The small-molecule tyrosine kinase inhibitor neratinib is now approved for the extended adjuvant treatment of patients with early-stage HER2 [human epidermal growth factor receptor]-positive breast cancer following postoperative trastuzumab. Trastuzumab is a HER2-targeted monoclonal antibody that has become standard of care in combination with chemotherapy for the treatment of this patient population in which it significantly improves survival. However, disease recurrence will occur in about a quarter of trastuzumab-treated patients owing to the development of resistance.

Neratinib may help overcome trastuzumab resistance thanks to its potent inhibition of the downstream phosphorylation of HER2 and other members of the HER family. Its approval was based on the phase 3 ExteNET trial, in which extended adjuvant treatment with neratinib was compared with placebo among 2,840 patients who remained disease free after 1 year of adjuvant trastuzumab.¹

The ExteNET trial was performed at 495 centers in Europe, Asia, Australia, New Zealand, and South America. Patients aged 18 years or older (≥20 years in Japan), with stage 1-3 HER2-positive breast cancer, who completed neoadjuvant and adjuvant trastuzumab therapy up to 1 year before randomization were eligible. Patients also had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), normal organ function, and a left ventricular ejection fraction within normal institutional range. Patients with clinically significant cardiac, gastrointesintal or psychiatric comorbidities and those who were not able to swallow oral medication were excluded from the study.

Patients randomly received oral neratinib 240 mg per day or matching placebo, and randomization was stratified according to HR status (positive or negative), nodal status (0, 1-3, or ≥4) and trastuzumab-adjuvant regimen (sequentially or concurrently with chemotherapy).

The primary outcome was invasive disease-free survival (iDFS). The 2-year iDFS rate was 93.9% for neratinib, compared with 91.6% for placebo (hazard ratio [HR], 0.66; P < .008). Recently, a 5-year analysis of the ExteNET trial showed that after a median follow-up of 5.2 years, the iDFS rates were 90.2% vs 87.7% (HR, 0.73; P = .0083).²

Adverse events

The most common adverse event (AE) was diarrhea, in 95% of patients, 40% of whom had grade 3 diarrhea, leading to dose reduction in 26% of patients and discontinuation in 16.8% of patients. Serious AEs occurred in 7% of patients in the neratinib and 6% of those in the placebo arms. In the 5-year analysis, there was no evidence of increased risk of long-term toxicity or adverse consequences of neratinib-associated diarrhea. Furthermore, the ongoing, open-label phase 2 CONTROL trial suggests that the occurrence and severity of neratinib-associated diarrhea can be effectively controlled with antidiarrheal prophylaxis, with drugs such as loperamide.³

At the January 2017 cut-off, 137 patients treated with neratinib (240 mg/day) for 1 year had also received treatment with loperamide monotherapy, 64 patients had received loperamide and budesonide, and 10 patients had received loperamide and colestipol. The safety data from the loperamide monotherapy arm were compared with the safety data from the ExteNET trial, which was based in a similar population of patients who did not receive antidiarrheal prophylaxis. The incidence of all-grade diarrhea was 77% vs 95%, respectively, for those who received antidiarrheal prophylaxis in the CONTROL trial compared with those in the ExteNET trial who did not, and the repective rates of grade 3 diarrhea were 31% and 40%. The rate of dose reductions and holds owing to diarrhea were also lower among those who received antidiarrheal prophylaxis, but the rate of discontinuation due to diarrhea was higher in the loperamide-treated cohort.
 

Warnings and precautions

Neratinib is marketed as Nerlynx by Puma Biotechnology Inc. The prescribing information describes warnings and precautions relating to diarrhea, hepatotoxicity, and embryofetal toxicity. Patients should be monitored for diarrhea and treated with antidiarrheals as needed. Severe diarrhea with dehydration should be treated with fluids and electrolytes as needed, treatment should be interrupted and resumed at a reduced dose. For grade 3/4 diarrhea or diarrhea with complicating features (eg, dehydration, fever, neutropenia), stool cultures should be performed to rule out infectious causes.

Total bilirubin, aspartate and alanine aminotransferase, and alkaline phosphatase levels should be measured before starting treatment, every 3 months during treatment, or as clinically indicated. Neratinib can cause fetal harm, so pregnant women should be advised of the risk to the fetus and patients of reproductive potential should be counseled on the need for effective contraception during treatment and for at least 1 month after the last dose.⁴

The small-molecule tyrosine kinase inhibitor neratinib is now approved for the extended adjuvant treatment of patients with early-stage HER2 [human epidermal growth factor receptor]-positive breast cancer following postoperative trastuzumab. Trastuzumab is a HER2-targeted monoclonal antibody that has become standard of care in combination with chemotherapy for the treatment of this patient population in which it significantly improves survival. However, disease recurrence will occur in about a quarter of trastuzumab-treated patients owing to the development of resistance.

Neratinib may help overcome trastuzumab resistance thanks to its potent inhibition of the downstream phosphorylation of HER2 and other members of the HER family. Its approval was based on the phase 3 ExteNET trial, in which extended adjuvant treatment with neratinib was compared with placebo among 2,840 patients who remained disease free after 1 year of adjuvant trastuzumab.¹

The ExteNET trial was performed at 495 centers in Europe, Asia, Australia, New Zealand, and South America. Patients aged 18 years or older (≥20 years in Japan), with stage 1-3 HER2-positive breast cancer, who completed neoadjuvant and adjuvant trastuzumab therapy up to 1 year before randomization were eligible. Patients also had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), normal organ function, and a left ventricular ejection fraction within normal institutional range. Patients with clinically significant cardiac, gastrointesintal or psychiatric comorbidities and those who were not able to swallow oral medication were excluded from the study.

Patients randomly received oral neratinib 240 mg per day or matching placebo, and randomization was stratified according to HR status (positive or negative), nodal status (0, 1-3, or ≥4) and trastuzumab-adjuvant regimen (sequentially or concurrently with chemotherapy).

The primary outcome was invasive disease-free survival (iDFS). The 2-year iDFS rate was 93.9% for neratinib, compared with 91.6% for placebo (hazard ratio [HR], 0.66; P < .008). Recently, a 5-year analysis of the ExteNET trial showed that after a median follow-up of 5.2 years, the iDFS rates were 90.2% vs 87.7% (HR, 0.73; P = .0083).²

Adverse events

The most common adverse event (AE) was diarrhea, in 95% of patients, 40% of whom had grade 3 diarrhea, leading to dose reduction in 26% of patients and discontinuation in 16.8% of patients. Serious AEs occurred in 7% of patients in the neratinib and 6% of those in the placebo arms. In the 5-year analysis, there was no evidence of increased risk of long-term toxicity or adverse consequences of neratinib-associated diarrhea. Furthermore, the ongoing, open-label phase 2 CONTROL trial suggests that the occurrence and severity of neratinib-associated diarrhea can be effectively controlled with antidiarrheal prophylaxis, with drugs such as loperamide.³

At the January 2017 cut-off, 137 patients treated with neratinib (240 mg/day) for 1 year had also received treatment with loperamide monotherapy, 64 patients had received loperamide and budesonide, and 10 patients had received loperamide and colestipol. The safety data from the loperamide monotherapy arm were compared with the safety data from the ExteNET trial, which was based in a similar population of patients who did not receive antidiarrheal prophylaxis. The incidence of all-grade diarrhea was 77% vs 95%, respectively, for those who received antidiarrheal prophylaxis in the CONTROL trial compared with those in the ExteNET trial who did not, and the repective rates of grade 3 diarrhea were 31% and 40%. The rate of dose reductions and holds owing to diarrhea were also lower among those who received antidiarrheal prophylaxis, but the rate of discontinuation due to diarrhea was higher in the loperamide-treated cohort.
 

Warnings and precautions

Neratinib is marketed as Nerlynx by Puma Biotechnology Inc. The prescribing information describes warnings and precautions relating to diarrhea, hepatotoxicity, and embryofetal toxicity. Patients should be monitored for diarrhea and treated with antidiarrheals as needed. Severe diarrhea with dehydration should be treated with fluids and electrolytes as needed, treatment should be interrupted and resumed at a reduced dose. For grade 3/4 diarrhea or diarrhea with complicating features (eg, dehydration, fever, neutropenia), stool cultures should be performed to rule out infectious causes.

Total bilirubin, aspartate and alanine aminotransferase, and alkaline phosphatase levels should be measured before starting treatment, every 3 months during treatment, or as clinically indicated. Neratinib can cause fetal harm, so pregnant women should be advised of the risk to the fetus and patients of reproductive potential should be counseled on the need for effective contraception during treatment and for at least 1 month after the last dose.⁴

The small-molecule tyrosine kinase inhibitor neratinib is now approved for the extended adjuvant treatment of patients with early-stage HER2 [human epidermal growth factor receptor]-positive breast cancer following postoperative trastuzumab. Trastuzumab is a HER2-targeted monoclonal antibody that has become standard of care in combination with chemotherapy for the treatment of this patient population in which it significantly improves survival. However, disease recurrence will occur in about a quarter of trastuzumab-treated patients owing to the development of resistance.

Neratinib may help overcome trastuzumab resistance thanks to its potent inhibition of the downstream phosphorylation of HER2 and other members of the HER family. Its approval was based on the phase 3 ExteNET trial, in which extended adjuvant treatment with neratinib was compared with placebo among 2,840 patients who remained disease free after 1 year of adjuvant trastuzumab.¹

The ExteNET trial was performed at 495 centers in Europe, Asia, Australia, New Zealand, and South America. Patients aged 18 years or older (≥20 years in Japan), with stage 1-3 HER2-positive breast cancer, who completed neoadjuvant and adjuvant trastuzumab therapy up to 1 year before randomization were eligible. Patients also had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (range, 0-5; 0, fully active, and 5, dead), normal organ function, and a left ventricular ejection fraction within normal institutional range. Patients with clinically significant cardiac, gastrointesintal or psychiatric comorbidities and those who were not able to swallow oral medication were excluded from the study.

Patients randomly received oral neratinib 240 mg per day or matching placebo, and randomization was stratified according to HR status (positive or negative), nodal status (0, 1-3, or ≥4) and trastuzumab-adjuvant regimen (sequentially or concurrently with chemotherapy).

The primary outcome was invasive disease-free survival (iDFS). The 2-year iDFS rate was 93.9% for neratinib, compared with 91.6% for placebo (hazard ratio [HR], 0.66; P < .008). Recently, a 5-year analysis of the ExteNET trial showed that after a median follow-up of 5.2 years, the iDFS rates were 90.2% vs 87.7% (HR, 0.73; P = .0083).²

Adverse events

The most common adverse event (AE) was diarrhea, in 95% of patients, 40% of whom had grade 3 diarrhea, leading to dose reduction in 26% of patients and discontinuation in 16.8% of patients. Serious AEs occurred in 7% of patients in the neratinib and 6% of those in the placebo arms. In the 5-year analysis, there was no evidence of increased risk of long-term toxicity or adverse consequences of neratinib-associated diarrhea. Furthermore, the ongoing, open-label phase 2 CONTROL trial suggests that the occurrence and severity of neratinib-associated diarrhea can be effectively controlled with antidiarrheal prophylaxis, with drugs such as loperamide.³

At the January 2017 cut-off, 137 patients treated with neratinib (240 mg/day) for 1 year had also received treatment with loperamide monotherapy, 64 patients had received loperamide and budesonide, and 10 patients had received loperamide and colestipol. The safety data from the loperamide monotherapy arm were compared with the safety data from the ExteNET trial, which was based in a similar population of patients who did not receive antidiarrheal prophylaxis. The incidence of all-grade diarrhea was 77% vs 95%, respectively, for those who received antidiarrheal prophylaxis in the CONTROL trial compared with those in the ExteNET trial who did not, and the repective rates of grade 3 diarrhea were 31% and 40%. The rate of dose reductions and holds owing to diarrhea were also lower among those who received antidiarrheal prophylaxis, but the rate of discontinuation due to diarrhea was higher in the loperamide-treated cohort.
 

Warnings and precautions

Neratinib is marketed as Nerlynx by Puma Biotechnology Inc. The prescribing information describes warnings and precautions relating to diarrhea, hepatotoxicity, and embryofetal toxicity. Patients should be monitored for diarrhea and treated with antidiarrheals as needed. Severe diarrhea with dehydration should be treated with fluids and electrolytes as needed, treatment should be interrupted and resumed at a reduced dose. For grade 3/4 diarrhea or diarrhea with complicating features (eg, dehydration, fever, neutropenia), stool cultures should be performed to rule out infectious causes.

Total bilirubin, aspartate and alanine aminotransferase, and alkaline phosphatase levels should be measured before starting treatment, every 3 months during treatment, or as clinically indicated. Neratinib can cause fetal harm, so pregnant women should be advised of the risk to the fetus and patients of reproductive potential should be counseled on the need for effective contraception during treatment and for at least 1 month after the last dose.⁴

Biosimilars are copies of FDA-approved biologic drugs (those generally derived from a living organism) that cannot be identical to the reference drug but demonstrate a high similarity to it. As patents on the reference drugs expire, biosimilars are being developed to increase competition in the marketplace to reduce costs and improve patient access to therapy. Although the US Food and Drug Administration (FDA) has no regulatory power over drug prices, it recently announced efforts to streamline the biosimilar approval process to facilitate access to therapies and curb the associated skyrocketing costs.

Several biosimilars have been approved by the agency in recent years, and earlier this year they were joined by 2 more: the approval in May of epoetin alfa-epbx (Retacrit; Hospira, a Pfizer company) for all indications of the reference product (epoetin alfa; Epogen/Procrit, Amgen), including the treatment of anemia caused by myelosuppressive chemotherapy, when there is a minimum of 2 additional months of planned chemotherapy;¹ and the June approval of pegfilgrastim-jmdb (Fulphila, Mylan and Biocon) for the treatment of patients undergoing myelosuppressive chemotherapy to help reduce the chance of infection as suggested by febrile neutropenia (fever, often with other signs of infection, associated with an abnormally low number of infection-fighting white blood cells).² The reference product for pegfilgrastim-jmdb is pegfilgrastim (Neulasta, Amgen).

The approval of both biosimilars was based on a review of a body of evidence that included structural and functional characterization, animal study data, human pharmacokinetic (PK) and pharmacodynamic (PD) data, clinical immunogenicity data, and other clinical safety and efficacy data. This evidence established that the biosimilars were highly similar to the already FDA-approved reference products, with no clinically relevant differences.



Biocon and Mylan-GmBH, which jointly developed pegfilgrastim-jmdb, originally filed for approval in 2017; and Hospira Inc, a Pfizer company that developed epoetin alfa-epbx, filed for the first time in 2015. They subsequently received complete response letters from the FDA, twice in the case of the epoetin alfa biosimilar, rejecting their approval. For pegfilgrastim-jmdb, the complete response letter was related to a pending update of the Biologic License Application as the result of requalification activities taken because of modifications at their manufacturing plant. For epoetin alfa-epbx, the FDA expressed concerns relating to a manufacturing facility. The companies addressed the concerns in the complete response letters and submitted corrective and preventive action plans.^3,4

Pegfilgrastim-jmdb

The results from a phase 3, multicenter, randomized, double-blind parallel-group trial of pegfilgrastim-jmdb compared with European Union-approved pegfilgrastim were published in 2016. Chemotherapy and radiation-naïve patients with newly diagnosed breast cancer (n = 194) received the biosimilar or reference product every 3 weeks for 6 cycles. The primary endpoint was duration of severe neutropenia in cycle 1, defined as days with absolute neutrophil count <0.5 x 10⁹/L. The mean standard deviation was 1.2 [0.93] in the pegfilgrastim-jmdb arm and 1.2 [1.10] in the EU-pegfilgrastim arm, and the 95% confidence interval of least squares means differences was within the -1 day, +1 day range, indicating equivalency.⁵

A characterization and similarity assessment of pegfilgrastim-jmdb compared with US- and EU-approved pegfilgrastim was presented at the 2018 Annual Meeting of the American Society of Clinical Oncology. G-CSF receptor (G-CSFR) binding was assessed by surface plasmon resonance and potency was measured by in vitro stimulated proliferation in a mouse myelogenous leukemia cell line. In vivo rodent studies were also performed and included a PD study with a single dose of up to 3 mg/kg.⁶

There was high similarity in the structure, molecular mass, impurities and functional activity of the biosimilar and reference products, as well as similar G-CSFR binding and equivalent relative potency. Neutrophil and leukocyte counts were increased to a similar degree, and toxicology and drug kinetics were also comparable.

The recommended dose of pegfilgrastim-jmdb is a 6 mg/0.6 ml injection in a single-dose prefilled syringe for manual use only, administered subcutaneously once per chemotherapy cycle. The prescribing information also has dosing guidelines for administration in pediatric patients who weigh less than 45 kg. Pegfilgrastim-jmdb should not be administered between 14 days before and 24 hours after administration of chemotherapy.

The prescribing information details warnings and precautions relating to splenic rupture, acute respiratory distress syndrome (ARDS), serious allergic reactions, potential for severe/fatal sickle cell crises in patients with sickle cell disorders, glomerulonephritis, leukocytosis, capillary leak syndrome, and the potential for tumor growth or recurrence.⁷

Patients should be evaluated for an enlarged spleen or splenic rupture if they report upper left abdominal or shoulder pain. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated for ARDS and treatment discontinued if a diagnosis is confirmed. Pegfilgrastim-jmdb should be permanently discontinued in patients who develop serious allergic reactions and should not be used in patients with a history of serious allergic reactions to pegfilgrastim or filgrastim products.

Dose-reduction or interruption should be considered in patients who develop glomerulonephritis. Complete blood counts should be monitored throughout treatment. Patients should be monitored closely for capillary leak syndrome and treated with standard therapy. Pegfilgrastim-jmdb is marketed as Fulphila.

Epoetin alfa-epbx

Epoetin alfa-epbx was evaluated in 2 clinical trials in healthy individuals. The EPOE-12-02 trial established the PK and PD following a single subcutaneous dose of 100 U/kg in 81 participants. The EPOE-14-1 study was designed to determine the PK and PD of multiple doses of subcutaneous 100 U/kg 3 times weekly for 3 weeks in 129 participants. Both studies met prespecified criteria for PK and PD similarity to US-approved epoetin alfa, including geometric mean of area under the curve (AUC)0-120h, AUC0-inf, C_max (maximum serum concentration achieved by a drug in a specified area of the body) and E_max (maximum response achievable for a drug dose).

Evidence of efficacy and safety were also evaluated using pooled data from EPOE-10-13 and EPOE-10-01, conducted in patients with chronic kidney disease, which was considered the most sensitive population in which to evaluate clinically meaningful differences between the biosimilar and reference product.^8,9

There were no clinically meaningful differences in efficacy and a similar adverse event profile. The most common side effects include high blood pressure, joint pain, muscle spasm, fever, dizziness, respiratory infection, and cough, among others.

The recommended dose of epoetin alfa-epbx, which is marketed as Retacrit, is 40,000 Units weekly or 150 U/kg 3 times weekly in adults and 600 U/kg intravenously weekly in pediatric patients aged 5 years or younger. Epoetin alfa-epbx comes with a boxed warning to alert health care providers to the increased risks of death, heart problems, stroke, and tumor growth, or recurrence. The prescribing information also details warnings and precautions relating to these risks, as well as hypertension, seizures, lack or loss of hemoglobin response, pure red cell aplasia, serious allergic reactions, and severe cutaneous reactions.⁹

Blood pressure should be appropriately controlled before treatment initiation, treatment should be reduced or withheld if it becomes uncontrollable, and patients should be advised of the importance of compliance with anti-hypertensive medication and dietary restrictions. Patients should be monitored closely for premonitory neurologic symptoms and advised to contact their provider in the event of new-onset seizures, premonitory symptoms, or change in seizure frequency.

The prescribing information has dosing recommendations for lack or loss of hemoglobin response to epoetin alfa-epbx. If severe anemia or low reticulocyte count occur, treatment should be withheld and patients evaluated for neutralizing antibodies to erythropoietin and, in the event that PRCA is confirmed, treatment should be permanently discontinued. Treatment should be immediately and permanently discontinued for serious allergic reactions or severe cutaneous reactions.

Biosimilars are copies of FDA-approved biologic drugs (those generally derived from a living organism) that cannot be identical to the reference drug but demonstrate a high similarity to it. As patents on the reference drugs expire, biosimilars are being developed to increase competition in the marketplace to reduce costs and improve patient access to therapy. Although the US Food and Drug Administration (FDA) has no regulatory power over drug prices, it recently announced efforts to streamline the biosimilar approval process to facilitate access to therapies and curb the associated skyrocketing costs.

Several biosimilars have been approved by the agency in recent years, and earlier this year they were joined by 2 more: the approval in May of epoetin alfa-epbx (Retacrit; Hospira, a Pfizer company) for all indications of the reference product (epoetin alfa; Epogen/Procrit, Amgen), including the treatment of anemia caused by myelosuppressive chemotherapy, when there is a minimum of 2 additional months of planned chemotherapy;¹ and the June approval of pegfilgrastim-jmdb (Fulphila, Mylan and Biocon) for the treatment of patients undergoing myelosuppressive chemotherapy to help reduce the chance of infection as suggested by febrile neutropenia (fever, often with other signs of infection, associated with an abnormally low number of infection-fighting white blood cells).² The reference product for pegfilgrastim-jmdb is pegfilgrastim (Neulasta, Amgen).

The approval of both biosimilars was based on a review of a body of evidence that included structural and functional characterization, animal study data, human pharmacokinetic (PK) and pharmacodynamic (PD) data, clinical immunogenicity data, and other clinical safety and efficacy data. This evidence established that the biosimilars were highly similar to the already FDA-approved reference products, with no clinically relevant differences.



Biocon and Mylan-GmBH, which jointly developed pegfilgrastim-jmdb, originally filed for approval in 2017; and Hospira Inc, a Pfizer company that developed epoetin alfa-epbx, filed for the first time in 2015. They subsequently received complete response letters from the FDA, twice in the case of the epoetin alfa biosimilar, rejecting their approval. For pegfilgrastim-jmdb, the complete response letter was related to a pending update of the Biologic License Application as the result of requalification activities taken because of modifications at their manufacturing plant. For epoetin alfa-epbx, the FDA expressed concerns relating to a manufacturing facility. The companies addressed the concerns in the complete response letters and submitted corrective and preventive action plans.^3,4

Pegfilgrastim-jmdb

The results from a phase 3, multicenter, randomized, double-blind parallel-group trial of pegfilgrastim-jmdb compared with European Union-approved pegfilgrastim were published in 2016. Chemotherapy and radiation-naïve patients with newly diagnosed breast cancer (n = 194) received the biosimilar or reference product every 3 weeks for 6 cycles. The primary endpoint was duration of severe neutropenia in cycle 1, defined as days with absolute neutrophil count <0.5 x 10⁹/L. The mean standard deviation was 1.2 [0.93] in the pegfilgrastim-jmdb arm and 1.2 [1.10] in the EU-pegfilgrastim arm, and the 95% confidence interval of least squares means differences was within the -1 day, +1 day range, indicating equivalency.⁵

A characterization and similarity assessment of pegfilgrastim-jmdb compared with US- and EU-approved pegfilgrastim was presented at the 2018 Annual Meeting of the American Society of Clinical Oncology. G-CSF receptor (G-CSFR) binding was assessed by surface plasmon resonance and potency was measured by in vitro stimulated proliferation in a mouse myelogenous leukemia cell line. In vivo rodent studies were also performed and included a PD study with a single dose of up to 3 mg/kg.⁶

There was high similarity in the structure, molecular mass, impurities and functional activity of the biosimilar and reference products, as well as similar G-CSFR binding and equivalent relative potency. Neutrophil and leukocyte counts were increased to a similar degree, and toxicology and drug kinetics were also comparable.

The recommended dose of pegfilgrastim-jmdb is a 6 mg/0.6 ml injection in a single-dose prefilled syringe for manual use only, administered subcutaneously once per chemotherapy cycle. The prescribing information also has dosing guidelines for administration in pediatric patients who weigh less than 45 kg. Pegfilgrastim-jmdb should not be administered between 14 days before and 24 hours after administration of chemotherapy.

The prescribing information details warnings and precautions relating to splenic rupture, acute respiratory distress syndrome (ARDS), serious allergic reactions, potential for severe/fatal sickle cell crises in patients with sickle cell disorders, glomerulonephritis, leukocytosis, capillary leak syndrome, and the potential for tumor growth or recurrence.⁷

Patients should be evaluated for an enlarged spleen or splenic rupture if they report upper left abdominal or shoulder pain. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated for ARDS and treatment discontinued if a diagnosis is confirmed. Pegfilgrastim-jmdb should be permanently discontinued in patients who develop serious allergic reactions and should not be used in patients with a history of serious allergic reactions to pegfilgrastim or filgrastim products.

Dose-reduction or interruption should be considered in patients who develop glomerulonephritis. Complete blood counts should be monitored throughout treatment. Patients should be monitored closely for capillary leak syndrome and treated with standard therapy. Pegfilgrastim-jmdb is marketed as Fulphila.

Epoetin alfa-epbx

Epoetin alfa-epbx was evaluated in 2 clinical trials in healthy individuals. The EPOE-12-02 trial established the PK and PD following a single subcutaneous dose of 100 U/kg in 81 participants. The EPOE-14-1 study was designed to determine the PK and PD of multiple doses of subcutaneous 100 U/kg 3 times weekly for 3 weeks in 129 participants. Both studies met prespecified criteria for PK and PD similarity to US-approved epoetin alfa, including geometric mean of area under the curve (AUC)0-120h, AUC0-inf, C_max (maximum serum concentration achieved by a drug in a specified area of the body) and E_max (maximum response achievable for a drug dose).

Evidence of efficacy and safety were also evaluated using pooled data from EPOE-10-13 and EPOE-10-01, conducted in patients with chronic kidney disease, which was considered the most sensitive population in which to evaluate clinically meaningful differences between the biosimilar and reference product.^8,9

There were no clinically meaningful differences in efficacy and a similar adverse event profile. The most common side effects include high blood pressure, joint pain, muscle spasm, fever, dizziness, respiratory infection, and cough, among others.

The recommended dose of epoetin alfa-epbx, which is marketed as Retacrit, is 40,000 Units weekly or 150 U/kg 3 times weekly in adults and 600 U/kg intravenously weekly in pediatric patients aged 5 years or younger. Epoetin alfa-epbx comes with a boxed warning to alert health care providers to the increased risks of death, heart problems, stroke, and tumor growth, or recurrence. The prescribing information also details warnings and precautions relating to these risks, as well as hypertension, seizures, lack or loss of hemoglobin response, pure red cell aplasia, serious allergic reactions, and severe cutaneous reactions.⁹

Blood pressure should be appropriately controlled before treatment initiation, treatment should be reduced or withheld if it becomes uncontrollable, and patients should be advised of the importance of compliance with anti-hypertensive medication and dietary restrictions. Patients should be monitored closely for premonitory neurologic symptoms and advised to contact their provider in the event of new-onset seizures, premonitory symptoms, or change in seizure frequency.

The prescribing information has dosing recommendations for lack or loss of hemoglobin response to epoetin alfa-epbx. If severe anemia or low reticulocyte count occur, treatment should be withheld and patients evaluated for neutralizing antibodies to erythropoietin and, in the event that PRCA is confirmed, treatment should be permanently discontinued. Treatment should be immediately and permanently discontinued for serious allergic reactions or severe cutaneous reactions.

Biosimilars are copies of FDA-approved biologic drugs (those generally derived from a living organism) that cannot be identical to the reference drug but demonstrate a high similarity to it. As patents on the reference drugs expire, biosimilars are being developed to increase competition in the marketplace to reduce costs and improve patient access to therapy. Although the US Food and Drug Administration (FDA) has no regulatory power over drug prices, it recently announced efforts to streamline the biosimilar approval process to facilitate access to therapies and curb the associated skyrocketing costs.

Several biosimilars have been approved by the agency in recent years, and earlier this year they were joined by 2 more: the approval in May of epoetin alfa-epbx (Retacrit; Hospira, a Pfizer company) for all indications of the reference product (epoetin alfa; Epogen/Procrit, Amgen), including the treatment of anemia caused by myelosuppressive chemotherapy, when there is a minimum of 2 additional months of planned chemotherapy;¹ and the June approval of pegfilgrastim-jmdb (Fulphila, Mylan and Biocon) for the treatment of patients undergoing myelosuppressive chemotherapy to help reduce the chance of infection as suggested by febrile neutropenia (fever, often with other signs of infection, associated with an abnormally low number of infection-fighting white blood cells).² The reference product for pegfilgrastim-jmdb is pegfilgrastim (Neulasta, Amgen).

The approval of both biosimilars was based on a review of a body of evidence that included structural and functional characterization, animal study data, human pharmacokinetic (PK) and pharmacodynamic (PD) data, clinical immunogenicity data, and other clinical safety and efficacy data. This evidence established that the biosimilars were highly similar to the already FDA-approved reference products, with no clinically relevant differences.



Biocon and Mylan-GmBH, which jointly developed pegfilgrastim-jmdb, originally filed for approval in 2017; and Hospira Inc, a Pfizer company that developed epoetin alfa-epbx, filed for the first time in 2015. They subsequently received complete response letters from the FDA, twice in the case of the epoetin alfa biosimilar, rejecting their approval. For pegfilgrastim-jmdb, the complete response letter was related to a pending update of the Biologic License Application as the result of requalification activities taken because of modifications at their manufacturing plant. For epoetin alfa-epbx, the FDA expressed concerns relating to a manufacturing facility. The companies addressed the concerns in the complete response letters and submitted corrective and preventive action plans.^3,4

Pegfilgrastim-jmdb

The results from a phase 3, multicenter, randomized, double-blind parallel-group trial of pegfilgrastim-jmdb compared with European Union-approved pegfilgrastim were published in 2016. Chemotherapy and radiation-naïve patients with newly diagnosed breast cancer (n = 194) received the biosimilar or reference product every 3 weeks for 6 cycles. The primary endpoint was duration of severe neutropenia in cycle 1, defined as days with absolute neutrophil count <0.5 x 10⁹/L. The mean standard deviation was 1.2 [0.93] in the pegfilgrastim-jmdb arm and 1.2 [1.10] in the EU-pegfilgrastim arm, and the 95% confidence interval of least squares means differences was within the -1 day, +1 day range, indicating equivalency.⁵

A characterization and similarity assessment of pegfilgrastim-jmdb compared with US- and EU-approved pegfilgrastim was presented at the 2018 Annual Meeting of the American Society of Clinical Oncology. G-CSF receptor (G-CSFR) binding was assessed by surface plasmon resonance and potency was measured by in vitro stimulated proliferation in a mouse myelogenous leukemia cell line. In vivo rodent studies were also performed and included a PD study with a single dose of up to 3 mg/kg.⁶

There was high similarity in the structure, molecular mass, impurities and functional activity of the biosimilar and reference products, as well as similar G-CSFR binding and equivalent relative potency. Neutrophil and leukocyte counts were increased to a similar degree, and toxicology and drug kinetics were also comparable.

The recommended dose of pegfilgrastim-jmdb is a 6 mg/0.6 ml injection in a single-dose prefilled syringe for manual use only, administered subcutaneously once per chemotherapy cycle. The prescribing information also has dosing guidelines for administration in pediatric patients who weigh less than 45 kg. Pegfilgrastim-jmdb should not be administered between 14 days before and 24 hours after administration of chemotherapy.

The prescribing information details warnings and precautions relating to splenic rupture, acute respiratory distress syndrome (ARDS), serious allergic reactions, potential for severe/fatal sickle cell crises in patients with sickle cell disorders, glomerulonephritis, leukocytosis, capillary leak syndrome, and the potential for tumor growth or recurrence.⁷

Patients should be evaluated for an enlarged spleen or splenic rupture if they report upper left abdominal or shoulder pain. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated for ARDS and treatment discontinued if a diagnosis is confirmed. Pegfilgrastim-jmdb should be permanently discontinued in patients who develop serious allergic reactions and should not be used in patients with a history of serious allergic reactions to pegfilgrastim or filgrastim products.

Dose-reduction or interruption should be considered in patients who develop glomerulonephritis. Complete blood counts should be monitored throughout treatment. Patients should be monitored closely for capillary leak syndrome and treated with standard therapy. Pegfilgrastim-jmdb is marketed as Fulphila.

Epoetin alfa-epbx

Epoetin alfa-epbx was evaluated in 2 clinical trials in healthy individuals. The EPOE-12-02 trial established the PK and PD following a single subcutaneous dose of 100 U/kg in 81 participants. The EPOE-14-1 study was designed to determine the PK and PD of multiple doses of subcutaneous 100 U/kg 3 times weekly for 3 weeks in 129 participants. Both studies met prespecified criteria for PK and PD similarity to US-approved epoetin alfa, including geometric mean of area under the curve (AUC)0-120h, AUC0-inf, C_max (maximum serum concentration achieved by a drug in a specified area of the body) and E_max (maximum response achievable for a drug dose).

Evidence of efficacy and safety were also evaluated using pooled data from EPOE-10-13 and EPOE-10-01, conducted in patients with chronic kidney disease, which was considered the most sensitive population in which to evaluate clinically meaningful differences between the biosimilar and reference product.^8,9

There were no clinically meaningful differences in efficacy and a similar adverse event profile. The most common side effects include high blood pressure, joint pain, muscle spasm, fever, dizziness, respiratory infection, and cough, among others.

The recommended dose of epoetin alfa-epbx, which is marketed as Retacrit, is 40,000 Units weekly or 150 U/kg 3 times weekly in adults and 600 U/kg intravenously weekly in pediatric patients aged 5 years or younger. Epoetin alfa-epbx comes with a boxed warning to alert health care providers to the increased risks of death, heart problems, stroke, and tumor growth, or recurrence. The prescribing information also details warnings and precautions relating to these risks, as well as hypertension, seizures, lack or loss of hemoglobin response, pure red cell aplasia, serious allergic reactions, and severe cutaneous reactions.⁹

Blood pressure should be appropriately controlled before treatment initiation, treatment should be reduced or withheld if it becomes uncontrollable, and patients should be advised of the importance of compliance with anti-hypertensive medication and dietary restrictions. Patients should be monitored closely for premonitory neurologic symptoms and advised to contact their provider in the event of new-onset seizures, premonitory symptoms, or change in seizure frequency.

The prescribing information has dosing recommendations for lack or loss of hemoglobin response to epoetin alfa-epbx. If severe anemia or low reticulocyte count occur, treatment should be withheld and patients evaluated for neutralizing antibodies to erythropoietin and, in the event that PRCA is confirmed, treatment should be permanently discontinued. Treatment should be immediately and permanently discontinued for serious allergic reactions or severe cutaneous reactions.

As summer winds down and we begin to gear up to return to school or work, I was thinking about new and returning hem-onc residents, fellows, and young attendings and a question I routinely get from them: what should I do next in my career? I always answer by holding up 3 fingers and telling them that they can practice 1, at a university hospital; 2, at a university teaching affiliate; or 3, at a community hospital or practice with a little or no university affiliation. These days, trainees in hematology-oncology are often advised to be highly specialty-specific when they plan their long-term careers and to focus on a particular cancer or hematologic disorder. That is fine if you want to remain in an academic or university-based practice, but not if community practice is your preference. So, what are the differences among these 3 options?

Option 1, to remain in a university setting where you can be highly focused and specialized in a single narrowly defined area, could be satisfying, but keep in mind that the institution expects results! You will be carefully monitored for research output and teaching and administration commitments, and your interaction with patients could add up to less than 50% of your time. Publication and grant renewal will also play a role and therefore take up your time.

If you are considering option 2 – to work at a university teaching affiliate hospital – you need to bear in mind that you likely will see a patient population with a much broader range of diagnoses than would be the case with the first option. Patient care for option 2 will take up more than 50% of your time, so it might be a little more challenging to stay current, but perhaps more refreshing if you enjoy contact with patients. Teaching, research, and administration will surely be available, and publication and grant renewal will play as big or small a role as you want.

Option 3 would be to join a community hospital or practice where the primary focus is on patient care and the diagnoses will span the hematology and oncology spectrum. This type of practice can be very demanding of one’s time, but as rewarding as the other options, especially if you value contact with patients. With this option, one is more likely to practice as a generalist, perhaps with an emphasis in one of the hem-onc specialties, but able to treat a cluster of different types of cancer as well.

I always advise trainees to be sure they ask physicians practicing in each of these options to give examples of what their best and worst days are like so that they can get some idea of what the daily humdrum and challenges would encompass. What did I choose? I have always gone with option 2 and have been very happy in that setting.

In this issue…

More biosimilars head our way. Turning to the current issue of the journal, on page e181, Dr Jane de Lartigue discusses 2 new biosimilars recently approved by the United States Food and Drug Administration (FDA) – epoetin alfa-epbx (Retacrit; Hospira, a Pfizer company) for chemotherapy-induced anemia (CIA), and pegfilgrastim-jmdb (Fulphila; Mylan and Biocon) for prevention of febrile neutropenia. As Dr de Lartigue notes, biosimilars are copies of FDA-approved biologic drugs that cannot be identical to the reference drug but demonstrate a high similarity to it. In this case, the reference drug for epoetin alfa-epbx is epoetin alfa (Epogen/Procrit, Amgen) and for pegfilgrastim-jmdb, it is pegfilgrastim (Neulasta, Amgen). As the reference drugs’ patents expire, biosimilars are being developed to increase competition in the marketplace in an effort to reduce costs and improve patient access to these therapies. Indeed, the FDA is working to streamline the biosimilar approval process to facilitate that access.

Reading this article got me thinking about something I often have to consider in the course of my work: transfusion versus erythropoiesis-stimulating agents (ESAs)? Recombinant erythropoietin drugs such as the biosimilar, epoetin alfa-epbx, and its reference drug are grouped together as ESAs, and have been used to treat CIA since the late 1980s. However, there were a few trials that used higher-dose ESA or set high hemoglobin targets, and their findings suggested that ESAs may shorten survival in patients with cancer or increase tumor growth, or both. The use of ESAs took a nosedive after the 2007 decision by the FDA’s Oncologic Drugs Advisory Committee to rein in their use for a hard start of ESA treatment at less than 10 g/dL hemoglobin, and not higher. Subsequent trials addressed the concerns about survival and tumor growth. A meta-analysis of 60 randomized, placebo-controlled trials of ESAs in CIA found that there was no difference in overall survival between the study and control groups.¹ Likewise, findings from an FDA-mandated trial with epoetin alfa (Procrit) in patients with metastatic breast cancer have reported that there was no significant difference in overall survival between the study and control groups.² The results of a second FDA-mandated trial with darbepoetin alfa (Aranesp, Amgen) in patients with metastatic lung cancer are expected to be released soon. The FDA lifted the ESA Risk Evaluation and Mitigation Strategy based on those findings. However, many practitioners, both young and old, continue to shy away from using ESAs because of the FDA black box warning that remains in place despite the latest data.³The use of transfusion ticked up reciprocally with the decline in ESA use, but perhaps we should re-evaluate the use of these agents in our practice, especially now that the less costly, equally safe and effective biosimilars are becoming available and we have the new survival data. Transfusions are time consuming and have side effects, including allergic reaction and infection risk, whereas ESAs are easily administered by injection, which patients might find preferable.

Malignancies in patients with HIV-AIDS. On page e188, Koppaka and colleagues report on a study in India of the patterns of malignancies in patients with HIV-AIDS. I began my career just as the first reports of what became known as HIV-AIDS emerged, and we were all mystified by what was killing these patients and the curious hematologic and oncologic problems they developed. Back then, the patients were profoundly immunosuppressed, and the immunosuppression cancers of non-Hodgkin lymphoma, usually higher grade, and Kaposi sarcoma were most prevalent and today are collectively labeled AIDS-defining malignancies (ADMs).

Fast forward to present day, and we have extremely effective antiretroviral therapies that have resulted in a significant reduction in mortality among HIV-infected individuals who are now living long enough to get what we call non–AIDS-defining malignancies (NADMs) such as anal or cervical cancers, hepatoma (hepatocellular carcinoma), Hodgkin lymphoma, and lung cancer. Of note is that these NADMs are all highly viral associated, with anal and cervical cancers linked to infection with the human papillomavirus; hepatoma linked to the hepatitis B/C viruses; Hodgkin lymphoma to the Epstein-Barr virus; and lung cancer, possibly also HPV. Fortunately, these days we can use standard-dose chemoradiation therapy for all HIV-related cancers because the patients’ immune systems are much better reconstituted and the modern-day antiretroviral therapies have much less drug–drug interaction thanks to the advent of the integrase inhibitors. The researchers give an excellent breakdown of the occurrence of these malignancies, as well as an analysis of the correlation between CD4 counts and the different malignancies.

Immunotherapy-related side effects in the ED. What happens when our patients who are on immunotherapy end up in the emergency department (ED) with therapy-related symptoms? And what can the treating oncologist do to help the ED physician achieve the best possible outcome for the patient? I spoke to Dr Maura Sammon, an ED physician, about some of the more common of these side effects – lung, gastrointestinal, rash, and endocrine-related problems – and she describes in detail how physicians in the ED would triage and treat the patient. Dr Sammon also emphasizes the importance of communication: first, between the treating oncologist and patient, about the differences between chemotherapy and immunotherapy; and second, between the ED physician and the treating oncologist as soon as possible after the patient has presented to ensure a good outcome. The interview is part of The JCSO Interview series. It is jam-packed with useful, how-to information, and you can read a transcript of it on page e216 of this issue, or you can listen to it online.⁴

We round off the issue with a selection of Case Reports (pp. e200-e209), an original report on the characteristics of urgent palliative cancer care consultations encountered by radiation oncologists (p. e193), and a New Therapies feature, also by Dr de Lartigue, focusing on the rarity and complexities of sarcomas (p. e210).

Those are my dog-day-of-summer thoughts as we head toward another Labor Day and a new academic year. Since we are all online now, we encourage you to listen to my bimonthly podcast of each issue on our website at www.jcso-online.com, and of course, follow us on Twitter (@jcs_onc) and Instagram (@jcsoncology) and like us on Facebook.

As summer winds down and we begin to gear up to return to school or work, I was thinking about new and returning hem-onc residents, fellows, and young attendings and a question I routinely get from them: what should I do next in my career? I always answer by holding up 3 fingers and telling them that they can practice 1, at a university hospital; 2, at a university teaching affiliate; or 3, at a community hospital or practice with a little or no university affiliation. These days, trainees in hematology-oncology are often advised to be highly specialty-specific when they plan their long-term careers and to focus on a particular cancer or hematologic disorder. That is fine if you want to remain in an academic or university-based practice, but not if community practice is your preference. So, what are the differences among these 3 options?

Option 1, to remain in a university setting where you can be highly focused and specialized in a single narrowly defined area, could be satisfying, but keep in mind that the institution expects results! You will be carefully monitored for research output and teaching and administration commitments, and your interaction with patients could add up to less than 50% of your time. Publication and grant renewal will also play a role and therefore take up your time.

If you are considering option 2 – to work at a university teaching affiliate hospital – you need to bear in mind that you likely will see a patient population with a much broader range of diagnoses than would be the case with the first option. Patient care for option 2 will take up more than 50% of your time, so it might be a little more challenging to stay current, but perhaps more refreshing if you enjoy contact with patients. Teaching, research, and administration will surely be available, and publication and grant renewal will play as big or small a role as you want.

Option 3 would be to join a community hospital or practice where the primary focus is on patient care and the diagnoses will span the hematology and oncology spectrum. This type of practice can be very demanding of one’s time, but as rewarding as the other options, especially if you value contact with patients. With this option, one is more likely to practice as a generalist, perhaps with an emphasis in one of the hem-onc specialties, but able to treat a cluster of different types of cancer as well.

I always advise trainees to be sure they ask physicians practicing in each of these options to give examples of what their best and worst days are like so that they can get some idea of what the daily humdrum and challenges would encompass. What did I choose? I have always gone with option 2 and have been very happy in that setting.

In this issue…

More biosimilars head our way. Turning to the current issue of the journal, on page e181, Dr Jane de Lartigue discusses 2 new biosimilars recently approved by the United States Food and Drug Administration (FDA) – epoetin alfa-epbx (Retacrit; Hospira, a Pfizer company) for chemotherapy-induced anemia (CIA), and pegfilgrastim-jmdb (Fulphila; Mylan and Biocon) for prevention of febrile neutropenia. As Dr de Lartigue notes, biosimilars are copies of FDA-approved biologic drugs that cannot be identical to the reference drug but demonstrate a high similarity to it. In this case, the reference drug for epoetin alfa-epbx is epoetin alfa (Epogen/Procrit, Amgen) and for pegfilgrastim-jmdb, it is pegfilgrastim (Neulasta, Amgen). As the reference drugs’ patents expire, biosimilars are being developed to increase competition in the marketplace in an effort to reduce costs and improve patient access to these therapies. Indeed, the FDA is working to streamline the biosimilar approval process to facilitate that access.

Reading this article got me thinking about something I often have to consider in the course of my work: transfusion versus erythropoiesis-stimulating agents (ESAs)? Recombinant erythropoietin drugs such as the biosimilar, epoetin alfa-epbx, and its reference drug are grouped together as ESAs, and have been used to treat CIA since the late 1980s. However, there were a few trials that used higher-dose ESA or set high hemoglobin targets, and their findings suggested that ESAs may shorten survival in patients with cancer or increase tumor growth, or both. The use of ESAs took a nosedive after the 2007 decision by the FDA’s Oncologic Drugs Advisory Committee to rein in their use for a hard start of ESA treatment at less than 10 g/dL hemoglobin, and not higher. Subsequent trials addressed the concerns about survival and tumor growth. A meta-analysis of 60 randomized, placebo-controlled trials of ESAs in CIA found that there was no difference in overall survival between the study and control groups.¹ Likewise, findings from an FDA-mandated trial with epoetin alfa (Procrit) in patients with metastatic breast cancer have reported that there was no significant difference in overall survival between the study and control groups.² The results of a second FDA-mandated trial with darbepoetin alfa (Aranesp, Amgen) in patients with metastatic lung cancer are expected to be released soon. The FDA lifted the ESA Risk Evaluation and Mitigation Strategy based on those findings. However, many practitioners, both young and old, continue to shy away from using ESAs because of the FDA black box warning that remains in place despite the latest data.³The use of transfusion ticked up reciprocally with the decline in ESA use, but perhaps we should re-evaluate the use of these agents in our practice, especially now that the less costly, equally safe and effective biosimilars are becoming available and we have the new survival data. Transfusions are time consuming and have side effects, including allergic reaction and infection risk, whereas ESAs are easily administered by injection, which patients might find preferable.

Malignancies in patients with HIV-AIDS. On page e188, Koppaka and colleagues report on a study in India of the patterns of malignancies in patients with HIV-AIDS. I began my career just as the first reports of what became known as HIV-AIDS emerged, and we were all mystified by what was killing these patients and the curious hematologic and oncologic problems they developed. Back then, the patients were profoundly immunosuppressed, and the immunosuppression cancers of non-Hodgkin lymphoma, usually higher grade, and Kaposi sarcoma were most prevalent and today are collectively labeled AIDS-defining malignancies (ADMs).

Fast forward to present day, and we have extremely effective antiretroviral therapies that have resulted in a significant reduction in mortality among HIV-infected individuals who are now living long enough to get what we call non–AIDS-defining malignancies (NADMs) such as anal or cervical cancers, hepatoma (hepatocellular carcinoma), Hodgkin lymphoma, and lung cancer. Of note is that these NADMs are all highly viral associated, with anal and cervical cancers linked to infection with the human papillomavirus; hepatoma linked to the hepatitis B/C viruses; Hodgkin lymphoma to the Epstein-Barr virus; and lung cancer, possibly also HPV. Fortunately, these days we can use standard-dose chemoradiation therapy for all HIV-related cancers because the patients’ immune systems are much better reconstituted and the modern-day antiretroviral therapies have much less drug–drug interaction thanks to the advent of the integrase inhibitors. The researchers give an excellent breakdown of the occurrence of these malignancies, as well as an analysis of the correlation between CD4 counts and the different malignancies.

Immunotherapy-related side effects in the ED. What happens when our patients who are on immunotherapy end up in the emergency department (ED) with therapy-related symptoms? And what can the treating oncologist do to help the ED physician achieve the best possible outcome for the patient? I spoke to Dr Maura Sammon, an ED physician, about some of the more common of these side effects – lung, gastrointestinal, rash, and endocrine-related problems – and she describes in detail how physicians in the ED would triage and treat the patient. Dr Sammon also emphasizes the importance of communication: first, between the treating oncologist and patient, about the differences between chemotherapy and immunotherapy; and second, between the ED physician and the treating oncologist as soon as possible after the patient has presented to ensure a good outcome. The interview is part of The JCSO Interview series. It is jam-packed with useful, how-to information, and you can read a transcript of it on page e216 of this issue, or you can listen to it online.⁴

We round off the issue with a selection of Case Reports (pp. e200-e209), an original report on the characteristics of urgent palliative cancer care consultations encountered by radiation oncologists (p. e193), and a New Therapies feature, also by Dr de Lartigue, focusing on the rarity and complexities of sarcomas (p. e210).

Those are my dog-day-of-summer thoughts as we head toward another Labor Day and a new academic year. Since we are all online now, we encourage you to listen to my bimonthly podcast of each issue on our website at www.jcso-online.com, and of course, follow us on Twitter (@jcs_onc) and Instagram (@jcsoncology) and like us on Facebook.

As summer winds down and we begin to gear up to return to school or work, I was thinking about new and returning hem-onc residents, fellows, and young attendings and a question I routinely get from them: what should I do next in my career? I always answer by holding up 3 fingers and telling them that they can practice 1, at a university hospital; 2, at a university teaching affiliate; or 3, at a community hospital or practice with a little or no university affiliation. These days, trainees in hematology-oncology are often advised to be highly specialty-specific when they plan their long-term careers and to focus on a particular cancer or hematologic disorder. That is fine if you want to remain in an academic or university-based practice, but not if community practice is your preference. So, what are the differences among these 3 options?

Option 1, to remain in a university setting where you can be highly focused and specialized in a single narrowly defined area, could be satisfying, but keep in mind that the institution expects results! You will be carefully monitored for research output and teaching and administration commitments, and your interaction with patients could add up to less than 50% of your time. Publication and grant renewal will also play a role and therefore take up your time.

If you are considering option 2 – to work at a university teaching affiliate hospital – you need to bear in mind that you likely will see a patient population with a much broader range of diagnoses than would be the case with the first option. Patient care for option 2 will take up more than 50% of your time, so it might be a little more challenging to stay current, but perhaps more refreshing if you enjoy contact with patients. Teaching, research, and administration will surely be available, and publication and grant renewal will play as big or small a role as you want.

Option 3 would be to join a community hospital or practice where the primary focus is on patient care and the diagnoses will span the hematology and oncology spectrum. This type of practice can be very demanding of one’s time, but as rewarding as the other options, especially if you value contact with patients. With this option, one is more likely to practice as a generalist, perhaps with an emphasis in one of the hem-onc specialties, but able to treat a cluster of different types of cancer as well.

I always advise trainees to be sure they ask physicians practicing in each of these options to give examples of what their best and worst days are like so that they can get some idea of what the daily humdrum and challenges would encompass. What did I choose? I have always gone with option 2 and have been very happy in that setting.

In this issue…

More biosimilars head our way. Turning to the current issue of the journal, on page e181, Dr Jane de Lartigue discusses 2 new biosimilars recently approved by the United States Food and Drug Administration (FDA) – epoetin alfa-epbx (Retacrit; Hospira, a Pfizer company) for chemotherapy-induced anemia (CIA), and pegfilgrastim-jmdb (Fulphila; Mylan and Biocon) for prevention of febrile neutropenia. As Dr de Lartigue notes, biosimilars are copies of FDA-approved biologic drugs that cannot be identical to the reference drug but demonstrate a high similarity to it. In this case, the reference drug for epoetin alfa-epbx is epoetin alfa (Epogen/Procrit, Amgen) and for pegfilgrastim-jmdb, it is pegfilgrastim (Neulasta, Amgen). As the reference drugs’ patents expire, biosimilars are being developed to increase competition in the marketplace in an effort to reduce costs and improve patient access to these therapies. Indeed, the FDA is working to streamline the biosimilar approval process to facilitate that access.

Reading this article got me thinking about something I often have to consider in the course of my work: transfusion versus erythropoiesis-stimulating agents (ESAs)? Recombinant erythropoietin drugs such as the biosimilar, epoetin alfa-epbx, and its reference drug are grouped together as ESAs, and have been used to treat CIA since the late 1980s. However, there were a few trials that used higher-dose ESA or set high hemoglobin targets, and their findings suggested that ESAs may shorten survival in patients with cancer or increase tumor growth, or both. The use of ESAs took a nosedive after the 2007 decision by the FDA’s Oncologic Drugs Advisory Committee to rein in their use for a hard start of ESA treatment at less than 10 g/dL hemoglobin, and not higher. Subsequent trials addressed the concerns about survival and tumor growth. A meta-analysis of 60 randomized, placebo-controlled trials of ESAs in CIA found that there was no difference in overall survival between the study and control groups.¹ Likewise, findings from an FDA-mandated trial with epoetin alfa (Procrit) in patients with metastatic breast cancer have reported that there was no significant difference in overall survival between the study and control groups.² The results of a second FDA-mandated trial with darbepoetin alfa (Aranesp, Amgen) in patients with metastatic lung cancer are expected to be released soon. The FDA lifted the ESA Risk Evaluation and Mitigation Strategy based on those findings. However, many practitioners, both young and old, continue to shy away from using ESAs because of the FDA black box warning that remains in place despite the latest data.³The use of transfusion ticked up reciprocally with the decline in ESA use, but perhaps we should re-evaluate the use of these agents in our practice, especially now that the less costly, equally safe and effective biosimilars are becoming available and we have the new survival data. Transfusions are time consuming and have side effects, including allergic reaction and infection risk, whereas ESAs are easily administered by injection, which patients might find preferable.

Malignancies in patients with HIV-AIDS. On page e188, Koppaka and colleagues report on a study in India of the patterns of malignancies in patients with HIV-AIDS. I began my career just as the first reports of what became known as HIV-AIDS emerged, and we were all mystified by what was killing these patients and the curious hematologic and oncologic problems they developed. Back then, the patients were profoundly immunosuppressed, and the immunosuppression cancers of non-Hodgkin lymphoma, usually higher grade, and Kaposi sarcoma were most prevalent and today are collectively labeled AIDS-defining malignancies (ADMs).

Fast forward to present day, and we have extremely effective antiretroviral therapies that have resulted in a significant reduction in mortality among HIV-infected individuals who are now living long enough to get what we call non–AIDS-defining malignancies (NADMs) such as anal or cervical cancers, hepatoma (hepatocellular carcinoma), Hodgkin lymphoma, and lung cancer. Of note is that these NADMs are all highly viral associated, with anal and cervical cancers linked to infection with the human papillomavirus; hepatoma linked to the hepatitis B/C viruses; Hodgkin lymphoma to the Epstein-Barr virus; and lung cancer, possibly also HPV. Fortunately, these days we can use standard-dose chemoradiation therapy for all HIV-related cancers because the patients’ immune systems are much better reconstituted and the modern-day antiretroviral therapies have much less drug–drug interaction thanks to the advent of the integrase inhibitors. The researchers give an excellent breakdown of the occurrence of these malignancies, as well as an analysis of the correlation between CD4 counts and the different malignancies.

Immunotherapy-related side effects in the ED. What happens when our patients who are on immunotherapy end up in the emergency department (ED) with therapy-related symptoms? And what can the treating oncologist do to help the ED physician achieve the best possible outcome for the patient? I spoke to Dr Maura Sammon, an ED physician, about some of the more common of these side effects – lung, gastrointestinal, rash, and endocrine-related problems – and she describes in detail how physicians in the ED would triage and treat the patient. Dr Sammon also emphasizes the importance of communication: first, between the treating oncologist and patient, about the differences between chemotherapy and immunotherapy; and second, between the ED physician and the treating oncologist as soon as possible after the patient has presented to ensure a good outcome. The interview is part of The JCSO Interview series. It is jam-packed with useful, how-to information, and you can read a transcript of it on page e216 of this issue, or you can listen to it online.⁴

We round off the issue with a selection of Case Reports (pp. e200-e209), an original report on the characteristics of urgent palliative cancer care consultations encountered by radiation oncologists (p. e193), and a New Therapies feature, also by Dr de Lartigue, focusing on the rarity and complexities of sarcomas (p. e210).

Those are my dog-day-of-summer thoughts as we head toward another Labor Day and a new academic year. Since we are all online now, we encourage you to listen to my bimonthly podcast of each issue on our website at www.jcso-online.com, and of course, follow us on Twitter (@jcs_onc) and Instagram (@jcsoncology) and like us on Facebook.

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”   

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

chackett@mdedge.com

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”   

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

chackett@mdedge.com

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”   

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

chackett@mdedge.com

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

The AGA Obesity Practice Guide provides physicians with a comprehensive, multi-disciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at https://www.gastro.org/practice-guidance/practice-updates/obesity-practice-guide.

chackett@mdedge.com

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

The AGA Obesity Practice Guide provides physicians with a comprehensive, multi-disciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at https://www.gastro.org/practice-guidance/practice-updates/obesity-practice-guide.

chackett@mdedge.com

MUNICH – Lorcaserin is the first weight-loss drug proven to have cardiovascular safety, Erin A. Bohula, MD, DPhil, told Mitchel L. Zoler in an interview.

Dr. Bohula reported on the results of the CAMELLIA-TIMI 61 trial, which was designed to evaluate the cardiovascular safety of the weight-loss drug lorcaserin in more than 10,000 patients. She presented the data at the annual congress of the European Society of Cardiology.

In CAMELLIA-TIMI 61, the primary safety endpoint, a composite of cardiovascular death, MI, or stroke, was nearly identical between patients on lorcaserin and those given placebo, 2% and 2.1% per year, at P less than .001 for noninferiority. Similarly, the primary efficacy outcome comprising heart failure, hospitalization for unstable angina, and coronary revascularization, was very close between the treated and placebo patients, occurring in 4.1% and 4.2% per year, respectively.

In addition, “there was a sustained weight loss, more than with lifestyle alone or lifestyle plus placebo, which at its peak was about 3 kg. With that there were small, but significant, reductions in heart rate, blood pressure, triglycerides, and hemoglobin A1c, and there was a significant reduction in new-onset diabetes.”

“Overall, there’s not a lot of use of pharmacologic agents for weight loss in the United States, and a lot of that is based on fear of the historical experience, which is that they were not safe. I suspect that having a drug that is proven safe will now lead people to reach for a pharmacologic agent like lorcaserin,” said Dr. Bohula, a cardiologist at of Brigham and Women’s Hospital and an investigator at the TIMI study group.

The AGA Obesity Practice Guide provides physicians with a comprehensive, multi-disciplinary process to guide and personalize innovative obesity care for safe and effective weight management. Learn more at https://www.gastro.org/practice-guidance/practice-updates/obesity-practice-guide.

chackett@mdedge.com

MUNICH – Patients with hypercholesterolemia, atherosclerotic cardiovascular disease, and metabolic syndrome received a bigger benefit from treatment with a PCSK9 inhibitor than did otherwise similar patients without metabolic syndrome in a post hoc analysis of data collected from a placebo-controlled trial of a PCSK9 inhibitor with more than 27,000 total participants.

The analysis showed that patients with metabolic syndrome (MetS) treated with the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab in the FOURIER study had a statistically significant 17% relative risk reduction in the study’s primary efficacy endpoint compared with placebo, while those without MetS had an 11% relative risk reduction that did not reach statistical significance, Prakash Deedwania, MD, said at the annual congress of the European Society of Cardiology. “Given their higher baseline risk [for cardiovascular disease events], patients with metabolic syndrome had a larger absolute reduction in cardiovascular events,” said Dr. Deedwania, a professor of medicine at the University of California, San Francisco.

For the study’s secondary endpoint of the combined rate of cardiovascular disease death, nonfatal MI, and nonfatal stroke, patients with MetS treated with evolocumab had a statistically significant 24% relative risk reduction compared with placebo, while those without MetS had an insignificant 14% reduction. Dr. Deedwania and his associates calculated these relative risk reductions and those for the primary endpoint using adjustments for baseline differences between the MetS and non-MetS subgroups in age, race, sex, history of diabetes, history of MI, heart failure, smoking, renal function, LDL cholesterol levels, and use of a high-intensity dosage of a statin. Among the 27,342 patients enrolled in the trial 16,361 (60%) had MetS at entry into the study, which made this “the largest study ever reported for patients with metabolic syndrome,” he noted.

“Evolocumab was still effective in patients without metabolic syndrome, but it was of lesser magnitude, and that combined with the fewer patients in the non–metabolic syndrome subgroup meant the effect did not reach statistical significance,” Dr. Deedwania explained. “These data help identify the patients who benefit the most from treatment with an expensive drug,” a PCSK9 inhibitor. Based on list prices the annual cost for treatment with a PCSK9 inhibitor such as evolocumab (Repatha) or a second approved drug from this class, alirocumab (Praluent), is roughly $14,000 (JAMA Cardiol. 2017 Oct;2[10]:1066-8).

The analysis run by Dr. Deedwania used data collected in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, which had showed an overall relative risk reduction of 15% compared with placebo during a median follow-up of 2.2 years for the primary endpoint of cardiovascular death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization (N Engl J Med. 2017 May 4;376[18]:1713-22). The study ran at 1,242 sites in 49 countries. He and his associates identified enrolled patients with MetS using the definition of the 2001 Third Report from the National Cholesterol Education Program: People with at least three of five criteria – fasting blood glucose of at least 100 mg/dL; waist circumference greater than 102 cm in men and 88 cm in women; systolic blood pressure of at least 135 mm Hg, diastolic blood pressure of at least 85 mm Hg, or a history of hypertension diagnosis; a triglyceride level greater than 150 mg/dL; and an HDL cholesterol level of less than 40 mg/dL in men and less than 50 mg/dL in women (JAMA. 2001 May 16;285[19]:2486-97).

The new analysis also showed that treatment with evolocumab led to an incremental, average reduction in LDL cholesterol of 58% in patients with MetS and 61% in patients without MetS at the time of enrollment. The patients with MetS in FOURIER overall had a significantly higher number of primary endpoint events, 15.8%, than enrolled patients without MetS, 12.9%, regardless of whether or not they received evolocumab, a relative risk of 21% more events after adjustment. The analysis also showed that treatment with evolocumab was equally safe and well tolerated by patients regardless of whether or not they had MetS, and that patients with MetS had no increased incidence of diabetes or elevations in fasting blood glucose or hemoglobin A1c while on treatment compared with those without MetS.

Dr. Deedwania has been a consultant to Amgen, the company that markets evolocumab, and to Sanofi, the company that markets a different PCSK9 inhibitor, alirocumab.

mzoler@mdedge.com

On Twitter @mitchelzoler

MUNICH – Patients with hypercholesterolemia, atherosclerotic cardiovascular disease, and metabolic syndrome received a bigger benefit from treatment with a PCSK9 inhibitor than did otherwise similar patients without metabolic syndrome in a post hoc analysis of data collected from a placebo-controlled trial of a PCSK9 inhibitor with more than 27,000 total participants.

The analysis showed that patients with metabolic syndrome (MetS) treated with the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab in the FOURIER study had a statistically significant 17% relative risk reduction in the study’s primary efficacy endpoint compared with placebo, while those without MetS had an 11% relative risk reduction that did not reach statistical significance, Prakash Deedwania, MD, said at the annual congress of the European Society of Cardiology. “Given their higher baseline risk [for cardiovascular disease events], patients with metabolic syndrome had a larger absolute reduction in cardiovascular events,” said Dr. Deedwania, a professor of medicine at the University of California, San Francisco.

For the study’s secondary endpoint of the combined rate of cardiovascular disease death, nonfatal MI, and nonfatal stroke, patients with MetS treated with evolocumab had a statistically significant 24% relative risk reduction compared with placebo, while those without MetS had an insignificant 14% reduction. Dr. Deedwania and his associates calculated these relative risk reductions and those for the primary endpoint using adjustments for baseline differences between the MetS and non-MetS subgroups in age, race, sex, history of diabetes, history of MI, heart failure, smoking, renal function, LDL cholesterol levels, and use of a high-intensity dosage of a statin. Among the 27,342 patients enrolled in the trial 16,361 (60%) had MetS at entry into the study, which made this “the largest study ever reported for patients with metabolic syndrome,” he noted.

“Evolocumab was still effective in patients without metabolic syndrome, but it was of lesser magnitude, and that combined with the fewer patients in the non–metabolic syndrome subgroup meant the effect did not reach statistical significance,” Dr. Deedwania explained. “These data help identify the patients who benefit the most from treatment with an expensive drug,” a PCSK9 inhibitor. Based on list prices the annual cost for treatment with a PCSK9 inhibitor such as evolocumab (Repatha) or a second approved drug from this class, alirocumab (Praluent), is roughly $14,000 (JAMA Cardiol. 2017 Oct;2[10]:1066-8).

The analysis run by Dr. Deedwania used data collected in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, which had showed an overall relative risk reduction of 15% compared with placebo during a median follow-up of 2.2 years for the primary endpoint of cardiovascular death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization (N Engl J Med. 2017 May 4;376[18]:1713-22). The study ran at 1,242 sites in 49 countries. He and his associates identified enrolled patients with MetS using the definition of the 2001 Third Report from the National Cholesterol Education Program: People with at least three of five criteria – fasting blood glucose of at least 100 mg/dL; waist circumference greater than 102 cm in men and 88 cm in women; systolic blood pressure of at least 135 mm Hg, diastolic blood pressure of at least 85 mm Hg, or a history of hypertension diagnosis; a triglyceride level greater than 150 mg/dL; and an HDL cholesterol level of less than 40 mg/dL in men and less than 50 mg/dL in women (JAMA. 2001 May 16;285[19]:2486-97).

The new analysis also showed that treatment with evolocumab led to an incremental, average reduction in LDL cholesterol of 58% in patients with MetS and 61% in patients without MetS at the time of enrollment. The patients with MetS in FOURIER overall had a significantly higher number of primary endpoint events, 15.8%, than enrolled patients without MetS, 12.9%, regardless of whether or not they received evolocumab, a relative risk of 21% more events after adjustment. The analysis also showed that treatment with evolocumab was equally safe and well tolerated by patients regardless of whether or not they had MetS, and that patients with MetS had no increased incidence of diabetes or elevations in fasting blood glucose or hemoglobin A1c while on treatment compared with those without MetS.

Dr. Deedwania has been a consultant to Amgen, the company that markets evolocumab, and to Sanofi, the company that markets a different PCSK9 inhibitor, alirocumab.

mzoler@mdedge.com

On Twitter @mitchelzoler

MUNICH – Patients with hypercholesterolemia, atherosclerotic cardiovascular disease, and metabolic syndrome received a bigger benefit from treatment with a PCSK9 inhibitor than did otherwise similar patients without metabolic syndrome in a post hoc analysis of data collected from a placebo-controlled trial of a PCSK9 inhibitor with more than 27,000 total participants.

The analysis showed that patients with metabolic syndrome (MetS) treated with the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab in the FOURIER study had a statistically significant 17% relative risk reduction in the study’s primary efficacy endpoint compared with placebo, while those without MetS had an 11% relative risk reduction that did not reach statistical significance, Prakash Deedwania, MD, said at the annual congress of the European Society of Cardiology. “Given their higher baseline risk [for cardiovascular disease events], patients with metabolic syndrome had a larger absolute reduction in cardiovascular events,” said Dr. Deedwania, a professor of medicine at the University of California, San Francisco.

For the study’s secondary endpoint of the combined rate of cardiovascular disease death, nonfatal MI, and nonfatal stroke, patients with MetS treated with evolocumab had a statistically significant 24% relative risk reduction compared with placebo, while those without MetS had an insignificant 14% reduction. Dr. Deedwania and his associates calculated these relative risk reductions and those for the primary endpoint using adjustments for baseline differences between the MetS and non-MetS subgroups in age, race, sex, history of diabetes, history of MI, heart failure, smoking, renal function, LDL cholesterol levels, and use of a high-intensity dosage of a statin. Among the 27,342 patients enrolled in the trial 16,361 (60%) had MetS at entry into the study, which made this “the largest study ever reported for patients with metabolic syndrome,” he noted.

“Evolocumab was still effective in patients without metabolic syndrome, but it was of lesser magnitude, and that combined with the fewer patients in the non–metabolic syndrome subgroup meant the effect did not reach statistical significance,” Dr. Deedwania explained. “These data help identify the patients who benefit the most from treatment with an expensive drug,” a PCSK9 inhibitor. Based on list prices the annual cost for treatment with a PCSK9 inhibitor such as evolocumab (Repatha) or a second approved drug from this class, alirocumab (Praluent), is roughly $14,000 (JAMA Cardiol. 2017 Oct;2[10]:1066-8).

The analysis run by Dr. Deedwania used data collected in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, which had showed an overall relative risk reduction of 15% compared with placebo during a median follow-up of 2.2 years for the primary endpoint of cardiovascular death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or coronary revascularization (N Engl J Med. 2017 May 4;376[18]:1713-22). The study ran at 1,242 sites in 49 countries. He and his associates identified enrolled patients with MetS using the definition of the 2001 Third Report from the National Cholesterol Education Program: People with at least three of five criteria – fasting blood glucose of at least 100 mg/dL; waist circumference greater than 102 cm in men and 88 cm in women; systolic blood pressure of at least 135 mm Hg, diastolic blood pressure of at least 85 mm Hg, or a history of hypertension diagnosis; a triglyceride level greater than 150 mg/dL; and an HDL cholesterol level of less than 40 mg/dL in men and less than 50 mg/dL in women (JAMA. 2001 May 16;285[19]:2486-97).

The new analysis also showed that treatment with evolocumab led to an incremental, average reduction in LDL cholesterol of 58% in patients with MetS and 61% in patients without MetS at the time of enrollment. The patients with MetS in FOURIER overall had a significantly higher number of primary endpoint events, 15.8%, than enrolled patients without MetS, 12.9%, regardless of whether or not they received evolocumab, a relative risk of 21% more events after adjustment. The analysis also showed that treatment with evolocumab was equally safe and well tolerated by patients regardless of whether or not they had MetS, and that patients with MetS had no increased incidence of diabetes or elevations in fasting blood glucose or hemoglobin A1c while on treatment compared with those without MetS.

Dr. Deedwania has been a consultant to Amgen, the company that markets evolocumab, and to Sanofi, the company that markets a different PCSK9 inhibitor, alirocumab.

mzoler@mdedge.com

On Twitter @mitchelzoler

For patients hospitalized for medical illness, giving rivaroxaban after discharge does not significantly reduce the risk of venous thromboembolism, investigators reported.

Previous research suggested that the risk of major bleeding from rivaroxaban outweighed its benefits; however, major bleeding was uncommon in the MARINER trial, reported lead author Alex C. Spyropoulos, MD, of Hofstra University in Hempstead, N.Y., and his colleagues.

“Patients who are hospitalized for acute medical illnesses, such as heart failure, respiratory insufficiency, stroke, and infectious or inflammatory diseases, are at increased risk for venous thromboembolism,” they wrote in the New England Journal of Medicine. The results were also presented at the annual congress of the European Society of Cardiology.

Although the increased risk of thromboembolism continues for at least 6 weeks after hospitalization, postdischarge anticoagulants, such as rivaroxaban, are controversial.

“Studies of extended thromboprophylaxis have shown either excess major bleeding or a benefit that is based mainly on reducing the risk of asymptomatic deep-vein thrombosis,” the investigators wrote.

The researchers aimed to clarify the benefits of rivaroxaban after hospitalization while modifying previous study regimens to limit major bleeding risk.

The double-blind MARINER study involved 12,019 patients who were hospitalized for medical illness and had an increased risk of venous thromboembolism. Hospitalization lasted 3-10 consecutive days. Sufficient risk of thromboembolism was defined by a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (range, 0-10), or an IMPROVE score of 2 or 3 with a plasma D-dimer measurement more than double the upper normal limit.

Patients were randomized to receive either 10 mg of rivaroxaban daily (n = 6,007) or placebo (n = 6,012) for 45 days after discharge. Patients with renal impairment had a reduced dose of 7.5 mg rivaroxaban.

A composite of symptomatic or fatal venous thromboembolism was the primary efficacy outcome. Major bleeding was the safety benchmark.

Efficacy was similar in both groups. Symptomatic or fatal venous thromboembolism occurred in 50 patients (0.83%) in the rivaroxaban group, compared with 66 patients (1.10%) in the placebo group (P = .14). These findings suggest that rivaroxaban provides a minor and insignificant benefit.

Although major bleeding was slightly more common in patients receiving rivaroxaban, compared with patients receiving placebo (0.28% vs. 0.15%), the researchers suggested that, in large populations, the marginal benefit of rivaroxaban might outweigh the increased bleeding risk. Still, the authors noted that “the usefulness of extended thromboprophylaxis remains uncertain.”

“Future studies should more accurately identify deaths caused by thrombotic mechanisms and focus on the patients who are at highest risk and who may benefit from anticoagulant prophylaxis,” the researchers wrote.

Funding was provided by Janssen Research and Development. Most of the study authors reported fees or grants from Janssen during the study, and relationships with other companies outside of the submitted work.

SOURCE : Spyropoulos AC et al. N Engl J Med. 2018 Aug 26. doi: 10.1056/NEJMoa1805090.

For patients hospitalized for medical illness, giving rivaroxaban after discharge does not significantly reduce the risk of venous thromboembolism, investigators reported.

Previous research suggested that the risk of major bleeding from rivaroxaban outweighed its benefits; however, major bleeding was uncommon in the MARINER trial, reported lead author Alex C. Spyropoulos, MD, of Hofstra University in Hempstead, N.Y., and his colleagues.

“Patients who are hospitalized for acute medical illnesses, such as heart failure, respiratory insufficiency, stroke, and infectious or inflammatory diseases, are at increased risk for venous thromboembolism,” they wrote in the New England Journal of Medicine. The results were also presented at the annual congress of the European Society of Cardiology.

Although the increased risk of thromboembolism continues for at least 6 weeks after hospitalization, postdischarge anticoagulants, such as rivaroxaban, are controversial.

“Studies of extended thromboprophylaxis have shown either excess major bleeding or a benefit that is based mainly on reducing the risk of asymptomatic deep-vein thrombosis,” the investigators wrote.

The researchers aimed to clarify the benefits of rivaroxaban after hospitalization while modifying previous study regimens to limit major bleeding risk.

The double-blind MARINER study involved 12,019 patients who were hospitalized for medical illness and had an increased risk of venous thromboembolism. Hospitalization lasted 3-10 consecutive days. Sufficient risk of thromboembolism was defined by a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (range, 0-10), or an IMPROVE score of 2 or 3 with a plasma D-dimer measurement more than double the upper normal limit.

Patients were randomized to receive either 10 mg of rivaroxaban daily (n = 6,007) or placebo (n = 6,012) for 45 days after discharge. Patients with renal impairment had a reduced dose of 7.5 mg rivaroxaban.

A composite of symptomatic or fatal venous thromboembolism was the primary efficacy outcome. Major bleeding was the safety benchmark.

Efficacy was similar in both groups. Symptomatic or fatal venous thromboembolism occurred in 50 patients (0.83%) in the rivaroxaban group, compared with 66 patients (1.10%) in the placebo group (P = .14). These findings suggest that rivaroxaban provides a minor and insignificant benefit.

Although major bleeding was slightly more common in patients receiving rivaroxaban, compared with patients receiving placebo (0.28% vs. 0.15%), the researchers suggested that, in large populations, the marginal benefit of rivaroxaban might outweigh the increased bleeding risk. Still, the authors noted that “the usefulness of extended thromboprophylaxis remains uncertain.”

“Future studies should more accurately identify deaths caused by thrombotic mechanisms and focus on the patients who are at highest risk and who may benefit from anticoagulant prophylaxis,” the researchers wrote.

Funding was provided by Janssen Research and Development. Most of the study authors reported fees or grants from Janssen during the study, and relationships with other companies outside of the submitted work.

SOURCE : Spyropoulos AC et al. N Engl J Med. 2018 Aug 26. doi: 10.1056/NEJMoa1805090.

For patients hospitalized for medical illness, giving rivaroxaban after discharge does not significantly reduce the risk of venous thromboembolism, investigators reported.

Previous research suggested that the risk of major bleeding from rivaroxaban outweighed its benefits; however, major bleeding was uncommon in the MARINER trial, reported lead author Alex C. Spyropoulos, MD, of Hofstra University in Hempstead, N.Y., and his colleagues.

“Patients who are hospitalized for acute medical illnesses, such as heart failure, respiratory insufficiency, stroke, and infectious or inflammatory diseases, are at increased risk for venous thromboembolism,” they wrote in the New England Journal of Medicine. The results were also presented at the annual congress of the European Society of Cardiology.

Although the increased risk of thromboembolism continues for at least 6 weeks after hospitalization, postdischarge anticoagulants, such as rivaroxaban, are controversial.

“Studies of extended thromboprophylaxis have shown either excess major bleeding or a benefit that is based mainly on reducing the risk of asymptomatic deep-vein thrombosis,” the investigators wrote.

The researchers aimed to clarify the benefits of rivaroxaban after hospitalization while modifying previous study regimens to limit major bleeding risk.

The double-blind MARINER study involved 12,019 patients who were hospitalized for medical illness and had an increased risk of venous thromboembolism. Hospitalization lasted 3-10 consecutive days. Sufficient risk of thromboembolism was defined by a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (range, 0-10), or an IMPROVE score of 2 or 3 with a plasma D-dimer measurement more than double the upper normal limit.

Patients were randomized to receive either 10 mg of rivaroxaban daily (n = 6,007) or placebo (n = 6,012) for 45 days after discharge. Patients with renal impairment had a reduced dose of 7.5 mg rivaroxaban.

A composite of symptomatic or fatal venous thromboembolism was the primary efficacy outcome. Major bleeding was the safety benchmark.

Efficacy was similar in both groups. Symptomatic or fatal venous thromboembolism occurred in 50 patients (0.83%) in the rivaroxaban group, compared with 66 patients (1.10%) in the placebo group (P = .14). These findings suggest that rivaroxaban provides a minor and insignificant benefit.

Although major bleeding was slightly more common in patients receiving rivaroxaban, compared with patients receiving placebo (0.28% vs. 0.15%), the researchers suggested that, in large populations, the marginal benefit of rivaroxaban might outweigh the increased bleeding risk. Still, the authors noted that “the usefulness of extended thromboprophylaxis remains uncertain.”

“Future studies should more accurately identify deaths caused by thrombotic mechanisms and focus on the patients who are at highest risk and who may benefit from anticoagulant prophylaxis,” the researchers wrote.

Funding was provided by Janssen Research and Development. Most of the study authors reported fees or grants from Janssen during the study, and relationships with other companies outside of the submitted work.

SOURCE : Spyropoulos AC et al. N Engl J Med. 2018 Aug 26. doi: 10.1056/NEJMoa1805090.

MUNICH – Restrictive transfusion strategy during cardiovascular surgery, versus a more traditional liberal approach, did not increase the risk of poor outcomes at 6 months in a large, randomized trial presented at the annual congress of the European Society of Cardiology, and published simultaneously in the New England Journal of Medicine.

The investigators previously reported that 28 day outcomes were non-inferior with the restrictive approach, but they wanted to look into 6 month results to rule out latent problems, such as sequelae from perioperative organ hypoxia.

The new outcomes from the study, dubbed the Transfusion Requirements in Cardiac Surgery (TRICS) III trial, offer some reassurance at a time when cardiac surgeons are shifting towards more restrictive transfusion policies (N Engl J Med. 2018 Aug 26.doi: 10.1056/NEJMoa1808561).

The trial randomized 2,317 patients to red cell transfusions if their hemoglobin concentrations fell below 7.5 g/dL intraoperatively or postoperatively. Another 2,347 were randomized to the liberal approach, with transfusions below 9.5 g/dL in the operating room and ICU, and below 8.5 g/dL outside of the ICU. The arms were well matched, with a mean score of 8 in both groups on the 47-point European System for Cardiac Operative Risk Evaluation I score.

M. Alexander Otto/Frontline Medical News

aotto@mdedge.com

SOURCE: Mazer CD et al. N Engl J Med. 2018 Aug 26. doi:10.1056/NEJMoa1808561

MUNICH – Restrictive transfusion strategy during cardiovascular surgery, versus a more traditional liberal approach, did not increase the risk of poor outcomes at 6 months in a large, randomized trial presented at the annual congress of the European Society of Cardiology, and published simultaneously in the New England Journal of Medicine.

The investigators previously reported that 28 day outcomes were non-inferior with the restrictive approach, but they wanted to look into 6 month results to rule out latent problems, such as sequelae from perioperative organ hypoxia.

The new outcomes from the study, dubbed the Transfusion Requirements in Cardiac Surgery (TRICS) III trial, offer some reassurance at a time when cardiac surgeons are shifting towards more restrictive transfusion policies (N Engl J Med. 2018 Aug 26.doi: 10.1056/NEJMoa1808561).

The trial randomized 2,317 patients to red cell transfusions if their hemoglobin concentrations fell below 7.5 g/dL intraoperatively or postoperatively. Another 2,347 were randomized to the liberal approach, with transfusions below 9.5 g/dL in the operating room and ICU, and below 8.5 g/dL outside of the ICU. The arms were well matched, with a mean score of 8 in both groups on the 47-point European System for Cardiac Operative Risk Evaluation I score.

M. Alexander Otto/Frontline Medical News

aotto@mdedge.com

SOURCE: Mazer CD et al. N Engl J Med. 2018 Aug 26. doi:10.1056/NEJMoa1808561

MUNICH – Restrictive transfusion strategy during cardiovascular surgery, versus a more traditional liberal approach, did not increase the risk of poor outcomes at 6 months in a large, randomized trial presented at the annual congress of the European Society of Cardiology, and published simultaneously in the New England Journal of Medicine.

The investigators previously reported that 28 day outcomes were non-inferior with the restrictive approach, but they wanted to look into 6 month results to rule out latent problems, such as sequelae from perioperative organ hypoxia.

The new outcomes from the study, dubbed the Transfusion Requirements in Cardiac Surgery (TRICS) III trial, offer some reassurance at a time when cardiac surgeons are shifting towards more restrictive transfusion policies (N Engl J Med. 2018 Aug 26.doi: 10.1056/NEJMoa1808561).

The trial randomized 2,317 patients to red cell transfusions if their hemoglobin concentrations fell below 7.5 g/dL intraoperatively or postoperatively. Another 2,347 were randomized to the liberal approach, with transfusions below 9.5 g/dL in the operating room and ICU, and below 8.5 g/dL outside of the ICU. The arms were well matched, with a mean score of 8 in both groups on the 47-point European System for Cardiac Operative Risk Evaluation I score.

M. Alexander Otto/Frontline Medical News

aotto@mdedge.com

SOURCE: Mazer CD et al. N Engl J Med. 2018 Aug 26. doi:10.1056/NEJMoa1808561

In myocardial infarction patients with cardiogenic shock and multivessel disease, culprit lesion–only and multivessel percutaneous coronary interventions (PCI) had similar mortality rates at 1 year.

At 30 days, culprit lesion–only PCI was associated with fewer cases of death or renal replacement therapy than immediate multivessel PCI.

However, not all the news was good for culprit lesion–only PCI: At 1 year, it was associated with a higher frequency of rehospitalization for heart failure and of repeat vascularization, according to Holger Thiele, MD, of the Heart Center Leipzig at the University of Leipzig (Germany) and his colleagues.

These results from the Culprit Only Lesion PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) study were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.

The 30-day results from the study, published in the journal last year, were enough to convince the creators of the European revascularization guidelines to downgrade immediate multivessel PCI in cardiogenic shock to a class III B recommendation, which indicates that it is not effective and may cause harm.

However, the results also caused controversy because complete revascularization via immediate multivessel PCI in cardiogenic shock patients might lead to long-term benefits. In fact, evidence from nonrandomized trials and a registry study had suggested that immediate multivessel PCI may reduce mortality at 1 year.

But the new 1-year data don’t support that hypothesis of long-term benefit, Dr. Thiele and his colleagues found.

The CULPRIT-SHOCK trial randomized 684 patients at 83 centers to culprit lesion–only PCI or multivessel PCI. At 30 days, death or renal replacement therapy occurred at a lower frequency in the culprit lesion–only group (45.9% vs. 55.4%; relative risk, 0.83; P = .01).

At 1 year, all-cause mortality was 50.0% in the group that underwent culprit lesion–only PCI, compared with 56.9% in the group that underwent multivessel PCI, a result that was not statistically significant (RR, 0.88; 95% CI, 0.76-1.01). There was also no significant difference in death from cardiovascular causes, 46.2% in culprit lesion–only patients, compared with 52.8% in multivessel patients (RR, 0.88; 95% CI, 0.75-1.02).

Mortality rates between baseline and 1 year were similar in the intention-to-treat, per-protocol, and as-treated populations.

The researchers conducted a post hoc analysis of the original primary endpoint – death or renal replacement therapy – at 1 year, and they found results similar to those seen at 30 days: 52.0% in the culprit lesion–only group and 59.5% in the multivessel group (RR, 0.87; 95% CI, 0.76-0.99).

Some results favored multivessel PCI: 32.3% of the culprit lesion–only group underwent repeat revascularization, compared with 9.4% of multivessel PCI (RR, 3.44; 95% CI, 2.39-4.95). Rehospitalizations for congestive heart failure were rare, but occurred in 5.2% of the culprit lesion–only group, compared with 1.2% of the multivessel group (RR, 4.46; 95% CI, 1.53-13.04).

The study was funded by the European Union Seventh Framework Programme, the German Heart Research Foundation, and the German Centre for Cardiovascular Research. Dr. Thiele had no relevant conflicts of interest.

SOURCE: Thiele H et al. N Engl J Med. 2018 Aug 25. doi: 10.1056/NEJMoa1808788.

In myocardial infarction patients with cardiogenic shock and multivessel disease, culprit lesion–only and multivessel percutaneous coronary interventions (PCI) had similar mortality rates at 1 year.

At 30 days, culprit lesion–only PCI was associated with fewer cases of death or renal replacement therapy than immediate multivessel PCI.

However, not all the news was good for culprit lesion–only PCI: At 1 year, it was associated with a higher frequency of rehospitalization for heart failure and of repeat vascularization, according to Holger Thiele, MD, of the Heart Center Leipzig at the University of Leipzig (Germany) and his colleagues.

These results from the Culprit Only Lesion PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) study were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.

The 30-day results from the study, published in the journal last year, were enough to convince the creators of the European revascularization guidelines to downgrade immediate multivessel PCI in cardiogenic shock to a class III B recommendation, which indicates that it is not effective and may cause harm.

However, the results also caused controversy because complete revascularization via immediate multivessel PCI in cardiogenic shock patients might lead to long-term benefits. In fact, evidence from nonrandomized trials and a registry study had suggested that immediate multivessel PCI may reduce mortality at 1 year.

But the new 1-year data don’t support that hypothesis of long-term benefit, Dr. Thiele and his colleagues found.

The CULPRIT-SHOCK trial randomized 684 patients at 83 centers to culprit lesion–only PCI or multivessel PCI. At 30 days, death or renal replacement therapy occurred at a lower frequency in the culprit lesion–only group (45.9% vs. 55.4%; relative risk, 0.83; P = .01).

At 1 year, all-cause mortality was 50.0% in the group that underwent culprit lesion–only PCI, compared with 56.9% in the group that underwent multivessel PCI, a result that was not statistically significant (RR, 0.88; 95% CI, 0.76-1.01). There was also no significant difference in death from cardiovascular causes, 46.2% in culprit lesion–only patients, compared with 52.8% in multivessel patients (RR, 0.88; 95% CI, 0.75-1.02).

Mortality rates between baseline and 1 year were similar in the intention-to-treat, per-protocol, and as-treated populations.

The researchers conducted a post hoc analysis of the original primary endpoint – death or renal replacement therapy – at 1 year, and they found results similar to those seen at 30 days: 52.0% in the culprit lesion–only group and 59.5% in the multivessel group (RR, 0.87; 95% CI, 0.76-0.99).

Some results favored multivessel PCI: 32.3% of the culprit lesion–only group underwent repeat revascularization, compared with 9.4% of multivessel PCI (RR, 3.44; 95% CI, 2.39-4.95). Rehospitalizations for congestive heart failure were rare, but occurred in 5.2% of the culprit lesion–only group, compared with 1.2% of the multivessel group (RR, 4.46; 95% CI, 1.53-13.04).

The study was funded by the European Union Seventh Framework Programme, the German Heart Research Foundation, and the German Centre for Cardiovascular Research. Dr. Thiele had no relevant conflicts of interest.

SOURCE: Thiele H et al. N Engl J Med. 2018 Aug 25. doi: 10.1056/NEJMoa1808788.

In myocardial infarction patients with cardiogenic shock and multivessel disease, culprit lesion–only and multivessel percutaneous coronary interventions (PCI) had similar mortality rates at 1 year.

At 30 days, culprit lesion–only PCI was associated with fewer cases of death or renal replacement therapy than immediate multivessel PCI.

However, not all the news was good for culprit lesion–only PCI: At 1 year, it was associated with a higher frequency of rehospitalization for heart failure and of repeat vascularization, according to Holger Thiele, MD, of the Heart Center Leipzig at the University of Leipzig (Germany) and his colleagues.

These results from the Culprit Only Lesion PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) study were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.

The 30-day results from the study, published in the journal last year, were enough to convince the creators of the European revascularization guidelines to downgrade immediate multivessel PCI in cardiogenic shock to a class III B recommendation, which indicates that it is not effective and may cause harm.

However, the results also caused controversy because complete revascularization via immediate multivessel PCI in cardiogenic shock patients might lead to long-term benefits. In fact, evidence from nonrandomized trials and a registry study had suggested that immediate multivessel PCI may reduce mortality at 1 year.

But the new 1-year data don’t support that hypothesis of long-term benefit, Dr. Thiele and his colleagues found.

The CULPRIT-SHOCK trial randomized 684 patients at 83 centers to culprit lesion–only PCI or multivessel PCI. At 30 days, death or renal replacement therapy occurred at a lower frequency in the culprit lesion–only group (45.9% vs. 55.4%; relative risk, 0.83; P = .01).

At 1 year, all-cause mortality was 50.0% in the group that underwent culprit lesion–only PCI, compared with 56.9% in the group that underwent multivessel PCI, a result that was not statistically significant (RR, 0.88; 95% CI, 0.76-1.01). There was also no significant difference in death from cardiovascular causes, 46.2% in culprit lesion–only patients, compared with 52.8% in multivessel patients (RR, 0.88; 95% CI, 0.75-1.02).

Mortality rates between baseline and 1 year were similar in the intention-to-treat, per-protocol, and as-treated populations.

The researchers conducted a post hoc analysis of the original primary endpoint – death or renal replacement therapy – at 1 year, and they found results similar to those seen at 30 days: 52.0% in the culprit lesion–only group and 59.5% in the multivessel group (RR, 0.87; 95% CI, 0.76-0.99).

Some results favored multivessel PCI: 32.3% of the culprit lesion–only group underwent repeat revascularization, compared with 9.4% of multivessel PCI (RR, 3.44; 95% CI, 2.39-4.95). Rehospitalizations for congestive heart failure were rare, but occurred in 5.2% of the culprit lesion–only group, compared with 1.2% of the multivessel group (RR, 4.46; 95% CI, 1.53-13.04).

The study was funded by the European Union Seventh Framework Programme, the German Heart Research Foundation, and the German Centre for Cardiovascular Research. Dr. Thiele had no relevant conflicts of interest.

SOURCE: Thiele H et al. N Engl J Med. 2018 Aug 25. doi: 10.1056/NEJMoa1808788.