHKS.

sworcester@frontlinemedcom.com

WASHINGTON – The perioperative use of disease-modifying antirheumatic drug monotherapy or combined therapy with methotrexate and a tumor necrosis factor (TNF) inhibitor is not associated with increased rates of postoperative infectious complications or wound infections in patients with rheumatoid arthritis, according to findings from a retrospective review of more than 9,000 surgeries.

With respect to monotherapy, treatment was continued in 1,951 of 2,601 surgeries among patients receiving methotrexate, in 1,496 of 2,012 surgeries among patients receiving hydroxychloroquine, and in 508 of 652 surgeries among patient receiving leflunomide. The odds ratios for postoperative infection (including urinary tract, pneumonia, or sepsis) and postoperative wound infection, respectively, were 0.79 and 0.77 with methotrexate continuation, 0.93 and 0.86 with hydroxychloroquine continuation, and 0.78 and 0.87 with leflunomide continuation, Hsin-Hsuan Juo, MD, reported at the annual meeting of the American College of Rheumatology.

Dmitrii Kotin/Thinkstock

sworcester@frontlinemedcom.com

WASHINGTON – The perioperative use of disease-modifying antirheumatic drug monotherapy or combined therapy with methotrexate and a tumor necrosis factor (TNF) inhibitor is not associated with increased rates of postoperative infectious complications or wound infections in patients with rheumatoid arthritis, according to findings from a retrospective review of more than 9,000 surgeries.

With respect to monotherapy, treatment was continued in 1,951 of 2,601 surgeries among patients receiving methotrexate, in 1,496 of 2,012 surgeries among patients receiving hydroxychloroquine, and in 508 of 652 surgeries among patient receiving leflunomide. The odds ratios for postoperative infection (including urinary tract, pneumonia, or sepsis) and postoperative wound infection, respectively, were 0.79 and 0.77 with methotrexate continuation, 0.93 and 0.86 with hydroxychloroquine continuation, and 0.78 and 0.87 with leflunomide continuation, Hsin-Hsuan Juo, MD, reported at the annual meeting of the American College of Rheumatology.

Dmitrii Kotin/Thinkstock

sworcester@frontlinemedcom.com

WASHINGTON – The perioperative use of disease-modifying antirheumatic drug monotherapy or combined therapy with methotrexate and a tumor necrosis factor (TNF) inhibitor is not associated with increased rates of postoperative infectious complications or wound infections in patients with rheumatoid arthritis, according to findings from a retrospective review of more than 9,000 surgeries.

With respect to monotherapy, treatment was continued in 1,951 of 2,601 surgeries among patients receiving methotrexate, in 1,496 of 2,012 surgeries among patients receiving hydroxychloroquine, and in 508 of 652 surgeries among patient receiving leflunomide. The odds ratios for postoperative infection (including urinary tract, pneumonia, or sepsis) and postoperative wound infection, respectively, were 0.79 and 0.77 with methotrexate continuation, 0.93 and 0.86 with hydroxychloroquine continuation, and 0.78 and 0.87 with leflunomide continuation, Hsin-Hsuan Juo, MD, reported at the annual meeting of the American College of Rheumatology.

Dmitrii Kotin/Thinkstock

sworcester@frontlinemedcom.com

WASHINGTON – Celecoxib conferred a 53% decreased risk of overall mortality upon patients with rheumatoid arthritis when compared with naproxen – a surprise finding in a subanalysis of the newly released PRECISION study of anti-inflammatory drugs in arthritis.

But it’s tough to know what to make of the difference, according to the investigators at the annual meeting of the American College of Rheumatology. Although statistically significant, the mortality finding was based on just 45 events: 30 among those taking naproxen and 15 among those taking celecoxib.

“While I would say we were surprised to see this, we really can’t say what it means – or if it means anything,” primary investigator Daniel Solomon, MD, said in an interview. “This is a finding we will continue to investigate and look at, but at this point it’s not enough to base any prescribing decisions on.”

PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) enrolled more than 24,000 patients with osteoarthritis or rheumatoid arthritis. They were randomized to celecoxib, naproxen, or ibuprofen for a mean of 20 months, with an additional mean follow-up of 34 months.

The primary outcome was the first occurrence of an adverse event from the Antiplatelet Trialists Collaboration criteria (APTC; death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke). Secondary outcomes included:

• Major cardiovascular events (heart attack, stroke, cardiovascular death, revascularization, and hospitalization for unstable angina or transient ischemic attack).

• Renal events (acute kidney injury, including hospitalization for renal failure).

• Gastrointestinal events (hemorrhage, perforation, gastroduodenal ulcer, anemia of gastrointestinal origin, and gastric outlet obstruction.

The main PRECISION findings were released Nov. 13 at the annual meeting of the American Heart Association and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593).

Overall, celecoxib was just as safe as were the other drugs on the APTC endpoint, which occurred in about 2% of each groups. The study found significantly decreased risks of both GI and renal events with celecoxib, compared with either naproxen or ibuprofen. Celecoxib and naproxen were equivalent with regard to GI and renal events.

The subanalysis, released at the ACR meeting, adds important disease-specific context to the overall PRECISION results.

“We wanted to really delve into the subtle differences in how these two patient groups responded to these medications,” said PRECISION coinvestigator Elaine Husni, MD, vice chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic.

“We learned that each of these NSAIDs has a unique safety profile that can be different in different groups. And in general, celecoxib seems less risky than the others.”

The cohort subanalysis broke down these endpoints among 21,600 patients with osteoarthritis and 2,400 with rheumatoid arthritis.

Among patients with osteoarthritis, celecoxib was also associated with a 16% decreased risk of a major adverse cardiovascular event, compared with ibuprofen. GI events were also less likely in this group: Celecoxib was associated with a 32% decreased risk, compared with ibuprofen, and a 27% decreased risk, compared with naproxen.

Renal outcomes were almost identical in all of the medications in both groups, Dr. Husni said.

In addition to the adverse event outcomes, the subanalysis examined how well patients responded to their assigned NSAID. There were also some subtle differences seen here, Dr. Solomon and Dr. Husni said.

For patients with RA, ibuprofen was slightly, but significantly, more effective than either celecoxib or ibuprofen at controlling pain as measured by a visual analog pain scale. Patients with osteoarthritis responded equally well to all of the drugs.

RA patients also responded best to ibuprofen as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). Again, patients with osteoarthritis responded equally well to all of the medications.

The overall findings, as well as the subanalysis, should be reassuring to both physicians and patients, said Dr. Solomon, chief of the section of clinical sciences in the divisions of rheumatology and pharmacoepidemiology at Brigham and Women’s Hospital, Boston.

“I can now stand in front of patients and say with confidence, ‘Each of these drugs is fairly safe, and together we can choose the one that will be best for you, based on your own individual history and your own individual risk factors.’ I feel good about that.”

Pfizer funded the trial. Dr. Husni has research grants from Genzyme/Sanofi on a knee osteoarthritis trial related to hyaluronic acid injections. Dr. Solomon has research grants from Pfizer on non-NSAID related topics. He also receives royalties from UpToDate on chapters related to NSAIDs and selective COX-2 inhibitors.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – Celecoxib conferred a 53% decreased risk of overall mortality upon patients with rheumatoid arthritis when compared with naproxen – a surprise finding in a subanalysis of the newly released PRECISION study of anti-inflammatory drugs in arthritis.

But it’s tough to know what to make of the difference, according to the investigators at the annual meeting of the American College of Rheumatology. Although statistically significant, the mortality finding was based on just 45 events: 30 among those taking naproxen and 15 among those taking celecoxib.

“While I would say we were surprised to see this, we really can’t say what it means – or if it means anything,” primary investigator Daniel Solomon, MD, said in an interview. “This is a finding we will continue to investigate and look at, but at this point it’s not enough to base any prescribing decisions on.”

PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) enrolled more than 24,000 patients with osteoarthritis or rheumatoid arthritis. They were randomized to celecoxib, naproxen, or ibuprofen for a mean of 20 months, with an additional mean follow-up of 34 months.

The primary outcome was the first occurrence of an adverse event from the Antiplatelet Trialists Collaboration criteria (APTC; death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke). Secondary outcomes included:

• Major cardiovascular events (heart attack, stroke, cardiovascular death, revascularization, and hospitalization for unstable angina or transient ischemic attack).

• Renal events (acute kidney injury, including hospitalization for renal failure).

• Gastrointestinal events (hemorrhage, perforation, gastroduodenal ulcer, anemia of gastrointestinal origin, and gastric outlet obstruction.

The main PRECISION findings were released Nov. 13 at the annual meeting of the American Heart Association and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593).

Overall, celecoxib was just as safe as were the other drugs on the APTC endpoint, which occurred in about 2% of each groups. The study found significantly decreased risks of both GI and renal events with celecoxib, compared with either naproxen or ibuprofen. Celecoxib and naproxen were equivalent with regard to GI and renal events.

The subanalysis, released at the ACR meeting, adds important disease-specific context to the overall PRECISION results.

“We wanted to really delve into the subtle differences in how these two patient groups responded to these medications,” said PRECISION coinvestigator Elaine Husni, MD, vice chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic.

“We learned that each of these NSAIDs has a unique safety profile that can be different in different groups. And in general, celecoxib seems less risky than the others.”

The cohort subanalysis broke down these endpoints among 21,600 patients with osteoarthritis and 2,400 with rheumatoid arthritis.

Among patients with osteoarthritis, celecoxib was also associated with a 16% decreased risk of a major adverse cardiovascular event, compared with ibuprofen. GI events were also less likely in this group: Celecoxib was associated with a 32% decreased risk, compared with ibuprofen, and a 27% decreased risk, compared with naproxen.

Renal outcomes were almost identical in all of the medications in both groups, Dr. Husni said.

In addition to the adverse event outcomes, the subanalysis examined how well patients responded to their assigned NSAID. There were also some subtle differences seen here, Dr. Solomon and Dr. Husni said.

For patients with RA, ibuprofen was slightly, but significantly, more effective than either celecoxib or ibuprofen at controlling pain as measured by a visual analog pain scale. Patients with osteoarthritis responded equally well to all of the drugs.

RA patients also responded best to ibuprofen as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). Again, patients with osteoarthritis responded equally well to all of the medications.

The overall findings, as well as the subanalysis, should be reassuring to both physicians and patients, said Dr. Solomon, chief of the section of clinical sciences in the divisions of rheumatology and pharmacoepidemiology at Brigham and Women’s Hospital, Boston.

“I can now stand in front of patients and say with confidence, ‘Each of these drugs is fairly safe, and together we can choose the one that will be best for you, based on your own individual history and your own individual risk factors.’ I feel good about that.”

Pfizer funded the trial. Dr. Husni has research grants from Genzyme/Sanofi on a knee osteoarthritis trial related to hyaluronic acid injections. Dr. Solomon has research grants from Pfizer on non-NSAID related topics. He also receives royalties from UpToDate on chapters related to NSAIDs and selective COX-2 inhibitors.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

WASHINGTON – Celecoxib conferred a 53% decreased risk of overall mortality upon patients with rheumatoid arthritis when compared with naproxen – a surprise finding in a subanalysis of the newly released PRECISION study of anti-inflammatory drugs in arthritis.

But it’s tough to know what to make of the difference, according to the investigators at the annual meeting of the American College of Rheumatology. Although statistically significant, the mortality finding was based on just 45 events: 30 among those taking naproxen and 15 among those taking celecoxib.

“While I would say we were surprised to see this, we really can’t say what it means – or if it means anything,” primary investigator Daniel Solomon, MD, said in an interview. “This is a finding we will continue to investigate and look at, but at this point it’s not enough to base any prescribing decisions on.”

PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) enrolled more than 24,000 patients with osteoarthritis or rheumatoid arthritis. They were randomized to celecoxib, naproxen, or ibuprofen for a mean of 20 months, with an additional mean follow-up of 34 months.

The primary outcome was the first occurrence of an adverse event from the Antiplatelet Trialists Collaboration criteria (APTC; death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke). Secondary outcomes included:

• Major cardiovascular events (heart attack, stroke, cardiovascular death, revascularization, and hospitalization for unstable angina or transient ischemic attack).

• Renal events (acute kidney injury, including hospitalization for renal failure).

• Gastrointestinal events (hemorrhage, perforation, gastroduodenal ulcer, anemia of gastrointestinal origin, and gastric outlet obstruction.

The main PRECISION findings were released Nov. 13 at the annual meeting of the American Heart Association and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593).

Overall, celecoxib was just as safe as were the other drugs on the APTC endpoint, which occurred in about 2% of each groups. The study found significantly decreased risks of both GI and renal events with celecoxib, compared with either naproxen or ibuprofen. Celecoxib and naproxen were equivalent with regard to GI and renal events.

The subanalysis, released at the ACR meeting, adds important disease-specific context to the overall PRECISION results.

“We wanted to really delve into the subtle differences in how these two patient groups responded to these medications,” said PRECISION coinvestigator Elaine Husni, MD, vice chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic.

“We learned that each of these NSAIDs has a unique safety profile that can be different in different groups. And in general, celecoxib seems less risky than the others.”

The cohort subanalysis broke down these endpoints among 21,600 patients with osteoarthritis and 2,400 with rheumatoid arthritis.

Among patients with osteoarthritis, celecoxib was also associated with a 16% decreased risk of a major adverse cardiovascular event, compared with ibuprofen. GI events were also less likely in this group: Celecoxib was associated with a 32% decreased risk, compared with ibuprofen, and a 27% decreased risk, compared with naproxen.

Renal outcomes were almost identical in all of the medications in both groups, Dr. Husni said.

In addition to the adverse event outcomes, the subanalysis examined how well patients responded to their assigned NSAID. There were also some subtle differences seen here, Dr. Solomon and Dr. Husni said.

For patients with RA, ibuprofen was slightly, but significantly, more effective than either celecoxib or ibuprofen at controlling pain as measured by a visual analog pain scale. Patients with osteoarthritis responded equally well to all of the drugs.

RA patients also responded best to ibuprofen as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). Again, patients with osteoarthritis responded equally well to all of the medications.

The overall findings, as well as the subanalysis, should be reassuring to both physicians and patients, said Dr. Solomon, chief of the section of clinical sciences in the divisions of rheumatology and pharmacoepidemiology at Brigham and Women’s Hospital, Boston.

“I can now stand in front of patients and say with confidence, ‘Each of these drugs is fairly safe, and together we can choose the one that will be best for you, based on your own individual history and your own individual risk factors.’ I feel good about that.”

Pfizer funded the trial. Dr. Husni has research grants from Genzyme/Sanofi on a knee osteoarthritis trial related to hyaluronic acid injections. Dr. Solomon has research grants from Pfizer on non-NSAID related topics. He also receives royalties from UpToDate on chapters related to NSAIDs and selective COX-2 inhibitors.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

NEW ORLEANS – The cardiovascular safety profile of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib, a selective inhibitor of COX-2, is no worse than those of the nonselective NSAIDs naproxen and ibuprofen, according to a trial reported at the American Heart Association scientific sessions.

The trial, known as PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen Or Naproxen) was undertaken after another selective COX-2 inhibitor, rofecoxib (Vioxx), was withdrawn from the market because of associated cardiovascular events. It compared the three drugs among more than 24,000 patients with painful arthritis and elevated cardiovascular risk.
Main results showed that 2%-3% of patients experienced a cardiovascular event (cardiovascular death, myocardial infarction, or stroke) during a follow-up approaching 3 years, regardless of which drug they were assigned to take, with the slight differences falling within predefined margins for noninferiority of celecoxib, investigators reported in a session and related press conference.

Additionally, celecoxib yielded a lower rate of gastrointestinal events when compared with each of the other drugs and a lower rate of renal events when compared with ibuprofen.

“After the withdrawal of rofecoxib, everybody thought they knew the answer, that COX-2 inhibitors had an unfavorable cardiovascular profile,” commented first author Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic in Ohio. “We didn’t find that. And this is the type of study that once again teaches us that if we jump to conclusions about this based on mechanistic considerations, we often make very bad decisions.”

A cautionary view

“The investigators addressed an extremely important question, which is what is the cardiovascular safety of agents that we administer for a general medical condition over the long term,” commented invited discussant Elliott M. Antman, MD, a senior physician at Brigham and Women’s Hospital and associate dean for Clinical and Translational Research at Harvard Medical School in Boston. “We don’t see a lot of trials like that, but we do need this information.”

Trial details

Patients were eligible for PRECISION, a Pfizer-funded trial, if they had osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk.

In all, 24,081 patients from 926 centers globally were randomly assigned to double-blind treatment with celecoxib, naproxen, or ibuprofen, all of which are now available as generics in the United States.

“Patients were randomized to the FDA-approved doses of these drugs, and they could have their dose increased if they had unrelieved pain up to the maximum allowed by regulatory authorities in the local jurisdictions where the study was done,” Dr. Nissen noted, pointing out that studies initially generating some concern about celecoxib used a supratherapeutic dose of 800 mg daily.

As COX-2 inhibitors are less likely than nonselective NSAIDs to cause ulcers, which might affect compliance and outcomes, all patients additionally received esomeprazole for gastroprotection “to try to level the playing field,” he explained.

The mean treatment duration was 20.3 months, and the mean follow-up duration was 34.1 months, according to data reported at the meeting and simultaneously published (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593). On average, the daily dose of drug received was 209 mg for celecoxib, 852 mg for naproxen, and 2,045 mg for ibuprofen.

In intention-to-treat analyses, the rate of the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke was 2.3% in the celecoxib group, 2.5% in the naproxen group, and 2.7% in the ibuprofen group. The hazard ratio was 0.93 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.85 for celecoxib versus ibuprofen (P less than .001 for noninferiority).

Differences were more marked in the on-treatment population. Here, the rate of the primary outcome was 1.7% in the celecoxib group, 1.8% in the naproxen group, and 1.9% in the ibuprofen group. The HR was 0.90 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.81 for celecoxib versus ibuprofen (P less than .001 for noninferiority).

Secondary outcomes, which tested for superiority, showed that the rate of major adverse cardiovascular events was 15% higher in the ibuprofen group as compared with the celecoxib group in the intent-to-treat population. The difference translated to a near-significant reduction in risk with the latter (HR, 0.87; P = .06) that appeared greater in the on-treatment population.

However, Dr. Nissen cautioned that he could not state that celecoxib was superior. “Secondary and tertiary endpoints in a clinical trial are hypothesis generating, and they are not considered definitive evidence,” he commented. At the same time, “the FDA is going to have to deal with that because what do they do with labeling? What do they do with over-the-counter access to these various drugs?”

The rate of all-cause mortality was 25% higher with naproxen than with celecoxib (HR, 0.80; P = .052).

The rate of gastrointestinal events was 54% higher with ibuprofen (HR, 0.65; P = .002) and 41% higher with naproxen (HR, 0.71; P = .01) as compared with celecoxib. And the rate of renal events was 64% higher with ibuprofen than with celecoxib (HR, 0.61; P = .004).

In a post hoc analysis of global safety, the rate of serious cardiovascular, gastrointestinal, and renal events was 28% higher with ibuprofen (HR, 0.78; P less than .001) and 15% higher with naproxen (HR, 0.87; P = .03) than with celecoxib.

Of note, the findings for the primary endpoint were similar regardless of whether patients were taking low-dose aspirin or not. “There was no interaction with aspirin use,” Dr. Nissen stated. “This was not about the interference of ibuprofen or naproxen with aspirin use.”

Analyses of pain relief using a visual analogue scale showed no clinically meaningful differences, suggesting that the drug doses used were equally analgesic, he said. Stopping of study drug because of lack of efficacy was slightly more common in the celecoxib group.

“We didn’t study the low-dose, intermittent use of these drugs that most of the public engages in, and it’s really important that we crisply communicate that to the public because somebody who takes occasionally ibuprofen or naproxen for a headache should not look at these comparative data in a way that should necessarily influence their behavior. We just don’t know the answer,” cautioned Dr. Nissen, who disclosed that he received grant support from Pfizer during the conduct of the trial.

But the findings are relevant for individuals who take over-the-counter NSAIDs at doses exceeding the label, a phenomenon known as dose creep. “We need to reemphasize to the public that the labeled over-the-counter dose is what you should take. You shouldn’t double up or triple up on the drugs because the issue of high-dose therapy, which is what we studied, suggests that there are really potentially important gastrointestinal, renal, and cardiovascular risks,” he said.

NEW ORLEANS – The cardiovascular safety profile of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib, a selective inhibitor of COX-2, is no worse than those of the nonselective NSAIDs naproxen and ibuprofen, according to a trial reported at the American Heart Association scientific sessions.

The trial, known as PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen Or Naproxen) was undertaken after another selective COX-2 inhibitor, rofecoxib (Vioxx), was withdrawn from the market because of associated cardiovascular events. It compared the three drugs among more than 24,000 patients with painful arthritis and elevated cardiovascular risk.
Main results showed that 2%-3% of patients experienced a cardiovascular event (cardiovascular death, myocardial infarction, or stroke) during a follow-up approaching 3 years, regardless of which drug they were assigned to take, with the slight differences falling within predefined margins for noninferiority of celecoxib, investigators reported in a session and related press conference.

Additionally, celecoxib yielded a lower rate of gastrointestinal events when compared with each of the other drugs and a lower rate of renal events when compared with ibuprofen.

“After the withdrawal of rofecoxib, everybody thought they knew the answer, that COX-2 inhibitors had an unfavorable cardiovascular profile,” commented first author Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic in Ohio. “We didn’t find that. And this is the type of study that once again teaches us that if we jump to conclusions about this based on mechanistic considerations, we often make very bad decisions.”

A cautionary view

“The investigators addressed an extremely important question, which is what is the cardiovascular safety of agents that we administer for a general medical condition over the long term,” commented invited discussant Elliott M. Antman, MD, a senior physician at Brigham and Women’s Hospital and associate dean for Clinical and Translational Research at Harvard Medical School in Boston. “We don’t see a lot of trials like that, but we do need this information.”

Trial details

Patients were eligible for PRECISION, a Pfizer-funded trial, if they had osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk.

In all, 24,081 patients from 926 centers globally were randomly assigned to double-blind treatment with celecoxib, naproxen, or ibuprofen, all of which are now available as generics in the United States.

“Patients were randomized to the FDA-approved doses of these drugs, and they could have their dose increased if they had unrelieved pain up to the maximum allowed by regulatory authorities in the local jurisdictions where the study was done,” Dr. Nissen noted, pointing out that studies initially generating some concern about celecoxib used a supratherapeutic dose of 800 mg daily.

As COX-2 inhibitors are less likely than nonselective NSAIDs to cause ulcers, which might affect compliance and outcomes, all patients additionally received esomeprazole for gastroprotection “to try to level the playing field,” he explained.

The mean treatment duration was 20.3 months, and the mean follow-up duration was 34.1 months, according to data reported at the meeting and simultaneously published (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593). On average, the daily dose of drug received was 209 mg for celecoxib, 852 mg for naproxen, and 2,045 mg for ibuprofen.

In intention-to-treat analyses, the rate of the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke was 2.3% in the celecoxib group, 2.5% in the naproxen group, and 2.7% in the ibuprofen group. The hazard ratio was 0.93 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.85 for celecoxib versus ibuprofen (P less than .001 for noninferiority).

Differences were more marked in the on-treatment population. Here, the rate of the primary outcome was 1.7% in the celecoxib group, 1.8% in the naproxen group, and 1.9% in the ibuprofen group. The HR was 0.90 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.81 for celecoxib versus ibuprofen (P less than .001 for noninferiority).

Secondary outcomes, which tested for superiority, showed that the rate of major adverse cardiovascular events was 15% higher in the ibuprofen group as compared with the celecoxib group in the intent-to-treat population. The difference translated to a near-significant reduction in risk with the latter (HR, 0.87; P = .06) that appeared greater in the on-treatment population.

However, Dr. Nissen cautioned that he could not state that celecoxib was superior. “Secondary and tertiary endpoints in a clinical trial are hypothesis generating, and they are not considered definitive evidence,” he commented. At the same time, “the FDA is going to have to deal with that because what do they do with labeling? What do they do with over-the-counter access to these various drugs?”

The rate of all-cause mortality was 25% higher with naproxen than with celecoxib (HR, 0.80; P = .052).

The rate of gastrointestinal events was 54% higher with ibuprofen (HR, 0.65; P = .002) and 41% higher with naproxen (HR, 0.71; P = .01) as compared with celecoxib. And the rate of renal events was 64% higher with ibuprofen than with celecoxib (HR, 0.61; P = .004).

In a post hoc analysis of global safety, the rate of serious cardiovascular, gastrointestinal, and renal events was 28% higher with ibuprofen (HR, 0.78; P less than .001) and 15% higher with naproxen (HR, 0.87; P = .03) than with celecoxib.

Of note, the findings for the primary endpoint were similar regardless of whether patients were taking low-dose aspirin or not. “There was no interaction with aspirin use,” Dr. Nissen stated. “This was not about the interference of ibuprofen or naproxen with aspirin use.”

Analyses of pain relief using a visual analogue scale showed no clinically meaningful differences, suggesting that the drug doses used were equally analgesic, he said. Stopping of study drug because of lack of efficacy was slightly more common in the celecoxib group.

“We didn’t study the low-dose, intermittent use of these drugs that most of the public engages in, and it’s really important that we crisply communicate that to the public because somebody who takes occasionally ibuprofen or naproxen for a headache should not look at these comparative data in a way that should necessarily influence their behavior. We just don’t know the answer,” cautioned Dr. Nissen, who disclosed that he received grant support from Pfizer during the conduct of the trial.

But the findings are relevant for individuals who take over-the-counter NSAIDs at doses exceeding the label, a phenomenon known as dose creep. “We need to reemphasize to the public that the labeled over-the-counter dose is what you should take. You shouldn’t double up or triple up on the drugs because the issue of high-dose therapy, which is what we studied, suggests that there are really potentially important gastrointestinal, renal, and cardiovascular risks,” he said.

NEW ORLEANS – The cardiovascular safety profile of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib, a selective inhibitor of COX-2, is no worse than those of the nonselective NSAIDs naproxen and ibuprofen, according to a trial reported at the American Heart Association scientific sessions.

The trial, known as PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen Or Naproxen) was undertaken after another selective COX-2 inhibitor, rofecoxib (Vioxx), was withdrawn from the market because of associated cardiovascular events. It compared the three drugs among more than 24,000 patients with painful arthritis and elevated cardiovascular risk.
Main results showed that 2%-3% of patients experienced a cardiovascular event (cardiovascular death, myocardial infarction, or stroke) during a follow-up approaching 3 years, regardless of which drug they were assigned to take, with the slight differences falling within predefined margins for noninferiority of celecoxib, investigators reported in a session and related press conference.

Additionally, celecoxib yielded a lower rate of gastrointestinal events when compared with each of the other drugs and a lower rate of renal events when compared with ibuprofen.

“After the withdrawal of rofecoxib, everybody thought they knew the answer, that COX-2 inhibitors had an unfavorable cardiovascular profile,” commented first author Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic in Ohio. “We didn’t find that. And this is the type of study that once again teaches us that if we jump to conclusions about this based on mechanistic considerations, we often make very bad decisions.”

A cautionary view

“The investigators addressed an extremely important question, which is what is the cardiovascular safety of agents that we administer for a general medical condition over the long term,” commented invited discussant Elliott M. Antman, MD, a senior physician at Brigham and Women’s Hospital and associate dean for Clinical and Translational Research at Harvard Medical School in Boston. “We don’t see a lot of trials like that, but we do need this information.”

Trial details

Patients were eligible for PRECISION, a Pfizer-funded trial, if they had osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk.

In all, 24,081 patients from 926 centers globally were randomly assigned to double-blind treatment with celecoxib, naproxen, or ibuprofen, all of which are now available as generics in the United States.

“Patients were randomized to the FDA-approved doses of these drugs, and they could have their dose increased if they had unrelieved pain up to the maximum allowed by regulatory authorities in the local jurisdictions where the study was done,” Dr. Nissen noted, pointing out that studies initially generating some concern about celecoxib used a supratherapeutic dose of 800 mg daily.

As COX-2 inhibitors are less likely than nonselective NSAIDs to cause ulcers, which might affect compliance and outcomes, all patients additionally received esomeprazole for gastroprotection “to try to level the playing field,” he explained.

The mean treatment duration was 20.3 months, and the mean follow-up duration was 34.1 months, according to data reported at the meeting and simultaneously published (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593). On average, the daily dose of drug received was 209 mg for celecoxib, 852 mg for naproxen, and 2,045 mg for ibuprofen.

In intention-to-treat analyses, the rate of the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke was 2.3% in the celecoxib group, 2.5% in the naproxen group, and 2.7% in the ibuprofen group. The hazard ratio was 0.93 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.85 for celecoxib versus ibuprofen (P less than .001 for noninferiority).

Differences were more marked in the on-treatment population. Here, the rate of the primary outcome was 1.7% in the celecoxib group, 1.8% in the naproxen group, and 1.9% in the ibuprofen group. The HR was 0.90 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.81 for celecoxib versus ibuprofen (P less than .001 for noninferiority).

Secondary outcomes, which tested for superiority, showed that the rate of major adverse cardiovascular events was 15% higher in the ibuprofen group as compared with the celecoxib group in the intent-to-treat population. The difference translated to a near-significant reduction in risk with the latter (HR, 0.87; P = .06) that appeared greater in the on-treatment population.

However, Dr. Nissen cautioned that he could not state that celecoxib was superior. “Secondary and tertiary endpoints in a clinical trial are hypothesis generating, and they are not considered definitive evidence,” he commented. At the same time, “the FDA is going to have to deal with that because what do they do with labeling? What do they do with over-the-counter access to these various drugs?”

The rate of all-cause mortality was 25% higher with naproxen than with celecoxib (HR, 0.80; P = .052).

The rate of gastrointestinal events was 54% higher with ibuprofen (HR, 0.65; P = .002) and 41% higher with naproxen (HR, 0.71; P = .01) as compared with celecoxib. And the rate of renal events was 64% higher with ibuprofen than with celecoxib (HR, 0.61; P = .004).

In a post hoc analysis of global safety, the rate of serious cardiovascular, gastrointestinal, and renal events was 28% higher with ibuprofen (HR, 0.78; P less than .001) and 15% higher with naproxen (HR, 0.87; P = .03) than with celecoxib.

Of note, the findings for the primary endpoint were similar regardless of whether patients were taking low-dose aspirin or not. “There was no interaction with aspirin use,” Dr. Nissen stated. “This was not about the interference of ibuprofen or naproxen with aspirin use.”

Analyses of pain relief using a visual analogue scale showed no clinically meaningful differences, suggesting that the drug doses used were equally analgesic, he said. Stopping of study drug because of lack of efficacy was slightly more common in the celecoxib group.

“We didn’t study the low-dose, intermittent use of these drugs that most of the public engages in, and it’s really important that we crisply communicate that to the public because somebody who takes occasionally ibuprofen or naproxen for a headache should not look at these comparative data in a way that should necessarily influence their behavior. We just don’t know the answer,” cautioned Dr. Nissen, who disclosed that he received grant support from Pfizer during the conduct of the trial.

But the findings are relevant for individuals who take over-the-counter NSAIDs at doses exceeding the label, a phenomenon known as dose creep. “We need to reemphasize to the public that the labeled over-the-counter dose is what you should take. You shouldn’t double up or triple up on the drugs because the issue of high-dose therapy, which is what we studied, suggests that there are really potentially important gastrointestinal, renal, and cardiovascular risks,” he said.

WASHINGTON – Chronic cardiac inflammation is present in rheumatoid arthritis patients and appears to resolve when they achieve a good clinical response to medical therapy.

The findings of two cardiac imaging studies offer a tantalizing clue to the link between RA and heart failure, said Isabelle Amigues, MD, who reported the findings at the annual meeting of the American College of Rheumatology.

“We know that the inflammation of RA is not just restricted to joints,” said Dr. Amigues, a rheumatology fellow at Columbia University, New York. “We see it throughout the body, so of course it makes sense that we would see it in the heart as well. And now we see that we may be able to manage this with good disease management.

The study that found improvement of myocarditis with RA therapy was very small – just 8 patients and 12 controls – but the results were surprising and encouraging, Dr. Amigues said.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

WASHINGTON – Chronic cardiac inflammation is present in rheumatoid arthritis patients and appears to resolve when they achieve a good clinical response to medical therapy.

The findings of two cardiac imaging studies offer a tantalizing clue to the link between RA and heart failure, said Isabelle Amigues, MD, who reported the findings at the annual meeting of the American College of Rheumatology.

“We know that the inflammation of RA is not just restricted to joints,” said Dr. Amigues, a rheumatology fellow at Columbia University, New York. “We see it throughout the body, so of course it makes sense that we would see it in the heart as well. And now we see that we may be able to manage this with good disease management.

The study that found improvement of myocarditis with RA therapy was very small – just 8 patients and 12 controls – but the results were surprising and encouraging, Dr. Amigues said.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

WASHINGTON – Chronic cardiac inflammation is present in rheumatoid arthritis patients and appears to resolve when they achieve a good clinical response to medical therapy.

The findings of two cardiac imaging studies offer a tantalizing clue to the link between RA and heart failure, said Isabelle Amigues, MD, who reported the findings at the annual meeting of the American College of Rheumatology.

“We know that the inflammation of RA is not just restricted to joints,” said Dr. Amigues, a rheumatology fellow at Columbia University, New York. “We see it throughout the body, so of course it makes sense that we would see it in the heart as well. And now we see that we may be able to manage this with good disease management.

The study that found improvement of myocarditis with RA therapy was very small – just 8 patients and 12 controls – but the results were surprising and encouraging, Dr. Amigues said.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal