Pharmacology

Purpose

To evaluate the impact that a pharmacistmanaged oral anticancer clinic has on patient adherence to oral anticancer therapy in regard to medication adherence and adherence to lab monitoring.

Background

Oral anticancer therapy is typically preconceived to be safer than intravenous. However, these medications have a narrow therapeutic window and significant toxicities, requiring close monitoring to ensure patient safety. Previous studies have shown that pharmacist-led oral anticancer clinics have improved adherence and decreased toxicity.

Methods

A retrospective chart review was completed for patients prescribed abiraterone, enzalutamide, or ibrutinib. The primary outcome assessed medication adherence by comparing the medication possession ratio (MPR) before (phase 1) and after (phase 2) the initiation of the pharmacist-led oral anticancer therapy clinic. The secondary outcome assessed lab monitoring adherence by patients and providers in phase 1 vs. phase 2. This study also examined descriptive outcomes in phase 2.

Data Analysis

Independent sample t tests were used to analyze primary and secondary endpoints. For descriptive endpoints, standard deviations and range of scores were assessed for continuous variables.

Results

A statistically significant increase in the mean MPR ratio was shown between phase 1 vs phase 2 (0.98 vs 1.05; P = .027). For patient adherence to lab monitoring, there was a statistically significant improvement for patients on abiraterone (21.9% vs. 67%; P < .001) and enzalutamide (35.7% vs 90.5%; P = .006). There was a decline in lab monitoring adherence for patient on ibrutinib but this effect was not statistically significant (56.2% vs. 51%; P = .283). Similar results were shown for provider adherence to lab monitoring. Descriptive outcomes showed that the pharmacist had on average 6.7 encounters per patient.

Conclusions/Implications

A pharmacist-led oral anticancer clinic can improve MPR ratios and patient adherence to oral anticancer regimens. Patient and provider lab monitoring adherence was improved for abiraterone and enzalutamide. Improvement in patient/ provider lab monitoring adherence for ibrutinib was not shown, possibly due to the impact of the COVID-19 pandemic, small sample size, and retrospective nature of this study. The results of this study supports that overall, a pharmacist-led oral anticancer clinic can significantly improve patient outcomes, which aligns with previous smaller studies.

Purpose

To evaluate the impact that a pharmacistmanaged oral anticancer clinic has on patient adherence to oral anticancer therapy in regard to medication adherence and adherence to lab monitoring.

Background

Oral anticancer therapy is typically preconceived to be safer than intravenous. However, these medications have a narrow therapeutic window and significant toxicities, requiring close monitoring to ensure patient safety. Previous studies have shown that pharmacist-led oral anticancer clinics have improved adherence and decreased toxicity.

Methods

A retrospective chart review was completed for patients prescribed abiraterone, enzalutamide, or ibrutinib. The primary outcome assessed medication adherence by comparing the medication possession ratio (MPR) before (phase 1) and after (phase 2) the initiation of the pharmacist-led oral anticancer therapy clinic. The secondary outcome assessed lab monitoring adherence by patients and providers in phase 1 vs. phase 2. This study also examined descriptive outcomes in phase 2.

Data Analysis

Independent sample t tests were used to analyze primary and secondary endpoints. For descriptive endpoints, standard deviations and range of scores were assessed for continuous variables.

Results

A statistically significant increase in the mean MPR ratio was shown between phase 1 vs phase 2 (0.98 vs 1.05; P = .027). For patient adherence to lab monitoring, there was a statistically significant improvement for patients on abiraterone (21.9% vs. 67%; P < .001) and enzalutamide (35.7% vs 90.5%; P = .006). There was a decline in lab monitoring adherence for patient on ibrutinib but this effect was not statistically significant (56.2% vs. 51%; P = .283). Similar results were shown for provider adherence to lab monitoring. Descriptive outcomes showed that the pharmacist had on average 6.7 encounters per patient.

Conclusions/Implications

A pharmacist-led oral anticancer clinic can improve MPR ratios and patient adherence to oral anticancer regimens. Patient and provider lab monitoring adherence was improved for abiraterone and enzalutamide. Improvement in patient/ provider lab monitoring adherence for ibrutinib was not shown, possibly due to the impact of the COVID-19 pandemic, small sample size, and retrospective nature of this study. The results of this study supports that overall, a pharmacist-led oral anticancer clinic can significantly improve patient outcomes, which aligns with previous smaller studies.

Purpose

To evaluate the impact that a pharmacistmanaged oral anticancer clinic has on patient adherence to oral anticancer therapy in regard to medication adherence and adherence to lab monitoring.

Background

Oral anticancer therapy is typically preconceived to be safer than intravenous. However, these medications have a narrow therapeutic window and significant toxicities, requiring close monitoring to ensure patient safety. Previous studies have shown that pharmacist-led oral anticancer clinics have improved adherence and decreased toxicity.

Methods

A retrospective chart review was completed for patients prescribed abiraterone, enzalutamide, or ibrutinib. The primary outcome assessed medication adherence by comparing the medication possession ratio (MPR) before (phase 1) and after (phase 2) the initiation of the pharmacist-led oral anticancer therapy clinic. The secondary outcome assessed lab monitoring adherence by patients and providers in phase 1 vs. phase 2. This study also examined descriptive outcomes in phase 2.

Data Analysis

Independent sample t tests were used to analyze primary and secondary endpoints. For descriptive endpoints, standard deviations and range of scores were assessed for continuous variables.

Results

A statistically significant increase in the mean MPR ratio was shown between phase 1 vs phase 2 (0.98 vs 1.05; P = .027). For patient adherence to lab monitoring, there was a statistically significant improvement for patients on abiraterone (21.9% vs. 67%; P < .001) and enzalutamide (35.7% vs 90.5%; P = .006). There was a decline in lab monitoring adherence for patient on ibrutinib but this effect was not statistically significant (56.2% vs. 51%; P = .283). Similar results were shown for provider adherence to lab monitoring. Descriptive outcomes showed that the pharmacist had on average 6.7 encounters per patient.

Conclusions/Implications

A pharmacist-led oral anticancer clinic can improve MPR ratios and patient adherence to oral anticancer regimens. Patient and provider lab monitoring adherence was improved for abiraterone and enzalutamide. Improvement in patient/ provider lab monitoring adherence for ibrutinib was not shown, possibly due to the impact of the COVID-19 pandemic, small sample size, and retrospective nature of this study. The results of this study supports that overall, a pharmacist-led oral anticancer clinic can significantly improve patient outcomes, which aligns with previous smaller studies.

A systematic review of immune checkpoint inhibitor (ICI) combinations suggests that they have a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib and should be made generally available to patients with advanced renal cell carcinoma (RCC).

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials that have examined ICIs in combination with VEGF-directed therapies.

In a study published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and one each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared with sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate/poor-risk patients, compared with sunitinib, but the combination led to more frequent discontinuation because of toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation because of toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation because of toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggested that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual-ICI combination therapy was similar to that seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors note that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, IMDC risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

Four of the authors reported receiving honoraria, research funding, or consulting for a variety of pharmaceutical companies, including AbbVie, Astellas, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, and TerSera.

A systematic review of immune checkpoint inhibitor (ICI) combinations suggests that they have a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib and should be made generally available to patients with advanced renal cell carcinoma (RCC).

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials that have examined ICIs in combination with VEGF-directed therapies.

In a study published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and one each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared with sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate/poor-risk patients, compared with sunitinib, but the combination led to more frequent discontinuation because of toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation because of toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation because of toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggested that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual-ICI combination therapy was similar to that seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors note that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, IMDC risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

Four of the authors reported receiving honoraria, research funding, or consulting for a variety of pharmaceutical companies, including AbbVie, Astellas, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, and TerSera.

A systematic review of immune checkpoint inhibitor (ICI) combinations suggests that they have a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib and should be made generally available to patients with advanced renal cell carcinoma (RCC).

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials that have examined ICIs in combination with VEGF-directed therapies.

In a study published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and one each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared with sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate/poor-risk patients, compared with sunitinib, but the combination led to more frequent discontinuation because of toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation because of toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation because of toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggested that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual-ICI combination therapy was similar to that seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors note that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, IMDC risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

Four of the authors reported receiving honoraria, research funding, or consulting for a variety of pharmaceutical companies, including AbbVie, Astellas, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, and TerSera.

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

A version of this article first appeared on Medscape.com.

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

A version of this article first appeared on Medscape.com.

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

A version of this article first appeared on Medscape.com.

The antiviral drug Paxlovid appears to reduce the risk of dying from COVID-19 by 79% and decrease hospitalizations by 73% in at-risk patients who are ages 65 and older, according to a new study published in The New England Journal of Medicine.

The pill, which is a combination of the drugs nirmatrelvir and ritonavir, received FDA emergency use authorization in December 2021 to treat mild to moderate disease in ages 12 and older who face high risks for having severe COVID-19, hospitalization, and death.

“The results of the study show unequivocally that treatment with Paxlovid significantly reduces the risk of hospitalization and death from COVID-19,” Doron Netzer, MD, the senior study author and a researcher with Clalit Health Services, Tel Aviv, told The Jerusalem Post.

“We are the country’s leader in the provision of giving Paxlovid to relevant patients,” he said. “It was given to patients all over the country, with medical teams monitoring the patients who took the pills.”

The research is considered one of the most thorough studies published to date about how well Paxlovid works, the news outlet reported. The research team analyzed information from Clalit’s electronic medical records. The health care organization covers about 52% of the Israeli population and almost two-thirds of older adults. More than 30,000 COVID-19 patients in Israel have been treated with the drug so far.

Dr. Netzer and colleagues looked at hospitalization and death data for at-risk COVID-19 patients ages 40 and older between Jan. 9 and March 31, when the original Omicron variant was the dominant strain in Israel. During that time, more than 1.1 million Clalit patients were infected with COVID-19, 109,000 patients were considered at-risk, and 3,900 patients received the drug.

The average age of the patients was 60, and 39% of the patients were 65 and older. Overall, 78% of the patients had previous COVID-19 immunity due to vaccination, prior infection, or both.

Among ages 65 and older, the rate of COVID-19 hospitalization was 14.7 cases per 100,000 person-days among treated patients, compared with 58.9 cases per 100,000 person-days among untreated patients. This represented a 73% lower chance of being hospitalized.

Among ages 40-64, the rate of hospitalization due to COVID-19 was 15.2 cases per 100,000 person-days among treated patients, compared with 15.8 cases per 100,000 person-days among untreated patients. The risk of hospitalization wasn’t significantly lower for this age group.

Among ages 65 and older, there were two deaths from COVID-19 in 2,484 treated patients, compared with 158 in the 40,337 untreated patients. This represented a 79% lower chance of dying from COVID-19.

Among ages 40-64, there was one death from COVID-19 in 1,418 treated patients, compared with 16 in the 65,015 untreated patients. The risk of death wasn’t significantly lower for this age group.

For both age groups, a lack of previous COVID-19 immunity and a previous hospitalization were most strongly linked to high rates of hospitalization during the Omicron wave.

The researchers noted that they didn’t break down the data on ages 40-64 who had cancer and other severe conditions that weaken the immune system. These patients may be more likely to benefit from Paxlovid, they said, though future studies will need to analyze the data.

The study didn’t receive any financial or in-kind support, the authors said.

A version of this article first appeared on WebMD.com.

The antiviral drug Paxlovid appears to reduce the risk of dying from COVID-19 by 79% and decrease hospitalizations by 73% in at-risk patients who are ages 65 and older, according to a new study published in The New England Journal of Medicine.

The pill, which is a combination of the drugs nirmatrelvir and ritonavir, received FDA emergency use authorization in December 2021 to treat mild to moderate disease in ages 12 and older who face high risks for having severe COVID-19, hospitalization, and death.

“The results of the study show unequivocally that treatment with Paxlovid significantly reduces the risk of hospitalization and death from COVID-19,” Doron Netzer, MD, the senior study author and a researcher with Clalit Health Services, Tel Aviv, told The Jerusalem Post.

“We are the country’s leader in the provision of giving Paxlovid to relevant patients,” he said. “It was given to patients all over the country, with medical teams monitoring the patients who took the pills.”

The research is considered one of the most thorough studies published to date about how well Paxlovid works, the news outlet reported. The research team analyzed information from Clalit’s electronic medical records. The health care organization covers about 52% of the Israeli population and almost two-thirds of older adults. More than 30,000 COVID-19 patients in Israel have been treated with the drug so far.

Dr. Netzer and colleagues looked at hospitalization and death data for at-risk COVID-19 patients ages 40 and older between Jan. 9 and March 31, when the original Omicron variant was the dominant strain in Israel. During that time, more than 1.1 million Clalit patients were infected with COVID-19, 109,000 patients were considered at-risk, and 3,900 patients received the drug.

The average age of the patients was 60, and 39% of the patients were 65 and older. Overall, 78% of the patients had previous COVID-19 immunity due to vaccination, prior infection, or both.

Among ages 65 and older, the rate of COVID-19 hospitalization was 14.7 cases per 100,000 person-days among treated patients, compared with 58.9 cases per 100,000 person-days among untreated patients. This represented a 73% lower chance of being hospitalized.

Among ages 40-64, the rate of hospitalization due to COVID-19 was 15.2 cases per 100,000 person-days among treated patients, compared with 15.8 cases per 100,000 person-days among untreated patients. The risk of hospitalization wasn’t significantly lower for this age group.

Among ages 65 and older, there were two deaths from COVID-19 in 2,484 treated patients, compared with 158 in the 40,337 untreated patients. This represented a 79% lower chance of dying from COVID-19.

Among ages 40-64, there was one death from COVID-19 in 1,418 treated patients, compared with 16 in the 65,015 untreated patients. The risk of death wasn’t significantly lower for this age group.

For both age groups, a lack of previous COVID-19 immunity and a previous hospitalization were most strongly linked to high rates of hospitalization during the Omicron wave.

The researchers noted that they didn’t break down the data on ages 40-64 who had cancer and other severe conditions that weaken the immune system. These patients may be more likely to benefit from Paxlovid, they said, though future studies will need to analyze the data.

The study didn’t receive any financial or in-kind support, the authors said.

A version of this article first appeared on WebMD.com.

The antiviral drug Paxlovid appears to reduce the risk of dying from COVID-19 by 79% and decrease hospitalizations by 73% in at-risk patients who are ages 65 and older, according to a new study published in The New England Journal of Medicine.

The pill, which is a combination of the drugs nirmatrelvir and ritonavir, received FDA emergency use authorization in December 2021 to treat mild to moderate disease in ages 12 and older who face high risks for having severe COVID-19, hospitalization, and death.

“The results of the study show unequivocally that treatment with Paxlovid significantly reduces the risk of hospitalization and death from COVID-19,” Doron Netzer, MD, the senior study author and a researcher with Clalit Health Services, Tel Aviv, told The Jerusalem Post.

“We are the country’s leader in the provision of giving Paxlovid to relevant patients,” he said. “It was given to patients all over the country, with medical teams monitoring the patients who took the pills.”

The research is considered one of the most thorough studies published to date about how well Paxlovid works, the news outlet reported. The research team analyzed information from Clalit’s electronic medical records. The health care organization covers about 52% of the Israeli population and almost two-thirds of older adults. More than 30,000 COVID-19 patients in Israel have been treated with the drug so far.

Dr. Netzer and colleagues looked at hospitalization and death data for at-risk COVID-19 patients ages 40 and older between Jan. 9 and March 31, when the original Omicron variant was the dominant strain in Israel. During that time, more than 1.1 million Clalit patients were infected with COVID-19, 109,000 patients were considered at-risk, and 3,900 patients received the drug.

The average age of the patients was 60, and 39% of the patients were 65 and older. Overall, 78% of the patients had previous COVID-19 immunity due to vaccination, prior infection, or both.

Among ages 65 and older, the rate of COVID-19 hospitalization was 14.7 cases per 100,000 person-days among treated patients, compared with 58.9 cases per 100,000 person-days among untreated patients. This represented a 73% lower chance of being hospitalized.

Among ages 40-64, the rate of hospitalization due to COVID-19 was 15.2 cases per 100,000 person-days among treated patients, compared with 15.8 cases per 100,000 person-days among untreated patients. The risk of hospitalization wasn’t significantly lower for this age group.

Among ages 65 and older, there were two deaths from COVID-19 in 2,484 treated patients, compared with 158 in the 40,337 untreated patients. This represented a 79% lower chance of dying from COVID-19.

Among ages 40-64, there was one death from COVID-19 in 1,418 treated patients, compared with 16 in the 65,015 untreated patients. The risk of death wasn’t significantly lower for this age group.

For both age groups, a lack of previous COVID-19 immunity and a previous hospitalization were most strongly linked to high rates of hospitalization during the Omicron wave.

The researchers noted that they didn’t break down the data on ages 40-64 who had cancer and other severe conditions that weaken the immune system. These patients may be more likely to benefit from Paxlovid, they said, though future studies will need to analyze the data.

The study didn’t receive any financial or in-kind support, the authors said.

A version of this article first appeared on WebMD.com.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

Catherine Hackett/MDedge News

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Catherine Hackett/MDedge News

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.

Key takeaway

• High-dose furosemide after cardiac surgery is associated with increased mortality and other adverse outcomes.

Why this matters

• The influence of furosemide on prognosis after cardiac surgery is not fully understood.
• The current findings suggest that high-dose furosemide after cardiac surgery is associated with increased risk for death and other adverse events and therefore should be used cautiously in that setting.

Study design

• The retrospective cohort of 6,752 cardiac surgery patients was divided into two groups according to average daily furosemide dosage after cardiac surgery: less than 20 mg (low-dose group, n = 6,033) and at least 20 mg (high-dose group, n = 719).
• The group were compared for total furosemide dose, total furosemide dose of at least 200 mg, total dose of furosemide by patient weight, and average daily furosemide dose of at least 20 mg.
• The primary outcomes were in-hospital mortality and mortality at 1 year after cardiac surgery. Secondary outcomes were length of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours.
• The study excluded patients aged younger than 18 whose weight data was missing or who had more than 5% of their data missing.

Key results

• Patients in the high-dose furosemide group tended to be older and have a higher body mass index (BMI) and higher rates of diabetes, chronic pulmonary diseases, heart failure, renal failure, blood transfusion, vasopressor use, and valvular surgery.
• They also tended have higher white cell counts and higher levels of blood urea nitrogen, creatinine, glucose, and lactate.
• Those in the high-dose group also were on vasopressors and ventilatory support longer.
• In adjusted multivariate analysis, increased in-hospital mortality was associated with average daily furosemide dose, average daily dose of at least 20 mg/d, and total dose of at least 200 mg.
• Increased mortality at 1 year was associated with total furosemide dose and average daily furosemide dose.
• Significant multivariate predictors of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours after cardiac surgery included total furosemide dose, total dose by weight, average daily furosemide dose of at least 20 mg/d, and total dose of at least 200 mg.
• In subgroup analyses, average daily furosemide dose of at least 20 mg/d significantly increased risk for in-hospital mortality among patients younger than 60 years or with BMI of at least 28 who received vasopressors or blood transfusions, those with renal failure, and those with heart failure not involving congestion.

Limitations

• No limitations were discussed.

Disclosures

• The study was supported by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Jiangsu Postdoctoral Science Foundation.
• The authors declared that they have no competing interests.

This is a summary of a preprint research study, “Association between furosemide administration and outcomes in patients undergoing cardiac surgery,” from Jinghang Li, First Affiliated Hospital of Nanjing (China) Medical University, and colleagues on published on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com. A version of this article first appeared on Medscape.com.

The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.

Key takeaway

• High-dose furosemide after cardiac surgery is associated with increased mortality and other adverse outcomes.

Why this matters

• The influence of furosemide on prognosis after cardiac surgery is not fully understood.
• The current findings suggest that high-dose furosemide after cardiac surgery is associated with increased risk for death and other adverse events and therefore should be used cautiously in that setting.

Study design

• The retrospective cohort of 6,752 cardiac surgery patients was divided into two groups according to average daily furosemide dosage after cardiac surgery: less than 20 mg (low-dose group, n = 6,033) and at least 20 mg (high-dose group, n = 719).
• The group were compared for total furosemide dose, total furosemide dose of at least 200 mg, total dose of furosemide by patient weight, and average daily furosemide dose of at least 20 mg.
• The primary outcomes were in-hospital mortality and mortality at 1 year after cardiac surgery. Secondary outcomes were length of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours.
• The study excluded patients aged younger than 18 whose weight data was missing or who had more than 5% of their data missing.

Key results

• Patients in the high-dose furosemide group tended to be older and have a higher body mass index (BMI) and higher rates of diabetes, chronic pulmonary diseases, heart failure, renal failure, blood transfusion, vasopressor use, and valvular surgery.
• They also tended have higher white cell counts and higher levels of blood urea nitrogen, creatinine, glucose, and lactate.
• Those in the high-dose group also were on vasopressors and ventilatory support longer.
• In adjusted multivariate analysis, increased in-hospital mortality was associated with average daily furosemide dose, average daily dose of at least 20 mg/d, and total dose of at least 200 mg.
• Increased mortality at 1 year was associated with total furosemide dose and average daily furosemide dose.
• Significant multivariate predictors of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours after cardiac surgery included total furosemide dose, total dose by weight, average daily furosemide dose of at least 20 mg/d, and total dose of at least 200 mg.
• In subgroup analyses, average daily furosemide dose of at least 20 mg/d significantly increased risk for in-hospital mortality among patients younger than 60 years or with BMI of at least 28 who received vasopressors or blood transfusions, those with renal failure, and those with heart failure not involving congestion.

Limitations

• No limitations were discussed.

Disclosures

• The study was supported by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Jiangsu Postdoctoral Science Foundation.
• The authors declared that they have no competing interests.

This is a summary of a preprint research study, “Association between furosemide administration and outcomes in patients undergoing cardiac surgery,” from Jinghang Li, First Affiliated Hospital of Nanjing (China) Medical University, and colleagues on published on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com. A version of this article first appeared on Medscape.com.

The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.

Key takeaway

• High-dose furosemide after cardiac surgery is associated with increased mortality and other adverse outcomes.

Why this matters

• The influence of furosemide on prognosis after cardiac surgery is not fully understood.
• The current findings suggest that high-dose furosemide after cardiac surgery is associated with increased risk for death and other adverse events and therefore should be used cautiously in that setting.

Study design

• The retrospective cohort of 6,752 cardiac surgery patients was divided into two groups according to average daily furosemide dosage after cardiac surgery: less than 20 mg (low-dose group, n = 6,033) and at least 20 mg (high-dose group, n = 719).
• The group were compared for total furosemide dose, total furosemide dose of at least 200 mg, total dose of furosemide by patient weight, and average daily furosemide dose of at least 20 mg.
• The primary outcomes were in-hospital mortality and mortality at 1 year after cardiac surgery. Secondary outcomes were length of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours.
• The study excluded patients aged younger than 18 whose weight data was missing or who had more than 5% of their data missing.

Key results

• Patients in the high-dose furosemide group tended to be older and have a higher body mass index (BMI) and higher rates of diabetes, chronic pulmonary diseases, heart failure, renal failure, blood transfusion, vasopressor use, and valvular surgery.
• They also tended have higher white cell counts and higher levels of blood urea nitrogen, creatinine, glucose, and lactate.
• Those in the high-dose group also were on vasopressors and ventilatory support longer.
• In adjusted multivariate analysis, increased in-hospital mortality was associated with average daily furosemide dose, average daily dose of at least 20 mg/d, and total dose of at least 200 mg.
• Increased mortality at 1 year was associated with total furosemide dose and average daily furosemide dose.
• Significant multivariate predictors of hospital stay of at least 14 days, length of ICU stay of at least 3 days, and mechanical ventilation for at least 48 hours after cardiac surgery included total furosemide dose, total dose by weight, average daily furosemide dose of at least 20 mg/d, and total dose of at least 200 mg.
• In subgroup analyses, average daily furosemide dose of at least 20 mg/d significantly increased risk for in-hospital mortality among patients younger than 60 years or with BMI of at least 28 who received vasopressors or blood transfusions, those with renal failure, and those with heart failure not involving congestion.

Limitations

• No limitations were discussed.

Disclosures

• The study was supported by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Jiangsu Postdoctoral Science Foundation.
• The authors declared that they have no competing interests.

This is a summary of a preprint research study, “Association between furosemide administration and outcomes in patients undergoing cardiac surgery,” from Jinghang Li, First Affiliated Hospital of Nanjing (China) Medical University, and colleagues on published on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com. A version of this article first appeared on Medscape.com.

Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.

“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).

AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
 

SECURE trial is latest test of polypill concept

A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.

The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.

The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.

Multiple polypill versions permit dose titration

The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.

The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).

When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).

In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.

The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.

Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.

“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.

One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.

Polypill benefit documented in all subgroups

While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.

“This really validates the importance of the study,” Dr. Fuster said.

In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.

American Heart Association

Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.

“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”

Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.

Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.

“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).

AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
 

SECURE trial is latest test of polypill concept

A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.

The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.

The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.

Multiple polypill versions permit dose titration

The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.

The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).

When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).

In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.

The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.

Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.

“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.

One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.

Polypill benefit documented in all subgroups

While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.

“This really validates the importance of the study,” Dr. Fuster said.

In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.

American Heart Association

Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.

“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”

Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.

Compared with separate medications in patients with a prior myocardial infarction, a single pill containing aspirin, a lipid-lowering agent, and an ACE inhibitor provided progressively greater protection from a second cardiovascular (CV) event over the course of a trial with several years of follow-up, according to results of a multinational trial.

“The curves began to separate at the very beginning of the trial, and they are continuing to separate, so we can begin to project the possibility that the results would be even more striking if we had an even longer follow-up,” said Valentin Fuster, MD, physician in chief, Mount Sinai Hospital, New York, who presented the results at the annual congress of the European Society of Cardiology.

MDedge News/Mitchel L. Zoler

By “striking,” Dr. Fuster was referring to a 24% reduction in the hazard ratio of major adverse CV events (MACE) for a trial in which patients were followed for a median of 3 years. The primary composite endpoint consisted of cardiovascular death, MI, stroke, and urgent revascularization (HR, 0.76; P = .02).

AS for the secondary composite endpoint, confined to CV death, MI, and stroke, use of the polypill linked to an even greater relative advantage over usual care (HR, 0.70; P = .005).
 

SECURE trial is latest test of polypill concept

A polypill strategy has been pursued for more than 15 years, according to Dr. Fuster. Other polypill studies have also generated positive results, but the latest trial, called SECURE, is the largest prospective randomized trial to evaluate a single pill combining multiple therapies for secondary prevention.

The degree of relative benefit has “huge implications for clinical care,” reported the ESC-invited commentator, Louise Bowman, MBBS, MD, professor of medicine and clinical trials, University of Oxford (England). She called the findings “in line with what was expected,” but she agreed that the results will drive practice change.

The SECURE trial, published online in the New England Journal of Medicine at the time of its presentation at the ESC congress, randomized 2,499 patients over the age of 65 years who had a MI within the previous 6 months and at least one other risk factor, such as diabetes mellitus, kidney dysfunction, or a prior coronary revascularization. They were enrolled at 113 participating study centers in seven European countries.

Multiple polypill versions permit dose titration

The polypill consisted of aspirin in a fixed dose of 100 mg, the HMG CoA reductase inhibitor atorvastatin, and the ACE inhibitor ramipril. For atorvastatin and ramipril, the target doses were 40 mg and 10 mg, respectively, but different versions of the polypill were available to permit titration to a tolerated dose. Usual care was provided by participating investigators according to ESC recommendations.

The average age of those enrolled was 76 years. Nearly one-third (31%) were women. At baseline, most had hypertension (77.9%), and the majority had diabetes (57.4%).

When the events in the primary endpoint were assessed individually, the polypill was associated with a 33% relative reduction in the risk of CV death (HR, 0.67; P = .03). The reductions in the risk of nonfatal MI (HR, 0.71) and stroke (HR, 0.70) were of the same general magnitude although they did not reach statistical significance. There was no meaningful reduction in urgent revascularization (HR, 0.96).

In addition, the reduction in all-cause mortality (HR, 0.97) was not significant.

The rate of adverse events over the course of the study was 32.7% in the polypill group and 31.6% in the usual-care group, which did not differ significantly. There was also no difference in types of adverse events, including bleeding and other adverse events of interest, according to Dr. Fuster.

Adherence, which was monitored at 6 and 24 months using the Morisky Medication Adherence Scale, was characterized as low, medium, or high. More patients in the polypill group reached high adherence at 6 months (70.6% vs. 62.7%) and at 24 months (74.1% vs. 63.2%). Conversely, fewer patients in the polypill group were deemed to have low adherence at both time points.

“Probably, adherence is the most important reason of how this works,” Dr. Fuster said. Although there were no substantial differences in lipid levels or in systolic or diastolic blood pressure between the two groups when compared at 24 months, there are several theories that might explain the lower event rates in the polypill group, including a more sustained anti-inflammatory effect from greater adherence.

One potential limitation was the open-label design, but Dr. Bowman said that this was unavoidable, given the difficulty of blinding and the fact that comparing a single pill with multiple pills was “the point of the study.” She noted that the 14% withdrawal rate over the course of the trial, which was attributed largely to the COVID-19 pandemic, and the lower than planned enrollment (2,500 vs. a projected 3,000 patients) are also limitations, prohibiting “a more robust result,” but she did not dispute the conclusions.

Polypill benefit documented in all subgroups

While acknowledging these limitations, Dr. Fuster emphasized the consistency of these results with prior polypill studies and within the study. Of the 16 predefined subgroups, such as those created with stratifications for age, sex, comorbidities, and country of treatment, all benefited to a similar degree.

“This really validates the importance of the study,” Dr. Fuster said.

In addition to the implications for risk management globally, Dr. Fuster and others, including Dr. Bowman, spoke of the potential of a relatively inexpensive polypill to improve care in resource-limited settings. Despite the move toward greater personalization of medicine, Dr. Fuster called “simplicity the key to global health” initiatives.

American Heart Association

Salim Yusuf, MD, DPhil, a leader in international polypill research, agreed. He believes the supportive data for this approach are conclusive.

“There are four positive trials of the polypill now and collectively the data are overwhelmingly clear,” Dr. Yusuf, professor of medicine, McMaster University, Hamilton, Ont., said in an interview. “The polypill should be considered in secondary prevention as well as in primary prevention for high-risk individuals. We have estimated that, if it is used in even 50% of those who should get it, it would avoid 2 million premature deaths from CV disease and 6 million nonfatal events. The next step is to implement the findings.”

Dr. Fuster, Dr. Bowman, and Dr. Yusuf reported no potential conflicts of interest.

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.

 

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.

 

People with diabetes who take nonsteroidal anti-inflammatory drugs even on a short-term basis may have about a 50% greater risk of developing heart failure, according to results from a national registry study of more than 330,000 patients to be presented at the annual congress of the European Society of Cardiology.

“According to data from this study, even short-term NSAID use – within 28 days – in patients with type 2 diabetes mellitus are associated with an increased risk of first-time heart failure hospitalization,” lead author Anders Holt, MD, said in an interview.

“Further, it seems that patients above 79 years of age or with elevated hemoglobin A1c levels, along with new users of NSAIDs, are particularly susceptible.” He added that no such association was found in patients below age 65 years with normal A1c levels.

Dr. Holt has a dual appointment as a cardiologist at Copenhagen University and Herlev-Gentofte Hospital in Hellerup, Denmark, and the department of epidemiology and biostatistics at the University of Auckland (New Zealand). Jarl Emmanuel Strange, MD, PhD, a fellow at Copenhagen University, is to present the abstract on Aug. 26.

“This is quite an important observation given that, unfortunately, NSAIDs continue to be prescribed rather easily to people with diabetes and these agents do have risk,” said Rodica Busui, MD, PhD, codirector of the JDRF Center of Excellence at the University of Michigan, Ann Arbor, and president-elect for medicine and science of the American Diabetes Association. Dr. Busui is also lead author of an ADA/American College of Cardiology consensus report on heart failure in diabetes.

The study hypothesized that fluid retention “is a known but underappreciated side effect” of NSAID use and that short-term NSAID use could lead to heart failure in patients with type 2 diabetes, which has been linked to subclinical cardiomyopathy and kidney dysfunction.

“According to this study and particularly the subgroups analyses, it seems that incident heart failure associated with short-term NSAID use could be more than ‘just fluid overload,’ ” Dr. Holt said. “Further investigations into the specific mechanisms causing these associations are warranted.”

The study identified 331,189 patients with type 2 diabetes in nationwide Danish registries from 1998 to 2018. Median age was 62 years, and 23,308 (7%) were hospitalized with heart failure during follow-up, Dr. Holt said. Of them, 16% claimed at least one NSAID prescription within 2 years and 3% claimed they had at least three prescriptions.

Study follow-up started 120 days after the first-time type 2 diabetes diagnosis and focused on patients who had no previous diagnosis of heart failure or rheumatologic disease. The investigators reported on patients who had one, two, three or four prescriptions for NSAID within a year of starting follow-up.

The study used a case-crossover design, which, the abstract stated, “uses each individual as his or her own control making it suitable to study the effect of short-term exposure on immediate events while mitigating unmeasured confounding.”

Dr. Holt noted that short-term NSAID use was linked to increased risk of heart failure hospitalization (odds ratio, 1.43; 95% confidence interval, 1.27-1.63). The investigators identified even greater risks in three subgroups: age of at least 80 years (OR, 1.78; 95% CI, 1.39-2.28), elevated A1c levels treated with one or less antidiabetic medication (OR 1.68; 95% CI, 1-2.88), and patients without previous NSAID use (OR, 2.71; 95% CI, 1.78-4.23).

In the cohort, celecoxib and naproxen were rarely used (0.4 and 0.9%, respectively), while 3.3% of patients took diclofenac or 12.2% ibuprofen. The latter two NSAIDs had ORs of 1.48 and 1.46, respectively, for hospitalization for new-onset heart failure using 28-day exposure windows (95% CI for both, 1.1­-2 and 1.26-1.69). No increased risk emerged for celecoxib or naproxen.

“High age and A1c levels and being a new user were tied to the strongest associations, along with known use of RASi [renin-angiotensin system inhibitors] and diuretics,” Dr. Holt said. “On the contrary, it seemed safe – from our data – to prescribe short-term NSAIDs for patients below 65 years of age and patients with normal A1c levels.

“Interestingly,” he added, “subclinical structural heart disease among patients with type 2 diabetes could play an important role.”

The findings are noteworthy, Dr. Busui said. “Although there are some limitations with the study design in general when one looks at data extracted from registers, the very large sample size and the fact that the Danish national register captures data in a standardized fashion does make the findings very relevant, especially now that we have confirmed that heart failure is the most prevalent cardiovascular complication in people with diabetes, as we have highlighted in the most recent ADA/ACC consensus on heart failure in diabetes.”

The study received funding from the Danish Heart Foundation and a number of private foundations. Dr. Holt and colleagues have no disclosures. Dr. Busui disclosed relationships with AstraZeneca, Boehringer Ingelheim–Lilly Alliance, Novo Nordisk, Averitas Pharma, Nevro, Regenacy Pharmaceuticals and Roche Diagnostics.

 

Psilocybin paired with psychotherapy is associated with a robust and sustained decrease in drinking among adults with alcohol use disorder (AUD), new research suggests.

Results from the first randomized, placebo-controlled trial of psilocybin for alcohol dependence showed that during the 8 months after first treatment dose, participants who received psilocybin had less than half as many heavy drinking days as their counterparts who received placebo.

In addition, 7 months after the last dose of medication, twice as many psilocybin-treated patients as placebo-treated patients were abstinent.

The effects observed with psilocybin were “considerably larger” than those of currently approved treatments for AUD, senior investigator Michael Bogenschutz, MD, psychiatrist and director of the NYU Langone Center for Psychedelic Medicine, New York, said during an Aug. 24 press briefing.

If the findings hold up in future trials, psilocybin will be a “real breakthrough” in the treatment of the condition, Dr. Bogenschutz said.

The findings were published online in JAMA Psychiatry.

83% reduction in drinking days

The study included 93 adults (mean age, 46 years) with alcohol dependence who consumed an average of seven drinks on the days they drank and had had at least four heavy drinking days during the month prior to treatment.

Of the participants, 48 were randomly assigned to receive two doses of psilocybin, and 45 were assigned to receive an antihistamine (diphenhydramine) placebo. Study medication was administered during 2 day-long sessions at week 4 and week 8.

The participants also received 12 psychotherapy sessions over a 12-week period. All were assessed at intervals from the beginning of the study until 32 weeks after the first medication session.

The primary outcome was percentage of days in which the patient drank heavily during the 32-week period following first medication dose. Heavy drinking was defined as having five or more drinks in a day for a man and four or more drinks in a day for a woman.

The percentage of heavy drinking days during the 32-week period was 9.7% for the psilocybin group and 23.6% for the placebo group, for a mean difference of 13.9% (P = .01).

“Compared to their baseline before the study, after receiving medication, the psilocybin group decreased their heavy drinking days by 83%, while the placebo group reduced their heavy drinking by 51%,” Dr. Bogenschutz reported.

During the last month of follow-up, which was 7 months after the final dose of study medication, 48% of the psilocybin group were entirely abstinent vs. 24% of the placebo group.

“It is remarkable that the effects of psilocybin treatment persisted for 7 months after people received the last dose of medication. This suggests that psilocybin is treating the underlying disorder of alcohol addiction rather than merely treating symptoms,” Dr. Bogenschutz noted.

Total alcohol consumption and problems related to alcohol use were also significantly less in the psilocybin group.

‘Encouraged and hopeful’

Adverse events related to psilocybin were mostly mild, self-limiting, and consistent with other recent trials that evaluated the drug’s effects in various conditions.

However, the current investigators note that they implemented measures to ensure safety, including careful medical and psychiatric screening, therapy, and monitoring that was provided by well-trained therapists, including a licensed psychiatrist. In addition, medications were available to treat acute psychiatric reactions.

A cited limitation of the study was that blinding was not maintained because the average intensity of experience with psilocybin was high, whereas it was low with diphenhydramine.

This difference undermined the masking of treatment such that more than 90% of participants and therapists correctly guessed the treatment assignment.

Another limitation was that objective measures to validate self-reported drinking outcomes were available for only 54% of study participants.

Despite these limitations, the study builds on earlier work by the NYU team that showed that two doses of psilocybin taken over a period of 8 weeks significantly reduced alcohol use and cravings in patients with AUD.

“We’re very encouraged by these findings and hopeful about where they could lead. Personally, it’s been very meaningful and rewarding for me to do this work and inspiring to witness the remarkable recoveries that some of our participants have experienced,” Dr. Bogenschutz told briefing attendees.

Urgent need

The authors of an accompanying editorial note that novel medications for alcohol dependence are “sorely needed. Recent renewed interest in the potential of hallucinogens for treating psychiatric disorders, including AUD, represents a potential move in that direction.”

Henry Kranzler, MD, and Emily Hartwell, PhD, both with the Center for Studies of Addiction, University of Pennsylvania, Philadelphia, write that the new findings “underscore the potential of developing psilocybin as an addition to the alcohol treatment pharmacopeia.”

They question, however, the feasibility of using hallucinogens in routine clinical practice because intensive psychotherapy, such as that provided in this study, requires a significant investment of time and labor.

“Such concomitant therapy, if necessary to realize the therapeutic benefits of psilocybin for treating AUD, could limit its uptake by clinicians,” Dr. Kranzler and Dr. Hartwell write.

The study was funded by the Heffter Research Institute and by individual donations from Carey and Claudia Turnbull, Dr. Efrem Nulman, Rodrigo Niño, and Cody Swift. Dr. Bogenschutz reports having received research funds from and serving as a consultant to Mind Medicine, the Multidisciplinary Association for Psychedelic Studies, B. More, AJNA Labs, Beckley Psytech, Journey Colab, and Bright Minds Biosciences. Dr. Kranzler and Dr. Hartwell have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Psilocybin paired with psychotherapy is associated with a robust and sustained decrease in drinking among adults with alcohol use disorder (AUD), new research suggests.

Results from the first randomized, placebo-controlled trial of psilocybin for alcohol dependence showed that during the 8 months after first treatment dose, participants who received psilocybin had less than half as many heavy drinking days as their counterparts who received placebo.

In addition, 7 months after the last dose of medication, twice as many psilocybin-treated patients as placebo-treated patients were abstinent.

The effects observed with psilocybin were “considerably larger” than those of currently approved treatments for AUD, senior investigator Michael Bogenschutz, MD, psychiatrist and director of the NYU Langone Center for Psychedelic Medicine, New York, said during an Aug. 24 press briefing.

If the findings hold up in future trials, psilocybin will be a “real breakthrough” in the treatment of the condition, Dr. Bogenschutz said.

The findings were published online in JAMA Psychiatry.

83% reduction in drinking days

The study included 93 adults (mean age, 46 years) with alcohol dependence who consumed an average of seven drinks on the days they drank and had had at least four heavy drinking days during the month prior to treatment.

Of the participants, 48 were randomly assigned to receive two doses of psilocybin, and 45 were assigned to receive an antihistamine (diphenhydramine) placebo. Study medication was administered during 2 day-long sessions at week 4 and week 8.

The participants also received 12 psychotherapy sessions over a 12-week period. All were assessed at intervals from the beginning of the study until 32 weeks after the first medication session.

The primary outcome was percentage of days in which the patient drank heavily during the 32-week period following first medication dose. Heavy drinking was defined as having five or more drinks in a day for a man and four or more drinks in a day for a woman.

The percentage of heavy drinking days during the 32-week period was 9.7% for the psilocybin group and 23.6% for the placebo group, for a mean difference of 13.9% (P = .01).

“Compared to their baseline before the study, after receiving medication, the psilocybin group decreased their heavy drinking days by 83%, while the placebo group reduced their heavy drinking by 51%,” Dr. Bogenschutz reported.

During the last month of follow-up, which was 7 months after the final dose of study medication, 48% of the psilocybin group were entirely abstinent vs. 24% of the placebo group.

“It is remarkable that the effects of psilocybin treatment persisted for 7 months after people received the last dose of medication. This suggests that psilocybin is treating the underlying disorder of alcohol addiction rather than merely treating symptoms,” Dr. Bogenschutz noted.

Total alcohol consumption and problems related to alcohol use were also significantly less in the psilocybin group.

‘Encouraged and hopeful’

Adverse events related to psilocybin were mostly mild, self-limiting, and consistent with other recent trials that evaluated the drug’s effects in various conditions.

However, the current investigators note that they implemented measures to ensure safety, including careful medical and psychiatric screening, therapy, and monitoring that was provided by well-trained therapists, including a licensed psychiatrist. In addition, medications were available to treat acute psychiatric reactions.

A cited limitation of the study was that blinding was not maintained because the average intensity of experience with psilocybin was high, whereas it was low with diphenhydramine.

This difference undermined the masking of treatment such that more than 90% of participants and therapists correctly guessed the treatment assignment.

Another limitation was that objective measures to validate self-reported drinking outcomes were available for only 54% of study participants.

Despite these limitations, the study builds on earlier work by the NYU team that showed that two doses of psilocybin taken over a period of 8 weeks significantly reduced alcohol use and cravings in patients with AUD.

“We’re very encouraged by these findings and hopeful about where they could lead. Personally, it’s been very meaningful and rewarding for me to do this work and inspiring to witness the remarkable recoveries that some of our participants have experienced,” Dr. Bogenschutz told briefing attendees.

Urgent need

The authors of an accompanying editorial note that novel medications for alcohol dependence are “sorely needed. Recent renewed interest in the potential of hallucinogens for treating psychiatric disorders, including AUD, represents a potential move in that direction.”

Henry Kranzler, MD, and Emily Hartwell, PhD, both with the Center for Studies of Addiction, University of Pennsylvania, Philadelphia, write that the new findings “underscore the potential of developing psilocybin as an addition to the alcohol treatment pharmacopeia.”

They question, however, the feasibility of using hallucinogens in routine clinical practice because intensive psychotherapy, such as that provided in this study, requires a significant investment of time and labor.

“Such concomitant therapy, if necessary to realize the therapeutic benefits of psilocybin for treating AUD, could limit its uptake by clinicians,” Dr. Kranzler and Dr. Hartwell write.

The study was funded by the Heffter Research Institute and by individual donations from Carey and Claudia Turnbull, Dr. Efrem Nulman, Rodrigo Niño, and Cody Swift. Dr. Bogenschutz reports having received research funds from and serving as a consultant to Mind Medicine, the Multidisciplinary Association for Psychedelic Studies, B. More, AJNA Labs, Beckley Psytech, Journey Colab, and Bright Minds Biosciences. Dr. Kranzler and Dr. Hartwell have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Psilocybin paired with psychotherapy is associated with a robust and sustained decrease in drinking among adults with alcohol use disorder (AUD), new research suggests.

Results from the first randomized, placebo-controlled trial of psilocybin for alcohol dependence showed that during the 8 months after first treatment dose, participants who received psilocybin had less than half as many heavy drinking days as their counterparts who received placebo.

In addition, 7 months after the last dose of medication, twice as many psilocybin-treated patients as placebo-treated patients were abstinent.

The effects observed with psilocybin were “considerably larger” than those of currently approved treatments for AUD, senior investigator Michael Bogenschutz, MD, psychiatrist and director of the NYU Langone Center for Psychedelic Medicine, New York, said during an Aug. 24 press briefing.

If the findings hold up in future trials, psilocybin will be a “real breakthrough” in the treatment of the condition, Dr. Bogenschutz said.

The findings were published online in JAMA Psychiatry.

83% reduction in drinking days

The study included 93 adults (mean age, 46 years) with alcohol dependence who consumed an average of seven drinks on the days they drank and had had at least four heavy drinking days during the month prior to treatment.

Of the participants, 48 were randomly assigned to receive two doses of psilocybin, and 45 were assigned to receive an antihistamine (diphenhydramine) placebo. Study medication was administered during 2 day-long sessions at week 4 and week 8.

The participants also received 12 psychotherapy sessions over a 12-week period. All were assessed at intervals from the beginning of the study until 32 weeks after the first medication session.

The primary outcome was percentage of days in which the patient drank heavily during the 32-week period following first medication dose. Heavy drinking was defined as having five or more drinks in a day for a man and four or more drinks in a day for a woman.

The percentage of heavy drinking days during the 32-week period was 9.7% for the psilocybin group and 23.6% for the placebo group, for a mean difference of 13.9% (P = .01).

“Compared to their baseline before the study, after receiving medication, the psilocybin group decreased their heavy drinking days by 83%, while the placebo group reduced their heavy drinking by 51%,” Dr. Bogenschutz reported.

During the last month of follow-up, which was 7 months after the final dose of study medication, 48% of the psilocybin group were entirely abstinent vs. 24% of the placebo group.

“It is remarkable that the effects of psilocybin treatment persisted for 7 months after people received the last dose of medication. This suggests that psilocybin is treating the underlying disorder of alcohol addiction rather than merely treating symptoms,” Dr. Bogenschutz noted.

Total alcohol consumption and problems related to alcohol use were also significantly less in the psilocybin group.

‘Encouraged and hopeful’

Adverse events related to psilocybin were mostly mild, self-limiting, and consistent with other recent trials that evaluated the drug’s effects in various conditions.

However, the current investigators note that they implemented measures to ensure safety, including careful medical and psychiatric screening, therapy, and monitoring that was provided by well-trained therapists, including a licensed psychiatrist. In addition, medications were available to treat acute psychiatric reactions.

A cited limitation of the study was that blinding was not maintained because the average intensity of experience with psilocybin was high, whereas it was low with diphenhydramine.

This difference undermined the masking of treatment such that more than 90% of participants and therapists correctly guessed the treatment assignment.

Another limitation was that objective measures to validate self-reported drinking outcomes were available for only 54% of study participants.

Despite these limitations, the study builds on earlier work by the NYU team that showed that two doses of psilocybin taken over a period of 8 weeks significantly reduced alcohol use and cravings in patients with AUD.

“We’re very encouraged by these findings and hopeful about where they could lead. Personally, it’s been very meaningful and rewarding for me to do this work and inspiring to witness the remarkable recoveries that some of our participants have experienced,” Dr. Bogenschutz told briefing attendees.

Urgent need

The authors of an accompanying editorial note that novel medications for alcohol dependence are “sorely needed. Recent renewed interest in the potential of hallucinogens for treating psychiatric disorders, including AUD, represents a potential move in that direction.”

Henry Kranzler, MD, and Emily Hartwell, PhD, both with the Center for Studies of Addiction, University of Pennsylvania, Philadelphia, write that the new findings “underscore the potential of developing psilocybin as an addition to the alcohol treatment pharmacopeia.”

They question, however, the feasibility of using hallucinogens in routine clinical practice because intensive psychotherapy, such as that provided in this study, requires a significant investment of time and labor.

“Such concomitant therapy, if necessary to realize the therapeutic benefits of psilocybin for treating AUD, could limit its uptake by clinicians,” Dr. Kranzler and Dr. Hartwell write.

The study was funded by the Heffter Research Institute and by individual donations from Carey and Claudia Turnbull, Dr. Efrem Nulman, Rodrigo Niño, and Cody Swift. Dr. Bogenschutz reports having received research funds from and serving as a consultant to Mind Medicine, the Multidisciplinary Association for Psychedelic Studies, B. More, AJNA Labs, Beckley Psytech, Journey Colab, and Bright Minds Biosciences. Dr. Kranzler and Dr. Hartwell have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.