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Effect of Romosozumab vs. Alendronate on Osteoporosis Fracture Risk
Study Overview
Objective. To determine if romosuzumab, an antisclerostin antibody, is superior to alendronate in reducing the incidence of fracture in postmenopausal women with osteoporosis at high-risk for fracture.
Design. Multicenter, international, double-blind, randomized clinical trial.
Setting and participants. 4093 postmenopausal women with osteoporosis and a previous fragility fracture were enrolled from over 40 countries worldwide. Patients were eligible for the study if they were 55 to 90 years old and were deemed at high risk for future fracture based on bone mineral density (BMD) T score at the total hip or femoral neck and fracture history. This included T score ≤ –2.5 and ≥ 1 moderate or severe vertebral fractures or ≥ 2 mild vertebral fractures; T score ≤ –2.0 and either ≥ 2 moderate or severe vertebral fractures or proximal femur fracture within 3 to 24 months before randomization. Subjects with a history of prior use of medications that affect bone metabolism were excluded, as were those with other metabolic bone disease, vitamin D deficiency, uncontrolled metabolic disease, malabsorption syndromes, history of transplant, severe renal insufficiency, malignancy or severe illness.
Intervention. Patients were randomized to either subcutaneous romosuzumab 210 mg monthly or oral alendronate 70 mg weekly for 12 months. Following the 12-month double-blind period, all patients received open-label weekly alendronate until the end of the trial, with maintenance of blinding to the initial treatment assignment. Primary analysis occurred when all subjects had completed the 24-month visit and clinical fractures had been confirmed in at least 330 patients. All patients received daily calcium and vitamin D. Lateral radiographs of the thoracic and lumbar spine were obtained at screening and months 12 and 24. The BMD at the lumbar spine and proximal femur was evaluated by dual-energy x-ray absorptiometry at baseline and every 12 months thereafter. Serum concentrations of bone-turnover markers were measured in a subgroup of patients.
Main outcome measures. The primary outcomes were the incidence of new vertebral fracture and the incidence of clinical fracture at 24 months. Clinical fractures included symptomatic vertebral fracture and nonvertebral fractures. The secondary outcomes were the BMD at the lumbar spine, total hip, and femoral neck at 12 and 24 months, the incidence of nonvertebral fracture, and fracture category. Safety outcomes included the incidence of adjudicated clinical events, including serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fracture. Serious cardiovascular events were defined as cardiac ischemic event, cerebrovascular event, heart failure, death, non-coronary revascularization and peripheral vascular ischemic event not requiring revascularization.
Analysis. An intention to treat approach was used for data analysis. For the incidence of fractures, the treatment groups were compared using a Cox proportional-hazards model and the Mantel-Haenszel method with adjustment for age (< 75 vs ≥ 75 years), the presence or absence of severe vertebral fracture at baseline, and baseline BMD T score at the total hip. Between-group comparisons of the percentage change in BMD from baseline were analyzed by means of a repeated-measures model with adjustment for treatment, age category, baseline severe vertebral fracture, visit, treatment-by-visit interaction, and baseline BMD. Percentage changes from baseline in bone turnover were assessed using a Wilcoxon rank-sum test. The safety analysis included cumulated incidence rates of adverse outcomes. Odds ratios and confidence intervals were estimated for serious cardiovascular adverse events with the use of a logistic regression model.
Main results. 2046 participants were randomized to the romosozumab group and 2047 to the alendronate group. A total of 3654 participants from both groups (89.3%) completed 12 months of the trial, and 3150 (77.0%) completed the primary analysis period. The treatment groups were similar in baseline age, ethnicity, and fracture history. The majority of patients in both groups were non-Hispanic (> 60%) and ≥ 75 years old (> 50%). The mean age of the patients was 74.3 years. Baseline mean bone mineral density T scores were –2.96 at the lumbar spine, –2.8 at the total hip, and –2.9 at the femoral neck.
After 24 months of treatment, 6.2% of patients in the romosozumab-alendronate group had a new vertebral fracture as compared to 11.9% in the alendronate-alendronate group. This represents a 48% lower risk (risk ratio 0.52, 95% confidence interval [CI] 0.4–0.66; P < 0.001) of new vertebral fractures with romosozumab. At the time of the primary analysis, romosozumab followed by alendronate resulted in a 27% lower risk of clinical fracture than alendronate alone (hazard ratio 0.73, 95% CI 0.61–0.88; P < 0.001). 8.7% of the romosozumab-alendronate group had a nonvertebral fracture versus 10.6% in the alendronate-alendronate group, representing a 19% lower risk with romosozumab (hazard ratio 0.81, 95% CI 0.66–0.99; P = 0.04). Hip fractures occurred in 2.0% of the romosozumab-alendronate group as compared with 3.2% in the alendronate-alendronate group, representing a 38% lower risk with romosozumab (hazard ratio 0.62, 95% CI 0.42–0.92; P
Patients in the romosozumab-alendronate group had greater gains in BMD from baseline at the lumbar spine (14.9% vs 8.5%) and total hip (7% vs 3.6%) compared to the alendronate-alendronate group. (P < 0.001 for all comparisons). At 12 months, romosozumab treatment resulted in decreased levels of bone resorption marker β-CTX and increased levels of bone formation marker P1NP. β-CTX and P1NP decreased and remained below baseline levels after transitioning to alendronate. In the alendronate-alendronate group, P1NP and β-CTX decreased within 1 month and remained below baseline levels at 36 months.
Overall, the adverse events and serious event rates were similar between the 2 treatment groups during the double-blind period with 2 exceptions. In the first 12 months, injection-site reactions were reported in 4.4% of patients receiving romosozumab compared to 2.6% in those receiving alendronate. Patients in the romosozumab group had an increased incidence of adjudicated serious cardiovascular outcomes during the double-blind period, 2.5% (50 of 2040 patients) compared to 1.9% (38 of 2014 patients) in the alendronate group. During the open-label period, osteonecrosis of the jaw occurred in one patient in each group. Two atypical femoral fractures occurred in the romosozumab-alendronate group, compared to 4 in the alendronate-alendronate group. During the first 18 months of the study, binding anti-romosozumab antibodies were observed in 15.3% of the romosozumab group, with neutralizing antibodies in 0.6%.
Conclusion. In postmenopausal woman with osteoporosis and high fracture risk, 12 months of romosozumab treatment followed by alendronate resulted in significantly lower risk of fracture than use of alendronate alone.
Commentary
Osteoporosis-related fragility fractures carry a substantial risk of morbidity and mortality [1]. The goal of osteoporosis treatment is to ameliorate this risk. The current FDA-approved medications for osteoporosis can be divided into anabolic (teriparatide, abaloparatide) and anti-resorptive (bisphosphonate, denosumab, selective estrogen receptor modulators) categories. Sclerostin is a glycoprotein produced by osteocytes that inhibits the Wnt signaling pathway, thereby impeding osteoblast proliferation and activity. Romosozumab is a monoclonal antisclerostin antibody that results in both increased bone formation and decreased bone resorption [1]. By apparently uncoupling bone formation and resorption to increase bone mass, this medication holds promise to become the ideal osteoporosis drug.
Initial studies have shown that 12 months of romosozumab treatment significantly increased BMD at the lumbar spine (+11.3%), as compared to placebo (–0.1%), alendronate (+4.1%), and teriparatide (+7.1%) [2]. The Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) was a large (7180 patients) randomized controlled trial that demonstrated that 12 months of romosozumab resulted in a 73% lower risk of vertebral fracture and 36% lower risk of clinical fracture compared to placebo [3]. However, there was no significant reduction in non-vertebral facture [3]. This may be due to the fact that FRAME excluded women at the highest risk for fracture. That is, exclusion criteria included history of hip fracture, any severe vertebral facture, or more than 2 moderate vertebral fractures. The current phase 3 ARCH trial (Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk) attempts to clarify the potential benefit of romosozumab treatment in this very high-risk patient population, compared to a common first-line osteoporosis treatment, alendronate.
Indeed, ARCH demonstrates that sequential therapy with romosozumab followed by alendronate is superior to alendronate alone in improving BMD at all sites and preventing new vertebral, clinical, and non-vertebral fractures in postmenopausal women with osteoporosis and a history of fragility fracture. While ARCH was not designed as a cardiovascular outcomes trial, the higher rate of serious cardiovascular adverse events in the romosozumab group raises concern that romosozumab may have a negative effect on vascular tissue. Sclerostin is expressed in vascular smooth muscle [4] and upregulated at sites of vascular calcification [5]. It is possible that inhibiting sclerostin activity could alter vascular remodeling or increase vascular calcification. However, it is interesting that in the larger FRAME trial, no increase in adverse cardiovascular events was seen in the romosozumab group compared to placebo. This may be due to the fact that the average age of patients in FRAME was lower than ARCH. However, it also raises the hypothesis that alendronate itself may be protective in terms of cardiovascular risk. It has been postulated that bisphosphonates may have cardiovascular protective effects, given animal studies have demonstrated that alendronate downregulates monocyte chemoattractant protein 1 and macrophage inflammatory protein 1 [6]. However no cardioprotective benefit was seen in meta-analysis [7].
ARCH has several strengths, including its design as an international, double-blind, and randomized clinical trial. The primary outcome of cumulative fracture incidence is a hard endpoint and is clinically relevant. The intervention is simple and the results are clearly defined. The statistical assessment yields significant results. However, there are some limitations to the study. The lead author has received research support from Amgen and UCB Pharma, the makers of romosuzumab. Amgen and UCB Pharma designed the trial, and Amgen was responsible for trial oversight and data analyses per a pre-specified statistical analysis plan. An external independent data monitoring committee monitored unblinded safety data. Because there was no placebo-controlled arm, it is difficult to determine whether the unexpected cardiovascular signal was due to romosuzumab itself or a protective effect of alendronate. In addition, the majority of study participants were non-Hispanic from Central or Eastern Europe and Latin America, with only ~2% of patients from North America. As a result, ARCH findings may not be generalizable to other regional or ethnic populations. Furthermore, the majority of the patients were ≥ 75 years of age and were at very high fracture risk. It is unclear if younger patients or those with lower risk of fracture would see the same fracture prevention and BMD gain. In addition, because of the relatively short length of the trial, the durability of the metabolic bone benefit and cardiovascular risk is unknown. While the authors reported the increased anti-romosozumab antibodies in the romosozumab group had no detectable effect on efficacy or safety, given the short duration of the trial, this has not been proven.
Applications for Clinical Practice
The dual anti-resorptive and anabolic effect of romosozumab makes it an attractive and promising new osteoporosis therapy. ARCH suggests that sequential therapy with romosuzumab and alendronate is superior in terms of fracture prevention to alendronate alone in elderly postmenopausal women with osteoporosis and a history of fragility fractures, although longer term studies are needed to define the durability of this effect. While the absolute number of serious adjudicated cardiovascular events was low, the increased incidence in the romosuzumab group will likely prevent the FDA from approving this medication for widespread use at this time. Additional studies are needed to clarify the cause and magnitude of this cardiovascular risk and to determine whether prevention of fracture-associated morbidity and mortality is enough to mitigate it.
—Simona Frunza-Stefan, MD, and Hillary B. Whitlach, MD, University of Maryland School of Medicine, Baltimore, MD
1. Cummings SR, Melton IJ. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002; 359:176107.
2. McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014;370:412–20.
3. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016;375:1532–43.
4. Zhu D, Mackenzie NCW, Millán JL, et al. The appearance and modulation of osteocyte marker expres- sion during calcification of vascular smooth muscle cells. PLoS One 2011;6:e19595.
5. Evenepoel P, Goffin E, Meijers B, et al. Sclerostin serum levels and vascular calcification progression in prevalent renal transplant recipients. J Clin Endocrinol Metab 2015;100:4669–76.
6. Masuda T, Deng X, Tamai R. Mouse macrophages primed with alendronate down-regulate monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) production in response to Toll-like receptor (TLR) 2 and TLR4 agonist via Smad3 activation. Int Immunopharmacol 2009;9:1115–21.
7. Kim DH, Rogers JR, Fulchino LA, et al. Bisphosphonates and risk of cardiovascular events: a meta-analysis. PLoS One 2015;10:e0122646.
Study Overview
Objective. To determine if romosuzumab, an antisclerostin antibody, is superior to alendronate in reducing the incidence of fracture in postmenopausal women with osteoporosis at high-risk for fracture.
Design. Multicenter, international, double-blind, randomized clinical trial.
Setting and participants. 4093 postmenopausal women with osteoporosis and a previous fragility fracture were enrolled from over 40 countries worldwide. Patients were eligible for the study if they were 55 to 90 years old and were deemed at high risk for future fracture based on bone mineral density (BMD) T score at the total hip or femoral neck and fracture history. This included T score ≤ –2.5 and ≥ 1 moderate or severe vertebral fractures or ≥ 2 mild vertebral fractures; T score ≤ –2.0 and either ≥ 2 moderate or severe vertebral fractures or proximal femur fracture within 3 to 24 months before randomization. Subjects with a history of prior use of medications that affect bone metabolism were excluded, as were those with other metabolic bone disease, vitamin D deficiency, uncontrolled metabolic disease, malabsorption syndromes, history of transplant, severe renal insufficiency, malignancy or severe illness.
Intervention. Patients were randomized to either subcutaneous romosuzumab 210 mg monthly or oral alendronate 70 mg weekly for 12 months. Following the 12-month double-blind period, all patients received open-label weekly alendronate until the end of the trial, with maintenance of blinding to the initial treatment assignment. Primary analysis occurred when all subjects had completed the 24-month visit and clinical fractures had been confirmed in at least 330 patients. All patients received daily calcium and vitamin D. Lateral radiographs of the thoracic and lumbar spine were obtained at screening and months 12 and 24. The BMD at the lumbar spine and proximal femur was evaluated by dual-energy x-ray absorptiometry at baseline and every 12 months thereafter. Serum concentrations of bone-turnover markers were measured in a subgroup of patients.
Main outcome measures. The primary outcomes were the incidence of new vertebral fracture and the incidence of clinical fracture at 24 months. Clinical fractures included symptomatic vertebral fracture and nonvertebral fractures. The secondary outcomes were the BMD at the lumbar spine, total hip, and femoral neck at 12 and 24 months, the incidence of nonvertebral fracture, and fracture category. Safety outcomes included the incidence of adjudicated clinical events, including serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fracture. Serious cardiovascular events were defined as cardiac ischemic event, cerebrovascular event, heart failure, death, non-coronary revascularization and peripheral vascular ischemic event not requiring revascularization.
Analysis. An intention to treat approach was used for data analysis. For the incidence of fractures, the treatment groups were compared using a Cox proportional-hazards model and the Mantel-Haenszel method with adjustment for age (< 75 vs ≥ 75 years), the presence or absence of severe vertebral fracture at baseline, and baseline BMD T score at the total hip. Between-group comparisons of the percentage change in BMD from baseline were analyzed by means of a repeated-measures model with adjustment for treatment, age category, baseline severe vertebral fracture, visit, treatment-by-visit interaction, and baseline BMD. Percentage changes from baseline in bone turnover were assessed using a Wilcoxon rank-sum test. The safety analysis included cumulated incidence rates of adverse outcomes. Odds ratios and confidence intervals were estimated for serious cardiovascular adverse events with the use of a logistic regression model.
Main results. 2046 participants were randomized to the romosozumab group and 2047 to the alendronate group. A total of 3654 participants from both groups (89.3%) completed 12 months of the trial, and 3150 (77.0%) completed the primary analysis period. The treatment groups were similar in baseline age, ethnicity, and fracture history. The majority of patients in both groups were non-Hispanic (> 60%) and ≥ 75 years old (> 50%). The mean age of the patients was 74.3 years. Baseline mean bone mineral density T scores were –2.96 at the lumbar spine, –2.8 at the total hip, and –2.9 at the femoral neck.
After 24 months of treatment, 6.2% of patients in the romosozumab-alendronate group had a new vertebral fracture as compared to 11.9% in the alendronate-alendronate group. This represents a 48% lower risk (risk ratio 0.52, 95% confidence interval [CI] 0.4–0.66; P < 0.001) of new vertebral fractures with romosozumab. At the time of the primary analysis, romosozumab followed by alendronate resulted in a 27% lower risk of clinical fracture than alendronate alone (hazard ratio 0.73, 95% CI 0.61–0.88; P < 0.001). 8.7% of the romosozumab-alendronate group had a nonvertebral fracture versus 10.6% in the alendronate-alendronate group, representing a 19% lower risk with romosozumab (hazard ratio 0.81, 95% CI 0.66–0.99; P = 0.04). Hip fractures occurred in 2.0% of the romosozumab-alendronate group as compared with 3.2% in the alendronate-alendronate group, representing a 38% lower risk with romosozumab (hazard ratio 0.62, 95% CI 0.42–0.92; P
Patients in the romosozumab-alendronate group had greater gains in BMD from baseline at the lumbar spine (14.9% vs 8.5%) and total hip (7% vs 3.6%) compared to the alendronate-alendronate group. (P < 0.001 for all comparisons). At 12 months, romosozumab treatment resulted in decreased levels of bone resorption marker β-CTX and increased levels of bone formation marker P1NP. β-CTX and P1NP decreased and remained below baseline levels after transitioning to alendronate. In the alendronate-alendronate group, P1NP and β-CTX decreased within 1 month and remained below baseline levels at 36 months.
Overall, the adverse events and serious event rates were similar between the 2 treatment groups during the double-blind period with 2 exceptions. In the first 12 months, injection-site reactions were reported in 4.4% of patients receiving romosozumab compared to 2.6% in those receiving alendronate. Patients in the romosozumab group had an increased incidence of adjudicated serious cardiovascular outcomes during the double-blind period, 2.5% (50 of 2040 patients) compared to 1.9% (38 of 2014 patients) in the alendronate group. During the open-label period, osteonecrosis of the jaw occurred in one patient in each group. Two atypical femoral fractures occurred in the romosozumab-alendronate group, compared to 4 in the alendronate-alendronate group. During the first 18 months of the study, binding anti-romosozumab antibodies were observed in 15.3% of the romosozumab group, with neutralizing antibodies in 0.6%.
Conclusion. In postmenopausal woman with osteoporosis and high fracture risk, 12 months of romosozumab treatment followed by alendronate resulted in significantly lower risk of fracture than use of alendronate alone.
Commentary
Osteoporosis-related fragility fractures carry a substantial risk of morbidity and mortality [1]. The goal of osteoporosis treatment is to ameliorate this risk. The current FDA-approved medications for osteoporosis can be divided into anabolic (teriparatide, abaloparatide) and anti-resorptive (bisphosphonate, denosumab, selective estrogen receptor modulators) categories. Sclerostin is a glycoprotein produced by osteocytes that inhibits the Wnt signaling pathway, thereby impeding osteoblast proliferation and activity. Romosozumab is a monoclonal antisclerostin antibody that results in both increased bone formation and decreased bone resorption [1]. By apparently uncoupling bone formation and resorption to increase bone mass, this medication holds promise to become the ideal osteoporosis drug.
Initial studies have shown that 12 months of romosozumab treatment significantly increased BMD at the lumbar spine (+11.3%), as compared to placebo (–0.1%), alendronate (+4.1%), and teriparatide (+7.1%) [2]. The Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) was a large (7180 patients) randomized controlled trial that demonstrated that 12 months of romosozumab resulted in a 73% lower risk of vertebral fracture and 36% lower risk of clinical fracture compared to placebo [3]. However, there was no significant reduction in non-vertebral facture [3]. This may be due to the fact that FRAME excluded women at the highest risk for fracture. That is, exclusion criteria included history of hip fracture, any severe vertebral facture, or more than 2 moderate vertebral fractures. The current phase 3 ARCH trial (Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk) attempts to clarify the potential benefit of romosozumab treatment in this very high-risk patient population, compared to a common first-line osteoporosis treatment, alendronate.
Indeed, ARCH demonstrates that sequential therapy with romosozumab followed by alendronate is superior to alendronate alone in improving BMD at all sites and preventing new vertebral, clinical, and non-vertebral fractures in postmenopausal women with osteoporosis and a history of fragility fracture. While ARCH was not designed as a cardiovascular outcomes trial, the higher rate of serious cardiovascular adverse events in the romosozumab group raises concern that romosozumab may have a negative effect on vascular tissue. Sclerostin is expressed in vascular smooth muscle [4] and upregulated at sites of vascular calcification [5]. It is possible that inhibiting sclerostin activity could alter vascular remodeling or increase vascular calcification. However, it is interesting that in the larger FRAME trial, no increase in adverse cardiovascular events was seen in the romosozumab group compared to placebo. This may be due to the fact that the average age of patients in FRAME was lower than ARCH. However, it also raises the hypothesis that alendronate itself may be protective in terms of cardiovascular risk. It has been postulated that bisphosphonates may have cardiovascular protective effects, given animal studies have demonstrated that alendronate downregulates monocyte chemoattractant protein 1 and macrophage inflammatory protein 1 [6]. However no cardioprotective benefit was seen in meta-analysis [7].
ARCH has several strengths, including its design as an international, double-blind, and randomized clinical trial. The primary outcome of cumulative fracture incidence is a hard endpoint and is clinically relevant. The intervention is simple and the results are clearly defined. The statistical assessment yields significant results. However, there are some limitations to the study. The lead author has received research support from Amgen and UCB Pharma, the makers of romosuzumab. Amgen and UCB Pharma designed the trial, and Amgen was responsible for trial oversight and data analyses per a pre-specified statistical analysis plan. An external independent data monitoring committee monitored unblinded safety data. Because there was no placebo-controlled arm, it is difficult to determine whether the unexpected cardiovascular signal was due to romosuzumab itself or a protective effect of alendronate. In addition, the majority of study participants were non-Hispanic from Central or Eastern Europe and Latin America, with only ~2% of patients from North America. As a result, ARCH findings may not be generalizable to other regional or ethnic populations. Furthermore, the majority of the patients were ≥ 75 years of age and were at very high fracture risk. It is unclear if younger patients or those with lower risk of fracture would see the same fracture prevention and BMD gain. In addition, because of the relatively short length of the trial, the durability of the metabolic bone benefit and cardiovascular risk is unknown. While the authors reported the increased anti-romosozumab antibodies in the romosozumab group had no detectable effect on efficacy or safety, given the short duration of the trial, this has not been proven.
Applications for Clinical Practice
The dual anti-resorptive and anabolic effect of romosozumab makes it an attractive and promising new osteoporosis therapy. ARCH suggests that sequential therapy with romosuzumab and alendronate is superior in terms of fracture prevention to alendronate alone in elderly postmenopausal women with osteoporosis and a history of fragility fractures, although longer term studies are needed to define the durability of this effect. While the absolute number of serious adjudicated cardiovascular events was low, the increased incidence in the romosuzumab group will likely prevent the FDA from approving this medication for widespread use at this time. Additional studies are needed to clarify the cause and magnitude of this cardiovascular risk and to determine whether prevention of fracture-associated morbidity and mortality is enough to mitigate it.
—Simona Frunza-Stefan, MD, and Hillary B. Whitlach, MD, University of Maryland School of Medicine, Baltimore, MD
Study Overview
Objective. To determine if romosuzumab, an antisclerostin antibody, is superior to alendronate in reducing the incidence of fracture in postmenopausal women with osteoporosis at high-risk for fracture.
Design. Multicenter, international, double-blind, randomized clinical trial.
Setting and participants. 4093 postmenopausal women with osteoporosis and a previous fragility fracture were enrolled from over 40 countries worldwide. Patients were eligible for the study if they were 55 to 90 years old and were deemed at high risk for future fracture based on bone mineral density (BMD) T score at the total hip or femoral neck and fracture history. This included T score ≤ –2.5 and ≥ 1 moderate or severe vertebral fractures or ≥ 2 mild vertebral fractures; T score ≤ –2.0 and either ≥ 2 moderate or severe vertebral fractures or proximal femur fracture within 3 to 24 months before randomization. Subjects with a history of prior use of medications that affect bone metabolism were excluded, as were those with other metabolic bone disease, vitamin D deficiency, uncontrolled metabolic disease, malabsorption syndromes, history of transplant, severe renal insufficiency, malignancy or severe illness.
Intervention. Patients were randomized to either subcutaneous romosuzumab 210 mg monthly or oral alendronate 70 mg weekly for 12 months. Following the 12-month double-blind period, all patients received open-label weekly alendronate until the end of the trial, with maintenance of blinding to the initial treatment assignment. Primary analysis occurred when all subjects had completed the 24-month visit and clinical fractures had been confirmed in at least 330 patients. All patients received daily calcium and vitamin D. Lateral radiographs of the thoracic and lumbar spine were obtained at screening and months 12 and 24. The BMD at the lumbar spine and proximal femur was evaluated by dual-energy x-ray absorptiometry at baseline and every 12 months thereafter. Serum concentrations of bone-turnover markers were measured in a subgroup of patients.
Main outcome measures. The primary outcomes were the incidence of new vertebral fracture and the incidence of clinical fracture at 24 months. Clinical fractures included symptomatic vertebral fracture and nonvertebral fractures. The secondary outcomes were the BMD at the lumbar spine, total hip, and femoral neck at 12 and 24 months, the incidence of nonvertebral fracture, and fracture category. Safety outcomes included the incidence of adjudicated clinical events, including serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fracture. Serious cardiovascular events were defined as cardiac ischemic event, cerebrovascular event, heart failure, death, non-coronary revascularization and peripheral vascular ischemic event not requiring revascularization.
Analysis. An intention to treat approach was used for data analysis. For the incidence of fractures, the treatment groups were compared using a Cox proportional-hazards model and the Mantel-Haenszel method with adjustment for age (< 75 vs ≥ 75 years), the presence or absence of severe vertebral fracture at baseline, and baseline BMD T score at the total hip. Between-group comparisons of the percentage change in BMD from baseline were analyzed by means of a repeated-measures model with adjustment for treatment, age category, baseline severe vertebral fracture, visit, treatment-by-visit interaction, and baseline BMD. Percentage changes from baseline in bone turnover were assessed using a Wilcoxon rank-sum test. The safety analysis included cumulated incidence rates of adverse outcomes. Odds ratios and confidence intervals were estimated for serious cardiovascular adverse events with the use of a logistic regression model.
Main results. 2046 participants were randomized to the romosozumab group and 2047 to the alendronate group. A total of 3654 participants from both groups (89.3%) completed 12 months of the trial, and 3150 (77.0%) completed the primary analysis period. The treatment groups were similar in baseline age, ethnicity, and fracture history. The majority of patients in both groups were non-Hispanic (> 60%) and ≥ 75 years old (> 50%). The mean age of the patients was 74.3 years. Baseline mean bone mineral density T scores were –2.96 at the lumbar spine, –2.8 at the total hip, and –2.9 at the femoral neck.
After 24 months of treatment, 6.2% of patients in the romosozumab-alendronate group had a new vertebral fracture as compared to 11.9% in the alendronate-alendronate group. This represents a 48% lower risk (risk ratio 0.52, 95% confidence interval [CI] 0.4–0.66; P < 0.001) of new vertebral fractures with romosozumab. At the time of the primary analysis, romosozumab followed by alendronate resulted in a 27% lower risk of clinical fracture than alendronate alone (hazard ratio 0.73, 95% CI 0.61–0.88; P < 0.001). 8.7% of the romosozumab-alendronate group had a nonvertebral fracture versus 10.6% in the alendronate-alendronate group, representing a 19% lower risk with romosozumab (hazard ratio 0.81, 95% CI 0.66–0.99; P = 0.04). Hip fractures occurred in 2.0% of the romosozumab-alendronate group as compared with 3.2% in the alendronate-alendronate group, representing a 38% lower risk with romosozumab (hazard ratio 0.62, 95% CI 0.42–0.92; P
Patients in the romosozumab-alendronate group had greater gains in BMD from baseline at the lumbar spine (14.9% vs 8.5%) and total hip (7% vs 3.6%) compared to the alendronate-alendronate group. (P < 0.001 for all comparisons). At 12 months, romosozumab treatment resulted in decreased levels of bone resorption marker β-CTX and increased levels of bone formation marker P1NP. β-CTX and P1NP decreased and remained below baseline levels after transitioning to alendronate. In the alendronate-alendronate group, P1NP and β-CTX decreased within 1 month and remained below baseline levels at 36 months.
Overall, the adverse events and serious event rates were similar between the 2 treatment groups during the double-blind period with 2 exceptions. In the first 12 months, injection-site reactions were reported in 4.4% of patients receiving romosozumab compared to 2.6% in those receiving alendronate. Patients in the romosozumab group had an increased incidence of adjudicated serious cardiovascular outcomes during the double-blind period, 2.5% (50 of 2040 patients) compared to 1.9% (38 of 2014 patients) in the alendronate group. During the open-label period, osteonecrosis of the jaw occurred in one patient in each group. Two atypical femoral fractures occurred in the romosozumab-alendronate group, compared to 4 in the alendronate-alendronate group. During the first 18 months of the study, binding anti-romosozumab antibodies were observed in 15.3% of the romosozumab group, with neutralizing antibodies in 0.6%.
Conclusion. In postmenopausal woman with osteoporosis and high fracture risk, 12 months of romosozumab treatment followed by alendronate resulted in significantly lower risk of fracture than use of alendronate alone.
Commentary
Osteoporosis-related fragility fractures carry a substantial risk of morbidity and mortality [1]. The goal of osteoporosis treatment is to ameliorate this risk. The current FDA-approved medications for osteoporosis can be divided into anabolic (teriparatide, abaloparatide) and anti-resorptive (bisphosphonate, denosumab, selective estrogen receptor modulators) categories. Sclerostin is a glycoprotein produced by osteocytes that inhibits the Wnt signaling pathway, thereby impeding osteoblast proliferation and activity. Romosozumab is a monoclonal antisclerostin antibody that results in both increased bone formation and decreased bone resorption [1]. By apparently uncoupling bone formation and resorption to increase bone mass, this medication holds promise to become the ideal osteoporosis drug.
Initial studies have shown that 12 months of romosozumab treatment significantly increased BMD at the lumbar spine (+11.3%), as compared to placebo (–0.1%), alendronate (+4.1%), and teriparatide (+7.1%) [2]. The Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) was a large (7180 patients) randomized controlled trial that demonstrated that 12 months of romosozumab resulted in a 73% lower risk of vertebral fracture and 36% lower risk of clinical fracture compared to placebo [3]. However, there was no significant reduction in non-vertebral facture [3]. This may be due to the fact that FRAME excluded women at the highest risk for fracture. That is, exclusion criteria included history of hip fracture, any severe vertebral facture, or more than 2 moderate vertebral fractures. The current phase 3 ARCH trial (Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk) attempts to clarify the potential benefit of romosozumab treatment in this very high-risk patient population, compared to a common first-line osteoporosis treatment, alendronate.
Indeed, ARCH demonstrates that sequential therapy with romosozumab followed by alendronate is superior to alendronate alone in improving BMD at all sites and preventing new vertebral, clinical, and non-vertebral fractures in postmenopausal women with osteoporosis and a history of fragility fracture. While ARCH was not designed as a cardiovascular outcomes trial, the higher rate of serious cardiovascular adverse events in the romosozumab group raises concern that romosozumab may have a negative effect on vascular tissue. Sclerostin is expressed in vascular smooth muscle [4] and upregulated at sites of vascular calcification [5]. It is possible that inhibiting sclerostin activity could alter vascular remodeling or increase vascular calcification. However, it is interesting that in the larger FRAME trial, no increase in adverse cardiovascular events was seen in the romosozumab group compared to placebo. This may be due to the fact that the average age of patients in FRAME was lower than ARCH. However, it also raises the hypothesis that alendronate itself may be protective in terms of cardiovascular risk. It has been postulated that bisphosphonates may have cardiovascular protective effects, given animal studies have demonstrated that alendronate downregulates monocyte chemoattractant protein 1 and macrophage inflammatory protein 1 [6]. However no cardioprotective benefit was seen in meta-analysis [7].
ARCH has several strengths, including its design as an international, double-blind, and randomized clinical trial. The primary outcome of cumulative fracture incidence is a hard endpoint and is clinically relevant. The intervention is simple and the results are clearly defined. The statistical assessment yields significant results. However, there are some limitations to the study. The lead author has received research support from Amgen and UCB Pharma, the makers of romosuzumab. Amgen and UCB Pharma designed the trial, and Amgen was responsible for trial oversight and data analyses per a pre-specified statistical analysis plan. An external independent data monitoring committee monitored unblinded safety data. Because there was no placebo-controlled arm, it is difficult to determine whether the unexpected cardiovascular signal was due to romosuzumab itself or a protective effect of alendronate. In addition, the majority of study participants were non-Hispanic from Central or Eastern Europe and Latin America, with only ~2% of patients from North America. As a result, ARCH findings may not be generalizable to other regional or ethnic populations. Furthermore, the majority of the patients were ≥ 75 years of age and were at very high fracture risk. It is unclear if younger patients or those with lower risk of fracture would see the same fracture prevention and BMD gain. In addition, because of the relatively short length of the trial, the durability of the metabolic bone benefit and cardiovascular risk is unknown. While the authors reported the increased anti-romosozumab antibodies in the romosozumab group had no detectable effect on efficacy or safety, given the short duration of the trial, this has not been proven.
Applications for Clinical Practice
The dual anti-resorptive and anabolic effect of romosozumab makes it an attractive and promising new osteoporosis therapy. ARCH suggests that sequential therapy with romosuzumab and alendronate is superior in terms of fracture prevention to alendronate alone in elderly postmenopausal women with osteoporosis and a history of fragility fractures, although longer term studies are needed to define the durability of this effect. While the absolute number of serious adjudicated cardiovascular events was low, the increased incidence in the romosuzumab group will likely prevent the FDA from approving this medication for widespread use at this time. Additional studies are needed to clarify the cause and magnitude of this cardiovascular risk and to determine whether prevention of fracture-associated morbidity and mortality is enough to mitigate it.
—Simona Frunza-Stefan, MD, and Hillary B. Whitlach, MD, University of Maryland School of Medicine, Baltimore, MD
1. Cummings SR, Melton IJ. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002; 359:176107.
2. McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014;370:412–20.
3. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016;375:1532–43.
4. Zhu D, Mackenzie NCW, Millán JL, et al. The appearance and modulation of osteocyte marker expres- sion during calcification of vascular smooth muscle cells. PLoS One 2011;6:e19595.
5. Evenepoel P, Goffin E, Meijers B, et al. Sclerostin serum levels and vascular calcification progression in prevalent renal transplant recipients. J Clin Endocrinol Metab 2015;100:4669–76.
6. Masuda T, Deng X, Tamai R. Mouse macrophages primed with alendronate down-regulate monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) production in response to Toll-like receptor (TLR) 2 and TLR4 agonist via Smad3 activation. Int Immunopharmacol 2009;9:1115–21.
7. Kim DH, Rogers JR, Fulchino LA, et al. Bisphosphonates and risk of cardiovascular events: a meta-analysis. PLoS One 2015;10:e0122646.
1. Cummings SR, Melton IJ. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002; 359:176107.
2. McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014;370:412–20.
3. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016;375:1532–43.
4. Zhu D, Mackenzie NCW, Millán JL, et al. The appearance and modulation of osteocyte marker expres- sion during calcification of vascular smooth muscle cells. PLoS One 2011;6:e19595.
5. Evenepoel P, Goffin E, Meijers B, et al. Sclerostin serum levels and vascular calcification progression in prevalent renal transplant recipients. J Clin Endocrinol Metab 2015;100:4669–76.
6. Masuda T, Deng X, Tamai R. Mouse macrophages primed with alendronate down-regulate monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) production in response to Toll-like receptor (TLR) 2 and TLR4 agonist via Smad3 activation. Int Immunopharmacol 2009;9:1115–21.
7. Kim DH, Rogers JR, Fulchino LA, et al. Bisphosphonates and risk of cardiovascular events: a meta-analysis. PLoS One 2015;10:e0122646.
Which Herpes Zoster Vaccine is Most Cost-Effective?
Study Overview
Objective. To assess the cost-effectiveness of the new adjuvanted herpes zoster subunit vaccine (HZ/su) as compared with that of the current live attenuated herpes zoster vaccine (ZVL), or no vaccine.
Design. Markov decision model evaluating 3 strategies from a societal perspective: (1) no vaccination, (2) vaccination with single dose ZVL, and (3) vaccination with 2-dose series of HZ/su.
Setting and participants. Data for the model were extracted from the US medical literature using PubMed through January 2015. Data were derived from studies of fewer than 100 patients to more than 30,000 patients, depending on the variable assessed. Variables included epidemiologic parameters, vaccine efficacy and adverse events, quality-adjusted life-years (QALYs), and costs. Because there is no standard willingness-to-pay (WTP) threshold for cost-effectiveness in the United States, $50,000 per QALY was chosen.
Main outcome measures. Total costs and QALYs.
Main results. At all ages, no vaccination was always the least expensive and least effective option, while HZ/su was always the most effective and less expensive than ZVL. At a proposed price of $280 per series ($140 per dose), HZ/su was more effective and less expensive than ZVL at all ages. The incremental cost-effectiveness ratios compared with no vaccination ranged from $20,038 to $30,084 per QALY, depending on vaccination age. The cost-effectiveness of HZ/su was insensitive to the waning rate of either vaccine due to its high efficacy, with initial level of protection close to 90% even among people 70 years or older.
Conclusion. At a manufacturer suggested price of $280 per series ($140 per dose), HZ/su would cost less than ZVL and has a high probability of offering good value.
Commentary
Herpes zosters is a localized, usually painful, cutaneous eruption resulting from reactivation of latent varicella zoster virus. It is a common disease with approximately one million cases occurring each year in the United States [1]. The incidence increases with age, from 5 cases per 1000 population in adults aged 50–59 years to 11 cases per 1000 population in persons aged ≥ 80 years. Postherpetic neuralgia, commonly defined as persistent pain for at least 90 days following the resolution of the herpes zoster rash, is the most common complication and occurs in 10% to 13% of herpes zoster cases in persons aged > 50 years [2,3].
In 2006, the US Food and Drug Administration (FDA) approved the ZVL vaccine Zostavax (Merck) for prevention of postherpetic neuralgia. By 2016, 33% of adults aged ≥ 60 years reported receipt of the vaccine [4]. However, ZVL does not prevent all herpes zoster, particularly among the elderly. Moreover, the efficacy wanes completely after approximately 10 years [5]. To address these shortcomings, a 2-dose HZ/su (Shingrix; GlaxoSmithKline) containing recombinant glycoprotein E in combination with a novel adjuvant (AS01B) was approved by the FDA in adults aged ≥ 50 years. In randomized controlled trials, HZ/su has an efficacy of close to 97%, even after age 70 years [6].
With the approval of the new attenuated herpes zoster vaccine, clinicians and patients face the question of which vaccine to get and when. The cost-effectiveness analysis published by Le and Rothberg in this study compare the value of HZ/su with ZVL vaccine and a no-vaccine strategy for individuals 60 years or older from the US societal perspective. The results suggest that, at $140 per dose, using HZ/su vaccine compared with no vaccine would cost between $20,038 and $30,084 per QALY and thus is a cost-effective strategy. The deterministic sensitivity analysis indicates that the overall results do not change under different assumptions about model input parameters, even if patients are nonadherent to the second dose of HZ/su vaccine.
As with any simulation study, the major limitation of this study is the accuracy of the model and the assumptions on which it is based. The body of evidence for benefits of ZVL was large, including multiple pre-licensure and post-licensure RCTs, as well as observational studies of effectiveness. On the other hand, the body of evidence for benefits of RZV was primarily informed by one high-quality RCT that studied vaccine efficacy through 4 years post-vaccination [4,6]. Currently, 3 other independent cost-effectiveness analysis are available. The Centers for Disease Control and Prevention model estimated HZ/su vaccine cost per QALY of $31,000 when vaccination occurred at age ≥ 50 years. The GlaxoSmithKline model, manufacturer of HZ/su vaccine, estimated a HZ/su vaccine cost per QALY of $12,000. While the Merck model, manufacturer of the ZVL vaccine, estimated a HZ/su vaccine cost per QALY of $107,000 [4]. In addition to model variables, the key assumption by Le and Rothberg are based on the HZ/su vaccine cost at $140 per dose and ZVL at $213. The study results need to be interpreted carefully if the vaccine prices turn out to be different in the future.
Applications for Clinical Practice
The current study by Le and Rothberg demonstrated the cost-effectiveness of the new HZ/su vaccine. Since the study’s publication, the CDC has updated their recommendations on immunization practices for use of herpes zoster vaccine [4]. HZ/su vaccine, also known as the recombinant zoster vaccine (RZV), is now preferred over ZVL for the prevention of herpes zoster and related complications. RZV is recommended for immunocompetent adults age 50 or older, 10 years earlier than previously for the ZVL. In addition, RZV is recommended for adults who previously received ZVL. Finally, RZV can be administered concomitantly with other adult vaccines, does not require screening for a history of varicella, and is likely safe for immunocompromised persons.
—Ka Ming Gordon Ngai, MD, MPH
1. Insinga RP, Itzler RF, Pellissier JM, et al. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 2005;20:748–53.
2. Yawn BP, Saddier P, Wollan PC, et al. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007;82:1341–9.
3. Oxman MN, Levin MJ, Johnson GR, et al. Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Eng J Med 2005;352:2271-84.
4. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep 2018;67:103–8.
5. Morrison VA, Johnson GR, Schmader KE, et al; Shingles Prevention Study Group. Long-term persistence of zoster vaccine efficacy. Clin Infect Dis 2015;60:900–9.
6. Lai H, Cunningham AL, Godeaux O, et al; ZOE-50 Study Group. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 2015;372:2087–96.
Study Overview
Objective. To assess the cost-effectiveness of the new adjuvanted herpes zoster subunit vaccine (HZ/su) as compared with that of the current live attenuated herpes zoster vaccine (ZVL), or no vaccine.
Design. Markov decision model evaluating 3 strategies from a societal perspective: (1) no vaccination, (2) vaccination with single dose ZVL, and (3) vaccination with 2-dose series of HZ/su.
Setting and participants. Data for the model were extracted from the US medical literature using PubMed through January 2015. Data were derived from studies of fewer than 100 patients to more than 30,000 patients, depending on the variable assessed. Variables included epidemiologic parameters, vaccine efficacy and adverse events, quality-adjusted life-years (QALYs), and costs. Because there is no standard willingness-to-pay (WTP) threshold for cost-effectiveness in the United States, $50,000 per QALY was chosen.
Main outcome measures. Total costs and QALYs.
Main results. At all ages, no vaccination was always the least expensive and least effective option, while HZ/su was always the most effective and less expensive than ZVL. At a proposed price of $280 per series ($140 per dose), HZ/su was more effective and less expensive than ZVL at all ages. The incremental cost-effectiveness ratios compared with no vaccination ranged from $20,038 to $30,084 per QALY, depending on vaccination age. The cost-effectiveness of HZ/su was insensitive to the waning rate of either vaccine due to its high efficacy, with initial level of protection close to 90% even among people 70 years or older.
Conclusion. At a manufacturer suggested price of $280 per series ($140 per dose), HZ/su would cost less than ZVL and has a high probability of offering good value.
Commentary
Herpes zosters is a localized, usually painful, cutaneous eruption resulting from reactivation of latent varicella zoster virus. It is a common disease with approximately one million cases occurring each year in the United States [1]. The incidence increases with age, from 5 cases per 1000 population in adults aged 50–59 years to 11 cases per 1000 population in persons aged ≥ 80 years. Postherpetic neuralgia, commonly defined as persistent pain for at least 90 days following the resolution of the herpes zoster rash, is the most common complication and occurs in 10% to 13% of herpes zoster cases in persons aged > 50 years [2,3].
In 2006, the US Food and Drug Administration (FDA) approved the ZVL vaccine Zostavax (Merck) for prevention of postherpetic neuralgia. By 2016, 33% of adults aged ≥ 60 years reported receipt of the vaccine [4]. However, ZVL does not prevent all herpes zoster, particularly among the elderly. Moreover, the efficacy wanes completely after approximately 10 years [5]. To address these shortcomings, a 2-dose HZ/su (Shingrix; GlaxoSmithKline) containing recombinant glycoprotein E in combination with a novel adjuvant (AS01B) was approved by the FDA in adults aged ≥ 50 years. In randomized controlled trials, HZ/su has an efficacy of close to 97%, even after age 70 years [6].
With the approval of the new attenuated herpes zoster vaccine, clinicians and patients face the question of which vaccine to get and when. The cost-effectiveness analysis published by Le and Rothberg in this study compare the value of HZ/su with ZVL vaccine and a no-vaccine strategy for individuals 60 years or older from the US societal perspective. The results suggest that, at $140 per dose, using HZ/su vaccine compared with no vaccine would cost between $20,038 and $30,084 per QALY and thus is a cost-effective strategy. The deterministic sensitivity analysis indicates that the overall results do not change under different assumptions about model input parameters, even if patients are nonadherent to the second dose of HZ/su vaccine.
As with any simulation study, the major limitation of this study is the accuracy of the model and the assumptions on which it is based. The body of evidence for benefits of ZVL was large, including multiple pre-licensure and post-licensure RCTs, as well as observational studies of effectiveness. On the other hand, the body of evidence for benefits of RZV was primarily informed by one high-quality RCT that studied vaccine efficacy through 4 years post-vaccination [4,6]. Currently, 3 other independent cost-effectiveness analysis are available. The Centers for Disease Control and Prevention model estimated HZ/su vaccine cost per QALY of $31,000 when vaccination occurred at age ≥ 50 years. The GlaxoSmithKline model, manufacturer of HZ/su vaccine, estimated a HZ/su vaccine cost per QALY of $12,000. While the Merck model, manufacturer of the ZVL vaccine, estimated a HZ/su vaccine cost per QALY of $107,000 [4]. In addition to model variables, the key assumption by Le and Rothberg are based on the HZ/su vaccine cost at $140 per dose and ZVL at $213. The study results need to be interpreted carefully if the vaccine prices turn out to be different in the future.
Applications for Clinical Practice
The current study by Le and Rothberg demonstrated the cost-effectiveness of the new HZ/su vaccine. Since the study’s publication, the CDC has updated their recommendations on immunization practices for use of herpes zoster vaccine [4]. HZ/su vaccine, also known as the recombinant zoster vaccine (RZV), is now preferred over ZVL for the prevention of herpes zoster and related complications. RZV is recommended for immunocompetent adults age 50 or older, 10 years earlier than previously for the ZVL. In addition, RZV is recommended for adults who previously received ZVL. Finally, RZV can be administered concomitantly with other adult vaccines, does not require screening for a history of varicella, and is likely safe for immunocompromised persons.
—Ka Ming Gordon Ngai, MD, MPH
Study Overview
Objective. To assess the cost-effectiveness of the new adjuvanted herpes zoster subunit vaccine (HZ/su) as compared with that of the current live attenuated herpes zoster vaccine (ZVL), or no vaccine.
Design. Markov decision model evaluating 3 strategies from a societal perspective: (1) no vaccination, (2) vaccination with single dose ZVL, and (3) vaccination with 2-dose series of HZ/su.
Setting and participants. Data for the model were extracted from the US medical literature using PubMed through January 2015. Data were derived from studies of fewer than 100 patients to more than 30,000 patients, depending on the variable assessed. Variables included epidemiologic parameters, vaccine efficacy and adverse events, quality-adjusted life-years (QALYs), and costs. Because there is no standard willingness-to-pay (WTP) threshold for cost-effectiveness in the United States, $50,000 per QALY was chosen.
Main outcome measures. Total costs and QALYs.
Main results. At all ages, no vaccination was always the least expensive and least effective option, while HZ/su was always the most effective and less expensive than ZVL. At a proposed price of $280 per series ($140 per dose), HZ/su was more effective and less expensive than ZVL at all ages. The incremental cost-effectiveness ratios compared with no vaccination ranged from $20,038 to $30,084 per QALY, depending on vaccination age. The cost-effectiveness of HZ/su was insensitive to the waning rate of either vaccine due to its high efficacy, with initial level of protection close to 90% even among people 70 years or older.
Conclusion. At a manufacturer suggested price of $280 per series ($140 per dose), HZ/su would cost less than ZVL and has a high probability of offering good value.
Commentary
Herpes zosters is a localized, usually painful, cutaneous eruption resulting from reactivation of latent varicella zoster virus. It is a common disease with approximately one million cases occurring each year in the United States [1]. The incidence increases with age, from 5 cases per 1000 population in adults aged 50–59 years to 11 cases per 1000 population in persons aged ≥ 80 years. Postherpetic neuralgia, commonly defined as persistent pain for at least 90 days following the resolution of the herpes zoster rash, is the most common complication and occurs in 10% to 13% of herpes zoster cases in persons aged > 50 years [2,3].
In 2006, the US Food and Drug Administration (FDA) approved the ZVL vaccine Zostavax (Merck) for prevention of postherpetic neuralgia. By 2016, 33% of adults aged ≥ 60 years reported receipt of the vaccine [4]. However, ZVL does not prevent all herpes zoster, particularly among the elderly. Moreover, the efficacy wanes completely after approximately 10 years [5]. To address these shortcomings, a 2-dose HZ/su (Shingrix; GlaxoSmithKline) containing recombinant glycoprotein E in combination with a novel adjuvant (AS01B) was approved by the FDA in adults aged ≥ 50 years. In randomized controlled trials, HZ/su has an efficacy of close to 97%, even after age 70 years [6].
With the approval of the new attenuated herpes zoster vaccine, clinicians and patients face the question of which vaccine to get and when. The cost-effectiveness analysis published by Le and Rothberg in this study compare the value of HZ/su with ZVL vaccine and a no-vaccine strategy for individuals 60 years or older from the US societal perspective. The results suggest that, at $140 per dose, using HZ/su vaccine compared with no vaccine would cost between $20,038 and $30,084 per QALY and thus is a cost-effective strategy. The deterministic sensitivity analysis indicates that the overall results do not change under different assumptions about model input parameters, even if patients are nonadherent to the second dose of HZ/su vaccine.
As with any simulation study, the major limitation of this study is the accuracy of the model and the assumptions on which it is based. The body of evidence for benefits of ZVL was large, including multiple pre-licensure and post-licensure RCTs, as well as observational studies of effectiveness. On the other hand, the body of evidence for benefits of RZV was primarily informed by one high-quality RCT that studied vaccine efficacy through 4 years post-vaccination [4,6]. Currently, 3 other independent cost-effectiveness analysis are available. The Centers for Disease Control and Prevention model estimated HZ/su vaccine cost per QALY of $31,000 when vaccination occurred at age ≥ 50 years. The GlaxoSmithKline model, manufacturer of HZ/su vaccine, estimated a HZ/su vaccine cost per QALY of $12,000. While the Merck model, manufacturer of the ZVL vaccine, estimated a HZ/su vaccine cost per QALY of $107,000 [4]. In addition to model variables, the key assumption by Le and Rothberg are based on the HZ/su vaccine cost at $140 per dose and ZVL at $213. The study results need to be interpreted carefully if the vaccine prices turn out to be different in the future.
Applications for Clinical Practice
The current study by Le and Rothberg demonstrated the cost-effectiveness of the new HZ/su vaccine. Since the study’s publication, the CDC has updated their recommendations on immunization practices for use of herpes zoster vaccine [4]. HZ/su vaccine, also known as the recombinant zoster vaccine (RZV), is now preferred over ZVL for the prevention of herpes zoster and related complications. RZV is recommended for immunocompetent adults age 50 or older, 10 years earlier than previously for the ZVL. In addition, RZV is recommended for adults who previously received ZVL. Finally, RZV can be administered concomitantly with other adult vaccines, does not require screening for a history of varicella, and is likely safe for immunocompromised persons.
—Ka Ming Gordon Ngai, MD, MPH
1. Insinga RP, Itzler RF, Pellissier JM, et al. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 2005;20:748–53.
2. Yawn BP, Saddier P, Wollan PC, et al. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007;82:1341–9.
3. Oxman MN, Levin MJ, Johnson GR, et al. Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Eng J Med 2005;352:2271-84.
4. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep 2018;67:103–8.
5. Morrison VA, Johnson GR, Schmader KE, et al; Shingles Prevention Study Group. Long-term persistence of zoster vaccine efficacy. Clin Infect Dis 2015;60:900–9.
6. Lai H, Cunningham AL, Godeaux O, et al; ZOE-50 Study Group. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 2015;372:2087–96.
1. Insinga RP, Itzler RF, Pellissier JM, et al. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 2005;20:748–53.
2. Yawn BP, Saddier P, Wollan PC, et al. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007;82:1341–9.
3. Oxman MN, Levin MJ, Johnson GR, et al. Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Eng J Med 2005;352:2271-84.
4. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep 2018;67:103–8.
5. Morrison VA, Johnson GR, Schmader KE, et al; Shingles Prevention Study Group. Long-term persistence of zoster vaccine efficacy. Clin Infect Dis 2015;60:900–9.
6. Lai H, Cunningham AL, Godeaux O, et al; ZOE-50 Study Group. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 2015;372:2087–96.
Non-Culprit Lesion PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock
Study Overview
Objective. To determine if percutaneous coronary intervention (PCI) of non-culprit vessels should be performed in patients with acute myocardial infarction and cardiogenic shock.
Design. Multicenter randomized controlled trial.
Setting and participants. 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock were assigned to one of 2 revascularization strategies: PCI of the culprit lesion only with the option of staged revascularization of non-culprit lesions, or immediate multivessel PCI.
Main outcome measures. The primary endpoint was the composite of death or severe renal failure leading to renal replacement therapy within 30 days after randomization. Safety endpoints included bleeding and stroke.
Main results. The primary endpoint of death or renal replacement therapy occurred in 158 /344 patients (45.9%) in the culprit lesion–only PCI group and 189/341 patients (55.4%) in the multivessel PCI group (relative risk [RR] 0.83, 95% CI 0.72–0.96, P = 0.01). The rate of death from any cause was lower in the culprit lesion–only PCI group compared to multivessel PCI group (RR 0.84, 95% CI 0.72–0.98, P = 0.03). There was no difference in stroke and numerically lower risk of bleeding in culprit lesion–only PCI group (RR 0.75, 95% CI 0.55–1.03).
Conclusion. Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of death or severe renal failure leading to renal replacement therapy was lower in patients who initially underwent PCI of the culprit lesion only compared with patients who underwent immediate multivessel PCI.
Commentary
Patients presenting with cardiogenic shock at the time of acute myocardial infarction have the highest mortality—up to 50%. Since the original SHOCK trial in 1999, it is known that the mortality can be reduced by early revascularization of the culprit vessel [1]. However, whether the non-culprit vessel should be revascularized at the time of presentation with acute myocardial infarction is unknown.
Recently, there have been multiple trials suggesting the benefit of non-culprit vessel revascularization in patients with acute myocardial infarction who are hemodynamically stable at the time of their presentation. Three recent trials—PRAMI, CvPRIT and DANAMI-PRIMULTI—investigated this clinical question and found benefit of non-culprit vessel revascularization [2–4]. The results of these trials led to a focused update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention in 2015 [5]. Noninfarct-related artery PCI in hemodynamically stable patients presenting with acute myocardial infarction was upgraded to class IIb from class III [5]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is not mentioned in the guidelines.
In the current CULPRIT-SHOCK trial, Thiele et al investigated this clinical question by performing a well-designed clinical trial in patients with acute myocardial infarction and cardiogenic shock. They found that the composite endpoint of death and renal replacement therapy at 30 days occurred more frequently in the multivessel PCI group compared with the culprit lesion–only group (relative risk [RR] 0.83, 95% CI 0.71–0.96, P = 0.01). The composite endpoint was mainly driven by death (43.3% vs 51.6%, RR 0.84, 95% CI 0.72–0.98, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (11.6% vs 16.4%, P = 0.07). The study was conducted in the sickest population compared to prior trials as evidenced by high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stay (median 5 days). The significance of non-culprit lesion was determined by angiogram (stenosis > 70%). The culprit vessel–only group had treatment of the culprit vessel only initially, but the staged intervention for non-culprit vessel was encouraged.
A unique point of this trial is that patients with chronic total occlusion (CTO) were included in the study and it was encouraged to attempt revascularization of CTO lesions, contrary to previous trials. Although CTO intervention improves angina and ejection fraction [6,7], whether CTO intervention has a mortality benefit needs further investigation. In the CULPRIT-SHOCK trial, 24% of patients had one or more CTO lesions. This most likely contributed to the increased contrast use in the multivessel PCI group (250 vs 190 mL, P < 0.01). CTO is considered a most challenging lesion to treat, and expertise and skill level vary among operators. In the hybrid CTO intervention model, it is recommended to stage the intervention as much as possible, as this type of intervention requires meticulous planning [8]. There is a possibility that attempting CTO intervention in this acute setting caused more harm than benefit. Furthermore, the investigators did not report the success rate of CTO intervention.
Another interesting finding of this trial is that the mortality of both groups was high (43.3% vs 51.6%). The revascularization arm of the original shock trial almost 20 years ago had a 30-day mortality of 46.7%, which is almost identical with the current CULPRIT-SHOCK study. Despite improvement in hemodynamic support such as Impella, TandemHeart, extracorporeal membrane oxygenation device, and improvement in medical therapy over the years, patients with cardiogenic shock with acute myocardial infarction have a dismal prognosis.
The CULPRIT-SHOCK trial has number of strengths, including low drop-out rate (3%) and adequate power, however, there are some limitations. Some patients crossed over from culprit-vessel only to multivessel PCI group due to lack of hemodynamic improvement, plaque shifts, and newly detected lesions after treatment of the culprit lesion. On the other hand, some patients crossed over from multivessel PCI from culprit lesion only due to multiple reasons, including technical difficulty of intervention.
Applications for Clinical Practice
In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion–only intervention and focusing on hemodynamic support with a staged intervention if necessary seems to be better strategy than immediate multivessel PCI, including non-culprit vessel PCI.
—Taishi Hirai, MD, University of Chicago Medical Center, Chicago, IL
1. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock. N Engl J Med 1999;341:625–34.
2. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med 2013;369:1115–23.
3. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol 2015;65:963–72.
4. Engstrom T, Kelbaek H, Helqvist S, et al. Complete revasculari Outcomes Research in Review www.mdedge.com/jcomjournal Vol. 25, No. 3 March 2018 JCOM 103 sation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet 2015;386:665–71.
5. Levine GN, Bates ER, Blankenship JC, et al. 2015 ACC/AHA/SCAI Focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol 2016;67:1235–50.
6. Sapontis J, Salisbury AC, Yeh RW, et al. Early procedural and health status outcomes after chronic total occlusion angioplasty: a report from the OPEN-CTO Registry (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures). JACC Cardiovasc Interv 2017;10:1523–34.
7. Henriques JP, Hoebers LP, Ramunddal T, et al. Percutaneous intervention for concurrent chronic total occlusions in patients with STEMI: the EXPLORE trial. J Am Coll Cardiol 2016;68:1622–32.
8. Brilakis ES, Grantham JA, Rinfret S, et al. A percutaneous treatment algorithm for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2012;5:367–79.
Study Overview
Objective. To determine if percutaneous coronary intervention (PCI) of non-culprit vessels should be performed in patients with acute myocardial infarction and cardiogenic shock.
Design. Multicenter randomized controlled trial.
Setting and participants. 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock were assigned to one of 2 revascularization strategies: PCI of the culprit lesion only with the option of staged revascularization of non-culprit lesions, or immediate multivessel PCI.
Main outcome measures. The primary endpoint was the composite of death or severe renal failure leading to renal replacement therapy within 30 days after randomization. Safety endpoints included bleeding and stroke.
Main results. The primary endpoint of death or renal replacement therapy occurred in 158 /344 patients (45.9%) in the culprit lesion–only PCI group and 189/341 patients (55.4%) in the multivessel PCI group (relative risk [RR] 0.83, 95% CI 0.72–0.96, P = 0.01). The rate of death from any cause was lower in the culprit lesion–only PCI group compared to multivessel PCI group (RR 0.84, 95% CI 0.72–0.98, P = 0.03). There was no difference in stroke and numerically lower risk of bleeding in culprit lesion–only PCI group (RR 0.75, 95% CI 0.55–1.03).
Conclusion. Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of death or severe renal failure leading to renal replacement therapy was lower in patients who initially underwent PCI of the culprit lesion only compared with patients who underwent immediate multivessel PCI.
Commentary
Patients presenting with cardiogenic shock at the time of acute myocardial infarction have the highest mortality—up to 50%. Since the original SHOCK trial in 1999, it is known that the mortality can be reduced by early revascularization of the culprit vessel [1]. However, whether the non-culprit vessel should be revascularized at the time of presentation with acute myocardial infarction is unknown.
Recently, there have been multiple trials suggesting the benefit of non-culprit vessel revascularization in patients with acute myocardial infarction who are hemodynamically stable at the time of their presentation. Three recent trials—PRAMI, CvPRIT and DANAMI-PRIMULTI—investigated this clinical question and found benefit of non-culprit vessel revascularization [2–4]. The results of these trials led to a focused update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention in 2015 [5]. Noninfarct-related artery PCI in hemodynamically stable patients presenting with acute myocardial infarction was upgraded to class IIb from class III [5]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is not mentioned in the guidelines.
In the current CULPRIT-SHOCK trial, Thiele et al investigated this clinical question by performing a well-designed clinical trial in patients with acute myocardial infarction and cardiogenic shock. They found that the composite endpoint of death and renal replacement therapy at 30 days occurred more frequently in the multivessel PCI group compared with the culprit lesion–only group (relative risk [RR] 0.83, 95% CI 0.71–0.96, P = 0.01). The composite endpoint was mainly driven by death (43.3% vs 51.6%, RR 0.84, 95% CI 0.72–0.98, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (11.6% vs 16.4%, P = 0.07). The study was conducted in the sickest population compared to prior trials as evidenced by high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stay (median 5 days). The significance of non-culprit lesion was determined by angiogram (stenosis > 70%). The culprit vessel–only group had treatment of the culprit vessel only initially, but the staged intervention for non-culprit vessel was encouraged.
A unique point of this trial is that patients with chronic total occlusion (CTO) were included in the study and it was encouraged to attempt revascularization of CTO lesions, contrary to previous trials. Although CTO intervention improves angina and ejection fraction [6,7], whether CTO intervention has a mortality benefit needs further investigation. In the CULPRIT-SHOCK trial, 24% of patients had one or more CTO lesions. This most likely contributed to the increased contrast use in the multivessel PCI group (250 vs 190 mL, P < 0.01). CTO is considered a most challenging lesion to treat, and expertise and skill level vary among operators. In the hybrid CTO intervention model, it is recommended to stage the intervention as much as possible, as this type of intervention requires meticulous planning [8]. There is a possibility that attempting CTO intervention in this acute setting caused more harm than benefit. Furthermore, the investigators did not report the success rate of CTO intervention.
Another interesting finding of this trial is that the mortality of both groups was high (43.3% vs 51.6%). The revascularization arm of the original shock trial almost 20 years ago had a 30-day mortality of 46.7%, which is almost identical with the current CULPRIT-SHOCK study. Despite improvement in hemodynamic support such as Impella, TandemHeart, extracorporeal membrane oxygenation device, and improvement in medical therapy over the years, patients with cardiogenic shock with acute myocardial infarction have a dismal prognosis.
The CULPRIT-SHOCK trial has number of strengths, including low drop-out rate (3%) and adequate power, however, there are some limitations. Some patients crossed over from culprit-vessel only to multivessel PCI group due to lack of hemodynamic improvement, plaque shifts, and newly detected lesions after treatment of the culprit lesion. On the other hand, some patients crossed over from multivessel PCI from culprit lesion only due to multiple reasons, including technical difficulty of intervention.
Applications for Clinical Practice
In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion–only intervention and focusing on hemodynamic support with a staged intervention if necessary seems to be better strategy than immediate multivessel PCI, including non-culprit vessel PCI.
—Taishi Hirai, MD, University of Chicago Medical Center, Chicago, IL
Study Overview
Objective. To determine if percutaneous coronary intervention (PCI) of non-culprit vessels should be performed in patients with acute myocardial infarction and cardiogenic shock.
Design. Multicenter randomized controlled trial.
Setting and participants. 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock were assigned to one of 2 revascularization strategies: PCI of the culprit lesion only with the option of staged revascularization of non-culprit lesions, or immediate multivessel PCI.
Main outcome measures. The primary endpoint was the composite of death or severe renal failure leading to renal replacement therapy within 30 days after randomization. Safety endpoints included bleeding and stroke.
Main results. The primary endpoint of death or renal replacement therapy occurred in 158 /344 patients (45.9%) in the culprit lesion–only PCI group and 189/341 patients (55.4%) in the multivessel PCI group (relative risk [RR] 0.83, 95% CI 0.72–0.96, P = 0.01). The rate of death from any cause was lower in the culprit lesion–only PCI group compared to multivessel PCI group (RR 0.84, 95% CI 0.72–0.98, P = 0.03). There was no difference in stroke and numerically lower risk of bleeding in culprit lesion–only PCI group (RR 0.75, 95% CI 0.55–1.03).
Conclusion. Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of death or severe renal failure leading to renal replacement therapy was lower in patients who initially underwent PCI of the culprit lesion only compared with patients who underwent immediate multivessel PCI.
Commentary
Patients presenting with cardiogenic shock at the time of acute myocardial infarction have the highest mortality—up to 50%. Since the original SHOCK trial in 1999, it is known that the mortality can be reduced by early revascularization of the culprit vessel [1]. However, whether the non-culprit vessel should be revascularized at the time of presentation with acute myocardial infarction is unknown.
Recently, there have been multiple trials suggesting the benefit of non-culprit vessel revascularization in patients with acute myocardial infarction who are hemodynamically stable at the time of their presentation. Three recent trials—PRAMI, CvPRIT and DANAMI-PRIMULTI—investigated this clinical question and found benefit of non-culprit vessel revascularization [2–4]. The results of these trials led to a focused update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention in 2015 [5]. Noninfarct-related artery PCI in hemodynamically stable patients presenting with acute myocardial infarction was upgraded to class IIb from class III [5]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is not mentioned in the guidelines.
In the current CULPRIT-SHOCK trial, Thiele et al investigated this clinical question by performing a well-designed clinical trial in patients with acute myocardial infarction and cardiogenic shock. They found that the composite endpoint of death and renal replacement therapy at 30 days occurred more frequently in the multivessel PCI group compared with the culprit lesion–only group (relative risk [RR] 0.83, 95% CI 0.71–0.96, P = 0.01). The composite endpoint was mainly driven by death (43.3% vs 51.6%, RR 0.84, 95% CI 0.72–0.98, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (11.6% vs 16.4%, P = 0.07). The study was conducted in the sickest population compared to prior trials as evidenced by high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stay (median 5 days). The significance of non-culprit lesion was determined by angiogram (stenosis > 70%). The culprit vessel–only group had treatment of the culprit vessel only initially, but the staged intervention for non-culprit vessel was encouraged.
A unique point of this trial is that patients with chronic total occlusion (CTO) were included in the study and it was encouraged to attempt revascularization of CTO lesions, contrary to previous trials. Although CTO intervention improves angina and ejection fraction [6,7], whether CTO intervention has a mortality benefit needs further investigation. In the CULPRIT-SHOCK trial, 24% of patients had one or more CTO lesions. This most likely contributed to the increased contrast use in the multivessel PCI group (250 vs 190 mL, P < 0.01). CTO is considered a most challenging lesion to treat, and expertise and skill level vary among operators. In the hybrid CTO intervention model, it is recommended to stage the intervention as much as possible, as this type of intervention requires meticulous planning [8]. There is a possibility that attempting CTO intervention in this acute setting caused more harm than benefit. Furthermore, the investigators did not report the success rate of CTO intervention.
Another interesting finding of this trial is that the mortality of both groups was high (43.3% vs 51.6%). The revascularization arm of the original shock trial almost 20 years ago had a 30-day mortality of 46.7%, which is almost identical with the current CULPRIT-SHOCK study. Despite improvement in hemodynamic support such as Impella, TandemHeart, extracorporeal membrane oxygenation device, and improvement in medical therapy over the years, patients with cardiogenic shock with acute myocardial infarction have a dismal prognosis.
The CULPRIT-SHOCK trial has number of strengths, including low drop-out rate (3%) and adequate power, however, there are some limitations. Some patients crossed over from culprit-vessel only to multivessel PCI group due to lack of hemodynamic improvement, plaque shifts, and newly detected lesions after treatment of the culprit lesion. On the other hand, some patients crossed over from multivessel PCI from culprit lesion only due to multiple reasons, including technical difficulty of intervention.
Applications for Clinical Practice
In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion–only intervention and focusing on hemodynamic support with a staged intervention if necessary seems to be better strategy than immediate multivessel PCI, including non-culprit vessel PCI.
—Taishi Hirai, MD, University of Chicago Medical Center, Chicago, IL
1. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock. N Engl J Med 1999;341:625–34.
2. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med 2013;369:1115–23.
3. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol 2015;65:963–72.
4. Engstrom T, Kelbaek H, Helqvist S, et al. Complete revasculari Outcomes Research in Review www.mdedge.com/jcomjournal Vol. 25, No. 3 March 2018 JCOM 103 sation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet 2015;386:665–71.
5. Levine GN, Bates ER, Blankenship JC, et al. 2015 ACC/AHA/SCAI Focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol 2016;67:1235–50.
6. Sapontis J, Salisbury AC, Yeh RW, et al. Early procedural and health status outcomes after chronic total occlusion angioplasty: a report from the OPEN-CTO Registry (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures). JACC Cardiovasc Interv 2017;10:1523–34.
7. Henriques JP, Hoebers LP, Ramunddal T, et al. Percutaneous intervention for concurrent chronic total occlusions in patients with STEMI: the EXPLORE trial. J Am Coll Cardiol 2016;68:1622–32.
8. Brilakis ES, Grantham JA, Rinfret S, et al. A percutaneous treatment algorithm for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2012;5:367–79.
1. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock. N Engl J Med 1999;341:625–34.
2. Wald DS, Morris JK, Wald NJ, et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med 2013;369:1115–23.
3. Gershlick AH, Khan JN, Kelly DJ, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol 2015;65:963–72.
4. Engstrom T, Kelbaek H, Helqvist S, et al. Complete revasculari Outcomes Research in Review www.mdedge.com/jcomjournal Vol. 25, No. 3 March 2018 JCOM 103 sation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet 2015;386:665–71.
5. Levine GN, Bates ER, Blankenship JC, et al. 2015 ACC/AHA/SCAI Focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol 2016;67:1235–50.
6. Sapontis J, Salisbury AC, Yeh RW, et al. Early procedural and health status outcomes after chronic total occlusion angioplasty: a report from the OPEN-CTO Registry (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures). JACC Cardiovasc Interv 2017;10:1523–34.
7. Henriques JP, Hoebers LP, Ramunddal T, et al. Percutaneous intervention for concurrent chronic total occlusions in patients with STEMI: the EXPLORE trial. J Am Coll Cardiol 2016;68:1622–32.
8. Brilakis ES, Grantham JA, Rinfret S, et al. A percutaneous treatment algorithm for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2012;5:367–79.
Pacritinib bests BAT, doesn’t seem to affect survival
Final results from the PERSIST-2 trial suggest pacritinib can be more effective than best available therapy (BAT) for patients with myelofibrosis and thrombocytopenia, and the drug has no significant effect on survival.
Patients who received pacritinib were more likely to experience at least a 35% reduction in spleen volume and a 50% reduction in total symptom score (TSS).
In addition, there was no significant difference in survival between patients who received pacritinib and those who received BAT.
Interim results from PERSIST-2 had indicated that pacritinib negatively impacted survival, which was consistent with results from PERSIST-1. Because of this, the US Food and Drug Administration placed pacritinib trials on clinical hold in February 2016. The hold was lifted in January 2017.
The final results from PERSIST-2 were published in JAMA Oncology. The study was sponsored by CTI BioPharma Corp.
In this phase 3 study, researchers compared 2 dosing schedules of pacritinib to BAT. The study enrolled patients with previously treated or untreated myelofibrosis (intermediate-1/2 or high-risk) and thrombocytopenia (platelet counts ≤ 100 x 109/L).
There were 311 patients randomized to receive pacritinib once daily (n=104), pacritinib twice daily (n=107), or BAT (n=100). Patients in the BAT arm received ruxolitinib (n=44), hydroxyurea (n=19), prednisone and/or prednisolone (n=13), as well as “watchful waiting” (n=19).
Patients could crossover from BAT to pacritinib after week 24 or for progression of splenomegaly. Fifty patients in the BAT arm did cross over.
All patients had discontinued treatment at a median of 23 weeks (pacritinib once daily), 25 weeks (twice daily), and 21 weeks (BAT) from the start of treatment.
Common reasons for discontinuation (in the once daily, twice daily, and BAT arms, respectively) were the clinical hold (59%, 71%, and 27%), adverse events (14%, 9%, and 4%), physician decision (5%, 3%, and 41%), progressive disease (5%, 7%, and 11%), and death (5%, 2%, and 5%).
Efficacy
The intention-to-treat efficacy population included 75 patients in the once-daily arm, 74 in the twice-daily arm, and 72 in the BAT arm. The researchers said baseline characteristics were balanced across the arms.
The co-primary endpoints were the rate of patients achieving a spleen volume reduction (SVR) of 35% or more and a 50% or more reduction in TSS at week 24.
Eighteen percent of patients in the combined pacritinib arms and 3% of patients in the BAT arm achieved an SVR of 35% or more (P=0.001). Fifteen percent of patients in the pacritinib once-daily arm and 22% of patients in the twice-daily arm achieved this endpoint (P values of 0.02 and 0.001, respectively, for comparison with BAT).
Twenty-five percent of patients in the combined pacritinib arms and 14% in the BAT arm had at least a 50% reduction in TSS (P=0.079). Seventeen percent of patients in the pacritinib once-daily arm and 32% of patients in the twice-daily arm achieved this endpoint (P values of 0.65 and 0.01, respectively, for comparison with BAT).
“Pacritinib was shown to reduce both spleen volume and total symptom score, 2 very important clinical measures in myelofibrosis patients with thrombocytopenia, including those patients who received prior treatment with ruxolitinib,” said study author John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York.
Survival
When the clinical hold was placed, there was no significant difference in overall survival between the 3 treatment arms.
The rates of death were 14% (n=14) in the pacritinib once-daily arm, 9% (n=10) in the twice-daily arm, and 14% (n=14) in the BAT arm. For patients in the BAT arm, the death rate was lower for those who crossed over to pacritinib (8%, n=4) than for those who did not (20%, n=10).
The hazard ratios for death were 1.18 in the once-daily pacritinib arm and 0.68 in the twice-daily pacritinib arm.
Safety
Dr Mascarenhas said pacritinib had “a generally manageable safety profile.”
Common adverse events—in the once daily, twice daily, and BAT arms, respectively—included:
- Diarrhea—67%, 48%, and 15%
- Nausea—38%, 32%, and 11%
- Thrombocytopenia—33%, 34%, and 23%
- Anemia—28%, 24%, and 15%
- Vomiting—21%, 19%, and 5%
- Fatigue—17%, 17%, and 16%
- Peripheral edema—13%, 2%, and 15%
- Dizziness—14%, 15%, and 5%
- Abdominal pain—19%, 9%, and 19%
- Pyrexia—11%, 15%, and 3%.
Grade 3/4 events—in the once daily, twice daily, and BAT arms, respectively—included:
- Thrombocytopenia—31%, 32%, and 18%
- Anemia—27%, 22%, and 14%
- Neutropenia—9%, 7%, and 5%
- Pneumonia—4%, 7%, and 3%
- Fatigue—7%, 3%, and 5%
- Diarrhea—5%, 4%, and 0%
- Epistaxis—2%, 5%, and 1%.
Serious adverse events—in the once daily, twice daily, and BAT arms, respectively—included:
- Anemia—5%, 8%, and 3%
- Thrombocytopenia—2%, 6%, and 2%
- Pneumonia—5%, 6%, and 4%
- Acute renal failure—5%, 2%, and 2%
- Congestive heart failure—1%, 4%, and 2%
- Atrial fibrillation—3%, 0%, and 3%
- Cardiac arrest—2%, 0%, and 0%
- Epistaxis—2%, 2%, and 1%
- Subdural hematoma—2%, 0%, and 0%.
Final results from the PERSIST-2 trial suggest pacritinib can be more effective than best available therapy (BAT) for patients with myelofibrosis and thrombocytopenia, and the drug has no significant effect on survival.
Patients who received pacritinib were more likely to experience at least a 35% reduction in spleen volume and a 50% reduction in total symptom score (TSS).
In addition, there was no significant difference in survival between patients who received pacritinib and those who received BAT.
Interim results from PERSIST-2 had indicated that pacritinib negatively impacted survival, which was consistent with results from PERSIST-1. Because of this, the US Food and Drug Administration placed pacritinib trials on clinical hold in February 2016. The hold was lifted in January 2017.
The final results from PERSIST-2 were published in JAMA Oncology. The study was sponsored by CTI BioPharma Corp.
In this phase 3 study, researchers compared 2 dosing schedules of pacritinib to BAT. The study enrolled patients with previously treated or untreated myelofibrosis (intermediate-1/2 or high-risk) and thrombocytopenia (platelet counts ≤ 100 x 109/L).
There were 311 patients randomized to receive pacritinib once daily (n=104), pacritinib twice daily (n=107), or BAT (n=100). Patients in the BAT arm received ruxolitinib (n=44), hydroxyurea (n=19), prednisone and/or prednisolone (n=13), as well as “watchful waiting” (n=19).
Patients could crossover from BAT to pacritinib after week 24 or for progression of splenomegaly. Fifty patients in the BAT arm did cross over.
All patients had discontinued treatment at a median of 23 weeks (pacritinib once daily), 25 weeks (twice daily), and 21 weeks (BAT) from the start of treatment.
Common reasons for discontinuation (in the once daily, twice daily, and BAT arms, respectively) were the clinical hold (59%, 71%, and 27%), adverse events (14%, 9%, and 4%), physician decision (5%, 3%, and 41%), progressive disease (5%, 7%, and 11%), and death (5%, 2%, and 5%).
Efficacy
The intention-to-treat efficacy population included 75 patients in the once-daily arm, 74 in the twice-daily arm, and 72 in the BAT arm. The researchers said baseline characteristics were balanced across the arms.
The co-primary endpoints were the rate of patients achieving a spleen volume reduction (SVR) of 35% or more and a 50% or more reduction in TSS at week 24.
Eighteen percent of patients in the combined pacritinib arms and 3% of patients in the BAT arm achieved an SVR of 35% or more (P=0.001). Fifteen percent of patients in the pacritinib once-daily arm and 22% of patients in the twice-daily arm achieved this endpoint (P values of 0.02 and 0.001, respectively, for comparison with BAT).
Twenty-five percent of patients in the combined pacritinib arms and 14% in the BAT arm had at least a 50% reduction in TSS (P=0.079). Seventeen percent of patients in the pacritinib once-daily arm and 32% of patients in the twice-daily arm achieved this endpoint (P values of 0.65 and 0.01, respectively, for comparison with BAT).
“Pacritinib was shown to reduce both spleen volume and total symptom score, 2 very important clinical measures in myelofibrosis patients with thrombocytopenia, including those patients who received prior treatment with ruxolitinib,” said study author John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York.
Survival
When the clinical hold was placed, there was no significant difference in overall survival between the 3 treatment arms.
The rates of death were 14% (n=14) in the pacritinib once-daily arm, 9% (n=10) in the twice-daily arm, and 14% (n=14) in the BAT arm. For patients in the BAT arm, the death rate was lower for those who crossed over to pacritinib (8%, n=4) than for those who did not (20%, n=10).
The hazard ratios for death were 1.18 in the once-daily pacritinib arm and 0.68 in the twice-daily pacritinib arm.
Safety
Dr Mascarenhas said pacritinib had “a generally manageable safety profile.”
Common adverse events—in the once daily, twice daily, and BAT arms, respectively—included:
- Diarrhea—67%, 48%, and 15%
- Nausea—38%, 32%, and 11%
- Thrombocytopenia—33%, 34%, and 23%
- Anemia—28%, 24%, and 15%
- Vomiting—21%, 19%, and 5%
- Fatigue—17%, 17%, and 16%
- Peripheral edema—13%, 2%, and 15%
- Dizziness—14%, 15%, and 5%
- Abdominal pain—19%, 9%, and 19%
- Pyrexia—11%, 15%, and 3%.
Grade 3/4 events—in the once daily, twice daily, and BAT arms, respectively—included:
- Thrombocytopenia—31%, 32%, and 18%
- Anemia—27%, 22%, and 14%
- Neutropenia—9%, 7%, and 5%
- Pneumonia—4%, 7%, and 3%
- Fatigue—7%, 3%, and 5%
- Diarrhea—5%, 4%, and 0%
- Epistaxis—2%, 5%, and 1%.
Serious adverse events—in the once daily, twice daily, and BAT arms, respectively—included:
- Anemia—5%, 8%, and 3%
- Thrombocytopenia—2%, 6%, and 2%
- Pneumonia—5%, 6%, and 4%
- Acute renal failure—5%, 2%, and 2%
- Congestive heart failure—1%, 4%, and 2%
- Atrial fibrillation—3%, 0%, and 3%
- Cardiac arrest—2%, 0%, and 0%
- Epistaxis—2%, 2%, and 1%
- Subdural hematoma—2%, 0%, and 0%.
Final results from the PERSIST-2 trial suggest pacritinib can be more effective than best available therapy (BAT) for patients with myelofibrosis and thrombocytopenia, and the drug has no significant effect on survival.
Patients who received pacritinib were more likely to experience at least a 35% reduction in spleen volume and a 50% reduction in total symptom score (TSS).
In addition, there was no significant difference in survival between patients who received pacritinib and those who received BAT.
Interim results from PERSIST-2 had indicated that pacritinib negatively impacted survival, which was consistent with results from PERSIST-1. Because of this, the US Food and Drug Administration placed pacritinib trials on clinical hold in February 2016. The hold was lifted in January 2017.
The final results from PERSIST-2 were published in JAMA Oncology. The study was sponsored by CTI BioPharma Corp.
In this phase 3 study, researchers compared 2 dosing schedules of pacritinib to BAT. The study enrolled patients with previously treated or untreated myelofibrosis (intermediate-1/2 or high-risk) and thrombocytopenia (platelet counts ≤ 100 x 109/L).
There were 311 patients randomized to receive pacritinib once daily (n=104), pacritinib twice daily (n=107), or BAT (n=100). Patients in the BAT arm received ruxolitinib (n=44), hydroxyurea (n=19), prednisone and/or prednisolone (n=13), as well as “watchful waiting” (n=19).
Patients could crossover from BAT to pacritinib after week 24 or for progression of splenomegaly. Fifty patients in the BAT arm did cross over.
All patients had discontinued treatment at a median of 23 weeks (pacritinib once daily), 25 weeks (twice daily), and 21 weeks (BAT) from the start of treatment.
Common reasons for discontinuation (in the once daily, twice daily, and BAT arms, respectively) were the clinical hold (59%, 71%, and 27%), adverse events (14%, 9%, and 4%), physician decision (5%, 3%, and 41%), progressive disease (5%, 7%, and 11%), and death (5%, 2%, and 5%).
Efficacy
The intention-to-treat efficacy population included 75 patients in the once-daily arm, 74 in the twice-daily arm, and 72 in the BAT arm. The researchers said baseline characteristics were balanced across the arms.
The co-primary endpoints were the rate of patients achieving a spleen volume reduction (SVR) of 35% or more and a 50% or more reduction in TSS at week 24.
Eighteen percent of patients in the combined pacritinib arms and 3% of patients in the BAT arm achieved an SVR of 35% or more (P=0.001). Fifteen percent of patients in the pacritinib once-daily arm and 22% of patients in the twice-daily arm achieved this endpoint (P values of 0.02 and 0.001, respectively, for comparison with BAT).
Twenty-five percent of patients in the combined pacritinib arms and 14% in the BAT arm had at least a 50% reduction in TSS (P=0.079). Seventeen percent of patients in the pacritinib once-daily arm and 32% of patients in the twice-daily arm achieved this endpoint (P values of 0.65 and 0.01, respectively, for comparison with BAT).
“Pacritinib was shown to reduce both spleen volume and total symptom score, 2 very important clinical measures in myelofibrosis patients with thrombocytopenia, including those patients who received prior treatment with ruxolitinib,” said study author John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York.
Survival
When the clinical hold was placed, there was no significant difference in overall survival between the 3 treatment arms.
The rates of death were 14% (n=14) in the pacritinib once-daily arm, 9% (n=10) in the twice-daily arm, and 14% (n=14) in the BAT arm. For patients in the BAT arm, the death rate was lower for those who crossed over to pacritinib (8%, n=4) than for those who did not (20%, n=10).
The hazard ratios for death were 1.18 in the once-daily pacritinib arm and 0.68 in the twice-daily pacritinib arm.
Safety
Dr Mascarenhas said pacritinib had “a generally manageable safety profile.”
Common adverse events—in the once daily, twice daily, and BAT arms, respectively—included:
- Diarrhea—67%, 48%, and 15%
- Nausea—38%, 32%, and 11%
- Thrombocytopenia—33%, 34%, and 23%
- Anemia—28%, 24%, and 15%
- Vomiting—21%, 19%, and 5%
- Fatigue—17%, 17%, and 16%
- Peripheral edema—13%, 2%, and 15%
- Dizziness—14%, 15%, and 5%
- Abdominal pain—19%, 9%, and 19%
- Pyrexia—11%, 15%, and 3%.
Grade 3/4 events—in the once daily, twice daily, and BAT arms, respectively—included:
- Thrombocytopenia—31%, 32%, and 18%
- Anemia—27%, 22%, and 14%
- Neutropenia—9%, 7%, and 5%
- Pneumonia—4%, 7%, and 3%
- Fatigue—7%, 3%, and 5%
- Diarrhea—5%, 4%, and 0%
- Epistaxis—2%, 5%, and 1%.
Serious adverse events—in the once daily, twice daily, and BAT arms, respectively—included:
- Anemia—5%, 8%, and 3%
- Thrombocytopenia—2%, 6%, and 2%
- Pneumonia—5%, 6%, and 4%
- Acute renal failure—5%, 2%, and 2%
- Congestive heart failure—1%, 4%, and 2%
- Atrial fibrillation—3%, 0%, and 3%
- Cardiac arrest—2%, 0%, and 0%
- Epistaxis—2%, 2%, and 1%
- Subdural hematoma—2%, 0%, and 0%.
The ACA and Multiple Sclerosis
Q) How has the Affordable Care Act affected people living with multiple sclerosis—an Americans with Disabilities Act recognized disease?
The Affordable Care Act (ACA) has been a source of controversy since it became law in 2010. Perhaps some of the tension surrounding it stems from misunderstanding; however, it is clear that individual experiences and/or perceptions flavor the ongoing debate. Rather than perpetuate the contention, we’d simply like to outline some of the ways in which patients with multiple sclerosis (MS) have benefited from the ACA—and what we must do to ensure continued quality and affordability of care in the event of changes to the law.
Living with MS in the United States is costly. According to the National Multiple Sclerosis Society, average annual costs—both direct and indirect (ie, lost wages)—are about $69,000. Health care costs account for more than half of this total (about $39,000). Total costs for all people in the US living with MS are estimated at $28 billion per year.1
In 2016, according to the US Census Bureau, almost 13% of Americans lived below the federal poverty level, and 6% of Americans reported “deep poverty”—defined as household income below 50% of the poverty threshold for that year.2 It has been reported that while at least 90% of people living with MS are insured, 70% are struggling to pay for health care. In fact, 30% put off seeking care because of costs; one consequence is delay in filling prescriptions.3
The burden of expense for our MS patients is considerable. Here’s how the ACA has impacted our patients by attempting to minimize the devastating cost.
Guaranteed Health Insurance Coverage for Pre-existing Conditions. When the ACA became law in March 2010, there were three main goals: making affordable health insurance available to more people, expanding the Medicaid program to cover all adults with income below 138% of the federal poverty level, and supporting innovative medical care delivery methods to lower the cost of health care.4
Following the ACA’s full implementation in 2014, private health insurance companies were prevented from refusing coverage to those with pre-existing conditions, such as MS. This was a game changer, since patients, regardless of their MS diagnosis, were now guaranteed individual insurance. Furthermore, they could not be charged increased premiums based on their prior medical history.5
Preventive Services Covered Without Cost-sharing. Under the ACA, health plans generally must provide preventive services, such as those rated A or B by the US Preventive Services Task Force. This includes routine immunizations for both adults and children, which represents a cost savings to patients living with MS. Another advantage is that women, including those living with MS, have access to sexually transmitted infection screenings, breastfeeding support and supplies, domestic violence screening, and contraceptives.6
Improved Coverage Through Medicare. The ACA mandated improvement in coverage with Medicare Part D benefits. In addition to the preventive care benefits noted above, which apply to Medicare recipients as well, the ACA reduced federal payments to Medicare Advantage plans over time and provided bonus payments to plans with high quality ratings.7
Further changes in Medicare spending included the creation of a 15-person, by-appointment board (known as the Independent Payment Advisory Board) tasked with identifying ways to “modify benefits, eligibility, premiums, or taxes,” which will hopefully continue to optimize the cost of care for patients living with MS and utilizing Medicare.7
Cost Savings With Medicaid Expansion. Medicaid expansion was enacted to keep patients with a costly illness, such as MS, from financial destitution because of their condition. As of January 2018, 32 states and the District of Columbia have seen expansion of their programs.8 In those states, people with a household income below 138% of the poverty level (less than $27,000 for a family of three) can now qualify for Medicaid. States that have not expanded coverage include Idaho, Wyoming, Utah, South Dakota, Nebraska, Kansas, Oklahoma, Texas, Missouri, Wisconsin, Tennessee, Mississippi, Alabama, Georgia, Virginia, North Carolina, South Carolina, and Florida.8 The expansion of Medicaid helps MS patients by shrinking the ever-present gap that still prevents some from qualifying for the additional financial assistance they need due to their chronic illness.
One thing we have learned is that MS patients may not realize they have access to some of these services—particularly preventive care—or they may hesitate to obtain services due to a lack of clarity on whether they are covered. Health care providers can remind patients that they may qualify for “unrealized services,” which could provide value and optimize general preventive care. MS patients with Medicare and Medicaid, for example, may not know that they have access to colorectal cancer screenings via a waived deductible.6
Since last year, there has been vigorous discussion about repealing, replacing, or otherwise amending the ACA. While a political discussion is beyond the bounds of this column, we do need to be aware of how changes to the ACA would affect patients with MS.
Optimizing wellness and prevention and providing access to care to patients with a costly disease, such as MS, is important. In addition to ensuring ongoing access to affordable services, we need to do more to improve mental health access and reduce the cost of needed medications. We also need to close the insurance gap in all 50 states. Continued dialogue will be necessary to help government leaders understand the cost impact of MS (and other diseases), in order to keep our country moving in a positive direction that optimizes wellness and health care reform. —ALD
Amy L. Dix, MPAS, PA-C, MSCS
Department of Neurology at Kansas City Multiple Sclerosis Center in Overland Park, Kansas
1. National Multiple Sclerosis Society. Health Policy Fact Sheet #2: Financial burdens for people with MS, their families, and society. www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Documents/Health-Policy-Fact-Sheet-2-Costs.pdf. Accessed February 8, 2018.
2. Center for Poverty Research, University of California—Davis. What is the current poverty rate in the United States? https://poverty.ucdavis.edu/faq/what-current-poverty-rate-united-states. Accessed February 8, 2018.
3. Iezzoni LI, Ngo L. Health, disability, and life insurance experiences of working-age persons with multiple sclerosis. Mult Scler. 2007;13(4):534-546.
4. Centers for Medicare & Medicaid Services. Affordable Care Act (ACA). HealthCare.gov. www.healthcare.gov/glossary/affordable-care-act. Accessed February 8, 2018.
5. US Department of Health and Human Services. About the ACA: pre-existing conditions. www.hhs.gov/healthcare/about-the-aca/pre-existing-conditions/index.html. Accessed February 8, 2018.
6. Tolbert J. The coverage provisions in the Affordable Care Act: an update. Kaiser Family Foundation. www.kff.org/report-section/the-coverage-provisions-in-the-affordable-care-act-an-update-health-insurance-market-reforms. Accessed February 8, 2018.
7. Kaiser Family Foundation. Focus on health reform: summary of key changes to Medicare in 2010 health reform law. https://kaiserfamilyfoundation.files.wordpress.com/2013/01/7948-02.pdf. Accessed February 8, 2018.
8. Families USA. A 50-state look at Medicaid expansion. http://familiesusa.org/product/50-state-look-medicaid-expansion. Accessed February 8, 2018.
Clinician Reviews in partnership with
MS Consult is edited by Colleen J. Harris, MN, NP, MSCN, Nurse Practitioner/Manager of the Multiple Sclerosis Clinic at Foothills Medical Centre in Calgary, Alberta, Canada, and Bryan Walker, MHS, PA-C, who is in the Department of Neurology, Division of MS and Neuroimmunology, at Duke University Medical Center in Durham, North Carolina. This month's responses were authored by Christen Kutz, PhD, PA-C, who practices at Colorado Springs Neurological Associates, and Amy L. Dix, MPAS, PA-C, MSCS, who practices in the Department of Neurology at Kansas City Multiple Sclerosis Center in Overland Park, Kansas.
Clinician Reviews in partnership with
MS Consult is edited by Colleen J. Harris, MN, NP, MSCN, Nurse Practitioner/Manager of the Multiple Sclerosis Clinic at Foothills Medical Centre in Calgary, Alberta, Canada, and Bryan Walker, MHS, PA-C, who is in the Department of Neurology, Division of MS and Neuroimmunology, at Duke University Medical Center in Durham, North Carolina. This month's responses were authored by Christen Kutz, PhD, PA-C, who practices at Colorado Springs Neurological Associates, and Amy L. Dix, MPAS, PA-C, MSCS, who practices in the Department of Neurology at Kansas City Multiple Sclerosis Center in Overland Park, Kansas.
Clinician Reviews in partnership with
MS Consult is edited by Colleen J. Harris, MN, NP, MSCN, Nurse Practitioner/Manager of the Multiple Sclerosis Clinic at Foothills Medical Centre in Calgary, Alberta, Canada, and Bryan Walker, MHS, PA-C, who is in the Department of Neurology, Division of MS and Neuroimmunology, at Duke University Medical Center in Durham, North Carolina. This month's responses were authored by Christen Kutz, PhD, PA-C, who practices at Colorado Springs Neurological Associates, and Amy L. Dix, MPAS, PA-C, MSCS, who practices in the Department of Neurology at Kansas City Multiple Sclerosis Center in Overland Park, Kansas.
Q) How has the Affordable Care Act affected people living with multiple sclerosis—an Americans with Disabilities Act recognized disease?
The Affordable Care Act (ACA) has been a source of controversy since it became law in 2010. Perhaps some of the tension surrounding it stems from misunderstanding; however, it is clear that individual experiences and/or perceptions flavor the ongoing debate. Rather than perpetuate the contention, we’d simply like to outline some of the ways in which patients with multiple sclerosis (MS) have benefited from the ACA—and what we must do to ensure continued quality and affordability of care in the event of changes to the law.
Living with MS in the United States is costly. According to the National Multiple Sclerosis Society, average annual costs—both direct and indirect (ie, lost wages)—are about $69,000. Health care costs account for more than half of this total (about $39,000). Total costs for all people in the US living with MS are estimated at $28 billion per year.1
In 2016, according to the US Census Bureau, almost 13% of Americans lived below the federal poverty level, and 6% of Americans reported “deep poverty”—defined as household income below 50% of the poverty threshold for that year.2 It has been reported that while at least 90% of people living with MS are insured, 70% are struggling to pay for health care. In fact, 30% put off seeking care because of costs; one consequence is delay in filling prescriptions.3
The burden of expense for our MS patients is considerable. Here’s how the ACA has impacted our patients by attempting to minimize the devastating cost.
Guaranteed Health Insurance Coverage for Pre-existing Conditions. When the ACA became law in March 2010, there were three main goals: making affordable health insurance available to more people, expanding the Medicaid program to cover all adults with income below 138% of the federal poverty level, and supporting innovative medical care delivery methods to lower the cost of health care.4
Following the ACA’s full implementation in 2014, private health insurance companies were prevented from refusing coverage to those with pre-existing conditions, such as MS. This was a game changer, since patients, regardless of their MS diagnosis, were now guaranteed individual insurance. Furthermore, they could not be charged increased premiums based on their prior medical history.5
Preventive Services Covered Without Cost-sharing. Under the ACA, health plans generally must provide preventive services, such as those rated A or B by the US Preventive Services Task Force. This includes routine immunizations for both adults and children, which represents a cost savings to patients living with MS. Another advantage is that women, including those living with MS, have access to sexually transmitted infection screenings, breastfeeding support and supplies, domestic violence screening, and contraceptives.6
Improved Coverage Through Medicare. The ACA mandated improvement in coverage with Medicare Part D benefits. In addition to the preventive care benefits noted above, which apply to Medicare recipients as well, the ACA reduced federal payments to Medicare Advantage plans over time and provided bonus payments to plans with high quality ratings.7
Further changes in Medicare spending included the creation of a 15-person, by-appointment board (known as the Independent Payment Advisory Board) tasked with identifying ways to “modify benefits, eligibility, premiums, or taxes,” which will hopefully continue to optimize the cost of care for patients living with MS and utilizing Medicare.7
Cost Savings With Medicaid Expansion. Medicaid expansion was enacted to keep patients with a costly illness, such as MS, from financial destitution because of their condition. As of January 2018, 32 states and the District of Columbia have seen expansion of their programs.8 In those states, people with a household income below 138% of the poverty level (less than $27,000 for a family of three) can now qualify for Medicaid. States that have not expanded coverage include Idaho, Wyoming, Utah, South Dakota, Nebraska, Kansas, Oklahoma, Texas, Missouri, Wisconsin, Tennessee, Mississippi, Alabama, Georgia, Virginia, North Carolina, South Carolina, and Florida.8 The expansion of Medicaid helps MS patients by shrinking the ever-present gap that still prevents some from qualifying for the additional financial assistance they need due to their chronic illness.
One thing we have learned is that MS patients may not realize they have access to some of these services—particularly preventive care—or they may hesitate to obtain services due to a lack of clarity on whether they are covered. Health care providers can remind patients that they may qualify for “unrealized services,” which could provide value and optimize general preventive care. MS patients with Medicare and Medicaid, for example, may not know that they have access to colorectal cancer screenings via a waived deductible.6
Since last year, there has been vigorous discussion about repealing, replacing, or otherwise amending the ACA. While a political discussion is beyond the bounds of this column, we do need to be aware of how changes to the ACA would affect patients with MS.
Optimizing wellness and prevention and providing access to care to patients with a costly disease, such as MS, is important. In addition to ensuring ongoing access to affordable services, we need to do more to improve mental health access and reduce the cost of needed medications. We also need to close the insurance gap in all 50 states. Continued dialogue will be necessary to help government leaders understand the cost impact of MS (and other diseases), in order to keep our country moving in a positive direction that optimizes wellness and health care reform. —ALD
Amy L. Dix, MPAS, PA-C, MSCS
Department of Neurology at Kansas City Multiple Sclerosis Center in Overland Park, Kansas
Q) How has the Affordable Care Act affected people living with multiple sclerosis—an Americans with Disabilities Act recognized disease?
The Affordable Care Act (ACA) has been a source of controversy since it became law in 2010. Perhaps some of the tension surrounding it stems from misunderstanding; however, it is clear that individual experiences and/or perceptions flavor the ongoing debate. Rather than perpetuate the contention, we’d simply like to outline some of the ways in which patients with multiple sclerosis (MS) have benefited from the ACA—and what we must do to ensure continued quality and affordability of care in the event of changes to the law.
Living with MS in the United States is costly. According to the National Multiple Sclerosis Society, average annual costs—both direct and indirect (ie, lost wages)—are about $69,000. Health care costs account for more than half of this total (about $39,000). Total costs for all people in the US living with MS are estimated at $28 billion per year.1
In 2016, according to the US Census Bureau, almost 13% of Americans lived below the federal poverty level, and 6% of Americans reported “deep poverty”—defined as household income below 50% of the poverty threshold for that year.2 It has been reported that while at least 90% of people living with MS are insured, 70% are struggling to pay for health care. In fact, 30% put off seeking care because of costs; one consequence is delay in filling prescriptions.3
The burden of expense for our MS patients is considerable. Here’s how the ACA has impacted our patients by attempting to minimize the devastating cost.
Guaranteed Health Insurance Coverage for Pre-existing Conditions. When the ACA became law in March 2010, there were three main goals: making affordable health insurance available to more people, expanding the Medicaid program to cover all adults with income below 138% of the federal poverty level, and supporting innovative medical care delivery methods to lower the cost of health care.4
Following the ACA’s full implementation in 2014, private health insurance companies were prevented from refusing coverage to those with pre-existing conditions, such as MS. This was a game changer, since patients, regardless of their MS diagnosis, were now guaranteed individual insurance. Furthermore, they could not be charged increased premiums based on their prior medical history.5
Preventive Services Covered Without Cost-sharing. Under the ACA, health plans generally must provide preventive services, such as those rated A or B by the US Preventive Services Task Force. This includes routine immunizations for both adults and children, which represents a cost savings to patients living with MS. Another advantage is that women, including those living with MS, have access to sexually transmitted infection screenings, breastfeeding support and supplies, domestic violence screening, and contraceptives.6
Improved Coverage Through Medicare. The ACA mandated improvement in coverage with Medicare Part D benefits. In addition to the preventive care benefits noted above, which apply to Medicare recipients as well, the ACA reduced federal payments to Medicare Advantage plans over time and provided bonus payments to plans with high quality ratings.7
Further changes in Medicare spending included the creation of a 15-person, by-appointment board (known as the Independent Payment Advisory Board) tasked with identifying ways to “modify benefits, eligibility, premiums, or taxes,” which will hopefully continue to optimize the cost of care for patients living with MS and utilizing Medicare.7
Cost Savings With Medicaid Expansion. Medicaid expansion was enacted to keep patients with a costly illness, such as MS, from financial destitution because of their condition. As of January 2018, 32 states and the District of Columbia have seen expansion of their programs.8 In those states, people with a household income below 138% of the poverty level (less than $27,000 for a family of three) can now qualify for Medicaid. States that have not expanded coverage include Idaho, Wyoming, Utah, South Dakota, Nebraska, Kansas, Oklahoma, Texas, Missouri, Wisconsin, Tennessee, Mississippi, Alabama, Georgia, Virginia, North Carolina, South Carolina, and Florida.8 The expansion of Medicaid helps MS patients by shrinking the ever-present gap that still prevents some from qualifying for the additional financial assistance they need due to their chronic illness.
One thing we have learned is that MS patients may not realize they have access to some of these services—particularly preventive care—or they may hesitate to obtain services due to a lack of clarity on whether they are covered. Health care providers can remind patients that they may qualify for “unrealized services,” which could provide value and optimize general preventive care. MS patients with Medicare and Medicaid, for example, may not know that they have access to colorectal cancer screenings via a waived deductible.6
Since last year, there has been vigorous discussion about repealing, replacing, or otherwise amending the ACA. While a political discussion is beyond the bounds of this column, we do need to be aware of how changes to the ACA would affect patients with MS.
Optimizing wellness and prevention and providing access to care to patients with a costly disease, such as MS, is important. In addition to ensuring ongoing access to affordable services, we need to do more to improve mental health access and reduce the cost of needed medications. We also need to close the insurance gap in all 50 states. Continued dialogue will be necessary to help government leaders understand the cost impact of MS (and other diseases), in order to keep our country moving in a positive direction that optimizes wellness and health care reform. —ALD
Amy L. Dix, MPAS, PA-C, MSCS
Department of Neurology at Kansas City Multiple Sclerosis Center in Overland Park, Kansas
1. National Multiple Sclerosis Society. Health Policy Fact Sheet #2: Financial burdens for people with MS, their families, and society. www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Documents/Health-Policy-Fact-Sheet-2-Costs.pdf. Accessed February 8, 2018.
2. Center for Poverty Research, University of California—Davis. What is the current poverty rate in the United States? https://poverty.ucdavis.edu/faq/what-current-poverty-rate-united-states. Accessed February 8, 2018.
3. Iezzoni LI, Ngo L. Health, disability, and life insurance experiences of working-age persons with multiple sclerosis. Mult Scler. 2007;13(4):534-546.
4. Centers for Medicare & Medicaid Services. Affordable Care Act (ACA). HealthCare.gov. www.healthcare.gov/glossary/affordable-care-act. Accessed February 8, 2018.
5. US Department of Health and Human Services. About the ACA: pre-existing conditions. www.hhs.gov/healthcare/about-the-aca/pre-existing-conditions/index.html. Accessed February 8, 2018.
6. Tolbert J. The coverage provisions in the Affordable Care Act: an update. Kaiser Family Foundation. www.kff.org/report-section/the-coverage-provisions-in-the-affordable-care-act-an-update-health-insurance-market-reforms. Accessed February 8, 2018.
7. Kaiser Family Foundation. Focus on health reform: summary of key changes to Medicare in 2010 health reform law. https://kaiserfamilyfoundation.files.wordpress.com/2013/01/7948-02.pdf. Accessed February 8, 2018.
8. Families USA. A 50-state look at Medicaid expansion. http://familiesusa.org/product/50-state-look-medicaid-expansion. Accessed February 8, 2018.
1. National Multiple Sclerosis Society. Health Policy Fact Sheet #2: Financial burdens for people with MS, their families, and society. www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Documents/Health-Policy-Fact-Sheet-2-Costs.pdf. Accessed February 8, 2018.
2. Center for Poverty Research, University of California—Davis. What is the current poverty rate in the United States? https://poverty.ucdavis.edu/faq/what-current-poverty-rate-united-states. Accessed February 8, 2018.
3. Iezzoni LI, Ngo L. Health, disability, and life insurance experiences of working-age persons with multiple sclerosis. Mult Scler. 2007;13(4):534-546.
4. Centers for Medicare & Medicaid Services. Affordable Care Act (ACA). HealthCare.gov. www.healthcare.gov/glossary/affordable-care-act. Accessed February 8, 2018.
5. US Department of Health and Human Services. About the ACA: pre-existing conditions. www.hhs.gov/healthcare/about-the-aca/pre-existing-conditions/index.html. Accessed February 8, 2018.
6. Tolbert J. The coverage provisions in the Affordable Care Act: an update. Kaiser Family Foundation. www.kff.org/report-section/the-coverage-provisions-in-the-affordable-care-act-an-update-health-insurance-market-reforms. Accessed February 8, 2018.
7. Kaiser Family Foundation. Focus on health reform: summary of key changes to Medicare in 2010 health reform law. https://kaiserfamilyfoundation.files.wordpress.com/2013/01/7948-02.pdf. Accessed February 8, 2018.
8. Families USA. A 50-state look at Medicaid expansion. http://familiesusa.org/product/50-state-look-medicaid-expansion. Accessed February 8, 2018.
Osteoporosis: Overview, Workup, Diagnosis
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
This video was filmed at Metabolic & Endocrine Disease Summit (MEDS). Click here to learn more.
Genotype did not significantly affect evacetrapib response
Evacetrapib missed its primary MACE endpoint compared with placebo among patients with high-risk vascular disease, including those who were homozygous (AA) for polymorphism rs1967309 of the ADCY gene, in a large nested case-control analysis of the ACCELERATE trial.
The results contradict those for another cholesteryl ester transfer protein (CETP) inhibitor – dalcetrapib – which has shown significant cardiovascular benefits only among AA patients.
“Although directionally similar to the dalcetrapib analysis, there was no significant interaction between genotype and cardiovascular outcome with evacetrapib,” Steven E. Nissen, MD, and his associates wrote simultaneously in JAMA Cardiology and reported at the annual meeting of the American College of Cardiology.
Four CETP inhibitors have reached full-scale development: evacetrapib, dalcetrapib, torcetrapib, and anacetrapib. They all markedly increase circulating HDL, and all except dalcetrapib cut circulating LDL. But those benefits largely haven’t extended to the key endpoint, major adverse cardiovascular events (MACE). In large trials, torcetrapib increased MACE, anacetrapib reduced MACE by such a small amount that its maker did not file for FDA approval, and evacetrapib and dalcetrapib had no effect on MACE.
But there was a caveat for dalcetrapib. In a post-hoc analysis of its placebo-controlled trial, the CETP inhibitor reduced MACE by 39% among AA individuals and increased MACE by 27% among GG individuals, those homozygous negative for the SNP rs1967309.
These findings could make sense because ADCY gene variants have been linked to carotid intimal medial thickness, high-sensitivity C-reactive protein, and cholesterol efflux capacity, wrote Dr. Nissen of the department of cardiovascular medicine, Cleveland Clinic, Cleveland, Ohio (JAMA Cardiol. 2018 Mar 11. doi: 10.1001/jamacardio.2018.0569).
To explore whether ADCY genotypep also affects evacetrapib response, he and his associates compared 1,427 cases with MACE with 1,532 matched controls from the international, randomized, double-blind ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial (NCT01687998). Participants had cerebrovascular atherosclerotic disease, peripheral arterial disease, coronary artery disease with diabetes, or recent acute coronary syndrome. They received oral evacetrapib (130 mg) or placebo, and the primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.
Evacetrapib missed this primary endpoint in all genetic subgroups. Odds ratios for evacetrapib compared with placebo were 0.88 (95% confidence interval, 0.69 to 1.12) among AA patients, 1.04 (95% CI, 0.90 to 1.21) among heterozygous (AG) patients, and 1.18 (95% CI, 0.98 to 1.41) among GG patients. A test for interaction also was insignificant (P = .17). A test for trend nearly reached significance (P = .06), but weakened when the investigators controlled for cardiovascular risk factors or looked only at hard cardiovascular outcomes, they said.
Thus, the relationship between evacetrapib response and AA genotype “was far less in magnitude than observed in the pharmacogenetic study with dalcetrapib,” they wrote. Dalcetrapib is a weaker CETP inhibitor than evacetrapib, the study populations weren’t identical, and the trials used different statistical methods, all of which could explain the discrepant findings, they added. “The completion of the dalcetrapib pharmacogenetics outcome trial should clarify whether this is a false signal or a paradigm-shifting discovery.”
Eli Lilly provided funding, helped design and conduct the study, and helped write the manuscript. Dr. Nissen reported receiving grants and nonfinancial support from Eli Lilly while conducting the study. Several coinvestigators also disclosed ties to Eli Lilly and six reported being employees of the company.
Source: JAMA Cardiol. doi:10.1001/jamacardio.2018.0569.
Evacetrapib missed its primary MACE endpoint compared with placebo among patients with high-risk vascular disease, including those who were homozygous (AA) for polymorphism rs1967309 of the ADCY gene, in a large nested case-control analysis of the ACCELERATE trial.
The results contradict those for another cholesteryl ester transfer protein (CETP) inhibitor – dalcetrapib – which has shown significant cardiovascular benefits only among AA patients.
“Although directionally similar to the dalcetrapib analysis, there was no significant interaction between genotype and cardiovascular outcome with evacetrapib,” Steven E. Nissen, MD, and his associates wrote simultaneously in JAMA Cardiology and reported at the annual meeting of the American College of Cardiology.
Four CETP inhibitors have reached full-scale development: evacetrapib, dalcetrapib, torcetrapib, and anacetrapib. They all markedly increase circulating HDL, and all except dalcetrapib cut circulating LDL. But those benefits largely haven’t extended to the key endpoint, major adverse cardiovascular events (MACE). In large trials, torcetrapib increased MACE, anacetrapib reduced MACE by such a small amount that its maker did not file for FDA approval, and evacetrapib and dalcetrapib had no effect on MACE.
But there was a caveat for dalcetrapib. In a post-hoc analysis of its placebo-controlled trial, the CETP inhibitor reduced MACE by 39% among AA individuals and increased MACE by 27% among GG individuals, those homozygous negative for the SNP rs1967309.
These findings could make sense because ADCY gene variants have been linked to carotid intimal medial thickness, high-sensitivity C-reactive protein, and cholesterol efflux capacity, wrote Dr. Nissen of the department of cardiovascular medicine, Cleveland Clinic, Cleveland, Ohio (JAMA Cardiol. 2018 Mar 11. doi: 10.1001/jamacardio.2018.0569).
To explore whether ADCY genotypep also affects evacetrapib response, he and his associates compared 1,427 cases with MACE with 1,532 matched controls from the international, randomized, double-blind ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial (NCT01687998). Participants had cerebrovascular atherosclerotic disease, peripheral arterial disease, coronary artery disease with diabetes, or recent acute coronary syndrome. They received oral evacetrapib (130 mg) or placebo, and the primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.
Evacetrapib missed this primary endpoint in all genetic subgroups. Odds ratios for evacetrapib compared with placebo were 0.88 (95% confidence interval, 0.69 to 1.12) among AA patients, 1.04 (95% CI, 0.90 to 1.21) among heterozygous (AG) patients, and 1.18 (95% CI, 0.98 to 1.41) among GG patients. A test for interaction also was insignificant (P = .17). A test for trend nearly reached significance (P = .06), but weakened when the investigators controlled for cardiovascular risk factors or looked only at hard cardiovascular outcomes, they said.
Thus, the relationship between evacetrapib response and AA genotype “was far less in magnitude than observed in the pharmacogenetic study with dalcetrapib,” they wrote. Dalcetrapib is a weaker CETP inhibitor than evacetrapib, the study populations weren’t identical, and the trials used different statistical methods, all of which could explain the discrepant findings, they added. “The completion of the dalcetrapib pharmacogenetics outcome trial should clarify whether this is a false signal or a paradigm-shifting discovery.”
Eli Lilly provided funding, helped design and conduct the study, and helped write the manuscript. Dr. Nissen reported receiving grants and nonfinancial support from Eli Lilly while conducting the study. Several coinvestigators also disclosed ties to Eli Lilly and six reported being employees of the company.
Source: JAMA Cardiol. doi:10.1001/jamacardio.2018.0569.
Evacetrapib missed its primary MACE endpoint compared with placebo among patients with high-risk vascular disease, including those who were homozygous (AA) for polymorphism rs1967309 of the ADCY gene, in a large nested case-control analysis of the ACCELERATE trial.
The results contradict those for another cholesteryl ester transfer protein (CETP) inhibitor – dalcetrapib – which has shown significant cardiovascular benefits only among AA patients.
“Although directionally similar to the dalcetrapib analysis, there was no significant interaction between genotype and cardiovascular outcome with evacetrapib,” Steven E. Nissen, MD, and his associates wrote simultaneously in JAMA Cardiology and reported at the annual meeting of the American College of Cardiology.
Four CETP inhibitors have reached full-scale development: evacetrapib, dalcetrapib, torcetrapib, and anacetrapib. They all markedly increase circulating HDL, and all except dalcetrapib cut circulating LDL. But those benefits largely haven’t extended to the key endpoint, major adverse cardiovascular events (MACE). In large trials, torcetrapib increased MACE, anacetrapib reduced MACE by such a small amount that its maker did not file for FDA approval, and evacetrapib and dalcetrapib had no effect on MACE.
But there was a caveat for dalcetrapib. In a post-hoc analysis of its placebo-controlled trial, the CETP inhibitor reduced MACE by 39% among AA individuals and increased MACE by 27% among GG individuals, those homozygous negative for the SNP rs1967309.
These findings could make sense because ADCY gene variants have been linked to carotid intimal medial thickness, high-sensitivity C-reactive protein, and cholesterol efflux capacity, wrote Dr. Nissen of the department of cardiovascular medicine, Cleveland Clinic, Cleveland, Ohio (JAMA Cardiol. 2018 Mar 11. doi: 10.1001/jamacardio.2018.0569).
To explore whether ADCY genotypep also affects evacetrapib response, he and his associates compared 1,427 cases with MACE with 1,532 matched controls from the international, randomized, double-blind ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial (NCT01687998). Participants had cerebrovascular atherosclerotic disease, peripheral arterial disease, coronary artery disease with diabetes, or recent acute coronary syndrome. They received oral evacetrapib (130 mg) or placebo, and the primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.
Evacetrapib missed this primary endpoint in all genetic subgroups. Odds ratios for evacetrapib compared with placebo were 0.88 (95% confidence interval, 0.69 to 1.12) among AA patients, 1.04 (95% CI, 0.90 to 1.21) among heterozygous (AG) patients, and 1.18 (95% CI, 0.98 to 1.41) among GG patients. A test for interaction also was insignificant (P = .17). A test for trend nearly reached significance (P = .06), but weakened when the investigators controlled for cardiovascular risk factors or looked only at hard cardiovascular outcomes, they said.
Thus, the relationship between evacetrapib response and AA genotype “was far less in magnitude than observed in the pharmacogenetic study with dalcetrapib,” they wrote. Dalcetrapib is a weaker CETP inhibitor than evacetrapib, the study populations weren’t identical, and the trials used different statistical methods, all of which could explain the discrepant findings, they added. “The completion of the dalcetrapib pharmacogenetics outcome trial should clarify whether this is a false signal or a paradigm-shifting discovery.”
Eli Lilly provided funding, helped design and conduct the study, and helped write the manuscript. Dr. Nissen reported receiving grants and nonfinancial support from Eli Lilly while conducting the study. Several coinvestigators also disclosed ties to Eli Lilly and six reported being employees of the company.
Source: JAMA Cardiol. doi:10.1001/jamacardio.2018.0569.
FROM ACC 2018
Key clinical point: Evacetrapib missed its primary MACE endpoint compared with placebo among patients with high-risk vascular disease, including those who were homozygous (AA) for polymorphism rs1967309 of the ADCY gene.
Major finding: Odds ratios for evacetrapib compared with placebo were 0.88 (95% confidence interval, 0.69 to 1.12) among AA patients; 1.04 (95% CI, 0.90 to 1.21) among heterozygous (AG) patients; and 1.18 (95% CI, 0.98 to 1.41) among GG patients. P-values for tests for trend exceeded .05.
Data source: A nested study of 1,427 cases with major adverse cardiovascular events and 1,532 matched controls from the ACCELERATE trial.
Disclosures: Eli Lilly provided funding and was involved in all aspects of the study and manuscript preparation. Dr. Nissen reported receiving grants and nonfinancial support from Eli Lilly while conducting the study. Several coinvestigators also disclosed ties to Eli Lilly and six reported being employees of the company.
Source: JAMA Cardiol. doi:10.1001/jamacardio.2018.0569.
CECCY: Carvedilol didn’t curb cardiotoxicity in breast cancer patients
ORLANDO – Anthracycline chemotherapy was associated with a cardiotoxicity incidence of roughly 14% of breast cancer patients regardless of treatment with carvedilol, based on data from a randomized trial of 200 patients.
“Cardio-oncology has been neglected,” Monica Samuel Avila, MD, of Hospital das Clínicas da Faculdade de Medicina da Universidade in São Paulo, Brazil, said in a video interview at the annual meeting of the American College of Cardiology. “We have seen improvement of survival in patients with cancer, but with that comes complications related to treatment. I think that the interactions between cardiologists and oncologists are increasing in a more important way,” she said.
In the Carvedilol for Prevention of Chemotherapy-Induced Cardiotoxicity (CECCY) Trial, Dr. Avila and colleagues evaluated primary prevention of cardiotoxicity in women with normal hearts who were undergoing chemotherapy for breast cancer.
Patients in the treatment group received a median carvedilol dose of 18.4 mg/day. The primary endpoint of cardiotoxicity, defined as a decrease in left ventricular ejection fraction (LVEF) of at least 10% at 6 months, occurred in 15% of carvedilol patients and 14% placebo patients, a nonsignificant difference. No significant differences occurred in diastolic dysfunction or in B-type natriuretic peptide (BNP) levels at 6 weeks, 12 weeks, or 24 weeks between the groups.
However, carvedilol patients showed significantly reduced troponin 1 levels compared with placebo, which suggests protection against myocardial injury, Dr. Avila said.
“In short follow up, we can see cardiotoxicity appearing, and we know we have to treat it promptly to prevent cardiac events,” she said.
Dr. Avila and colleagues identified 200 women older than 18 years with HER2-negative breast cancer tumor status and normal left ventricular ejection fraction. The patients were undergoing chemotherapy with 240 mg/m2 of anthracycline and were randomized to treatment with carvedilol or a placebo. Baseline characteristics were similar between the two groups.
Adverse effects were not significantly different between the groups, and the most common events in each group included dizziness, dry mouth, symptomatic hypertension, stomachache, and nausea. Although the results suggest that carvedilol can reduce the risk of myocardial injury, more research is needed to address the question of the increase in troponin without change in the LVEF, Dr. Avila noted. The study is ongoing and the research team intends to follow the low-risk patient population for a total of 2 years. “For high-risk patients, I am already giving carvedilol,” she said. “We believe if we find a difference in LVEF or clinical events, we could encourage cardiologists to give carvedilol in a low-risk population,” she said.
“This study highlights that there is no safe dose of anthracycline,” commented Bonnie Ky, MD of the University of Pennsylvania, Philadelphia, at a press briefing. She emphasized the value of carvedilol for a high-risk population, and stressed the importance of following long-term changes in heart injury markers after 1-2 years for low-risk patients.
Dr. Avila had no financial conflicts to disclose. Dr. Ky disclosed relationships with multiple companies including Bioinvent and Bristol Myers.
The findings were published simultaneously in the Journal of the American College of Cardiology.
SOURCE: Avila, M. ACC 18
ORLANDO – Anthracycline chemotherapy was associated with a cardiotoxicity incidence of roughly 14% of breast cancer patients regardless of treatment with carvedilol, based on data from a randomized trial of 200 patients.
“Cardio-oncology has been neglected,” Monica Samuel Avila, MD, of Hospital das Clínicas da Faculdade de Medicina da Universidade in São Paulo, Brazil, said in a video interview at the annual meeting of the American College of Cardiology. “We have seen improvement of survival in patients with cancer, but with that comes complications related to treatment. I think that the interactions between cardiologists and oncologists are increasing in a more important way,” she said.
In the Carvedilol for Prevention of Chemotherapy-Induced Cardiotoxicity (CECCY) Trial, Dr. Avila and colleagues evaluated primary prevention of cardiotoxicity in women with normal hearts who were undergoing chemotherapy for breast cancer.
Patients in the treatment group received a median carvedilol dose of 18.4 mg/day. The primary endpoint of cardiotoxicity, defined as a decrease in left ventricular ejection fraction (LVEF) of at least 10% at 6 months, occurred in 15% of carvedilol patients and 14% placebo patients, a nonsignificant difference. No significant differences occurred in diastolic dysfunction or in B-type natriuretic peptide (BNP) levels at 6 weeks, 12 weeks, or 24 weeks between the groups.
However, carvedilol patients showed significantly reduced troponin 1 levels compared with placebo, which suggests protection against myocardial injury, Dr. Avila said.
“In short follow up, we can see cardiotoxicity appearing, and we know we have to treat it promptly to prevent cardiac events,” she said.
Dr. Avila and colleagues identified 200 women older than 18 years with HER2-negative breast cancer tumor status and normal left ventricular ejection fraction. The patients were undergoing chemotherapy with 240 mg/m2 of anthracycline and were randomized to treatment with carvedilol or a placebo. Baseline characteristics were similar between the two groups.
Adverse effects were not significantly different between the groups, and the most common events in each group included dizziness, dry mouth, symptomatic hypertension, stomachache, and nausea. Although the results suggest that carvedilol can reduce the risk of myocardial injury, more research is needed to address the question of the increase in troponin without change in the LVEF, Dr. Avila noted. The study is ongoing and the research team intends to follow the low-risk patient population for a total of 2 years. “For high-risk patients, I am already giving carvedilol,” she said. “We believe if we find a difference in LVEF or clinical events, we could encourage cardiologists to give carvedilol in a low-risk population,” she said.
“This study highlights that there is no safe dose of anthracycline,” commented Bonnie Ky, MD of the University of Pennsylvania, Philadelphia, at a press briefing. She emphasized the value of carvedilol for a high-risk population, and stressed the importance of following long-term changes in heart injury markers after 1-2 years for low-risk patients.
Dr. Avila had no financial conflicts to disclose. Dr. Ky disclosed relationships with multiple companies including Bioinvent and Bristol Myers.
The findings were published simultaneously in the Journal of the American College of Cardiology.
SOURCE: Avila, M. ACC 18
ORLANDO – Anthracycline chemotherapy was associated with a cardiotoxicity incidence of roughly 14% of breast cancer patients regardless of treatment with carvedilol, based on data from a randomized trial of 200 patients.
“Cardio-oncology has been neglected,” Monica Samuel Avila, MD, of Hospital das Clínicas da Faculdade de Medicina da Universidade in São Paulo, Brazil, said in a video interview at the annual meeting of the American College of Cardiology. “We have seen improvement of survival in patients with cancer, but with that comes complications related to treatment. I think that the interactions between cardiologists and oncologists are increasing in a more important way,” she said.
In the Carvedilol for Prevention of Chemotherapy-Induced Cardiotoxicity (CECCY) Trial, Dr. Avila and colleagues evaluated primary prevention of cardiotoxicity in women with normal hearts who were undergoing chemotherapy for breast cancer.
Patients in the treatment group received a median carvedilol dose of 18.4 mg/day. The primary endpoint of cardiotoxicity, defined as a decrease in left ventricular ejection fraction (LVEF) of at least 10% at 6 months, occurred in 15% of carvedilol patients and 14% placebo patients, a nonsignificant difference. No significant differences occurred in diastolic dysfunction or in B-type natriuretic peptide (BNP) levels at 6 weeks, 12 weeks, or 24 weeks between the groups.
However, carvedilol patients showed significantly reduced troponin 1 levels compared with placebo, which suggests protection against myocardial injury, Dr. Avila said.
“In short follow up, we can see cardiotoxicity appearing, and we know we have to treat it promptly to prevent cardiac events,” she said.
Dr. Avila and colleagues identified 200 women older than 18 years with HER2-negative breast cancer tumor status and normal left ventricular ejection fraction. The patients were undergoing chemotherapy with 240 mg/m2 of anthracycline and were randomized to treatment with carvedilol or a placebo. Baseline characteristics were similar between the two groups.
Adverse effects were not significantly different between the groups, and the most common events in each group included dizziness, dry mouth, symptomatic hypertension, stomachache, and nausea. Although the results suggest that carvedilol can reduce the risk of myocardial injury, more research is needed to address the question of the increase in troponin without change in the LVEF, Dr. Avila noted. The study is ongoing and the research team intends to follow the low-risk patient population for a total of 2 years. “For high-risk patients, I am already giving carvedilol,” she said. “We believe if we find a difference in LVEF or clinical events, we could encourage cardiologists to give carvedilol in a low-risk population,” she said.
“This study highlights that there is no safe dose of anthracycline,” commented Bonnie Ky, MD of the University of Pennsylvania, Philadelphia, at a press briefing. She emphasized the value of carvedilol for a high-risk population, and stressed the importance of following long-term changes in heart injury markers after 1-2 years for low-risk patients.
Dr. Avila had no financial conflicts to disclose. Dr. Ky disclosed relationships with multiple companies including Bioinvent and Bristol Myers.
The findings were published simultaneously in the Journal of the American College of Cardiology.
SOURCE: Avila, M. ACC 18
REPORTING FROM ACC 18
Key clinical point:
Major finding: Cardiotoxicity was roughly 14% in breast cancer patients treated with anthracycline whether they received carvedilol or placebo.
Study details: CECCY was a randomized, placebo-controlled trial of 200 patients with HER2-negative breast cancer tumor status.
Disclosures: Dr. Avila had no financial conflicts to disclose.
Source: Avila M. ACC 2018.
Wearable defibrillator cuts mortality in post-MI patients
ORLANDO – Wearable cardioverter defibrillator vests failed to significantly cut the rate of arrhythmic death in at-risk post-MI patients but succeeded in significantly dropping total mortality during a median of 84 days of use in the first randomized trial of nonimplanted defibrillators in such patients.
But despite this overall mortality benefit, the 1,524 patients randomized to the WCD group failed to show a significant improvement in the rate of sudden and ventricular tachycardia death, the primary endpoint for the study, said Dr. Olgin, chief of cardiology at the University of California, San Francisco. Total mortality was a secondary endpoint in the study. Based on the total mortality benefit observed and the “totality of evidence” from prior, uncontrolled observational studies, Dr. Olgin concluded that it is now “reasonable” to protect post-MI patients with ejection fractions of 35% or less during the first 40-90 days following an MI when patients can then be assessed for receiving an implantable cardioverter defibrillator.
That would be an upgrade from the current American College of Cardiology/American Heart Association guidelines on managing ventricular arrhythmias and preventing sudden cardiac death, issued in 2017, that classified WCDs as a class IIb recommendations – “may be reasonable” – for post-MI patients with a reduced left ventricular ejection fraction (Circulation. 2017 Oct 30;doi:10.1161/CIR.0000000000000549).
WCDs are currently approved for routine prescribing by U.S. physicians, but their use is very variable in post-MI patients. Just before Dr. Olgin delivered his report at the meeting, a poll of the several thousand meeting attendees who heard his talk showed that roughly a third reported routinely prescribing WCDs, with the other two thirds saying they did not.
Several electrophysiologists who heard the report agreed that further research needs to better tease out which post-MI patients get the most benefit from this treatment.
The patients enrolled in the study “were not a sick population; they had a low event rate,” commented Sana M. Al-Khatib, MD, professor of medicine at Duke University in Durham, N.C. and chair of the panel that wrote the 2017 ventricular arrhythmia guidelines. She suggested testing the efficacy of WCDs in post-MI patients with lower ejection fractions or those with a greater history of heart disease prior to their index MI. Nearly half of the patients enrolled in the study had New York Heart Association class I symptoms, indicating that they had mild heart disease, she noted in an interview. Another issue left unresolved by the results Dr. Olgin reported was how much of the mortality benefit was attributable to the shocks delivered by the tested WCDs and how much derived from the arrhythmia monitoring that the WCDs provided.
Another way to better target WCDs to post-MI patients who could derive the most benefit might be to focus on patients with frequent premature ventricular contractions and nonsustained ventricular tachycardia, suggested Dhanunjaya Lakkireddy, MD, professor of medicine and director of the Center for Excellence in AF and Complex Arrhythmias at the University of Kansas Medical Center in Kansas City. But Dr. Lakkireddy acknowledged that currently left ventricular ejection fraction is the primary surrogate marker cardiologists rely on to identify post-MI patients who are at increased risk for ventricular arrhythmia.
Dr. Olgin countered that the total mortality rate seen among the control, usual care patients in his study, 4.9% during the median 84 day follow-up, closely matched the 5% rate reported in prior trials of at-risk patients who received implantable cardioverter defibrillators.
During follow-up, total mortality occurred in 3.1% of the patients randomized to WCD use and 4.9% among the control patients.
The results also showed that 19% of the patients randomized to the WCD arm failed to ever use the device, and that over the course of follow-up the usage rate fell below 50%. Patients who used the device generally wore it as directed, however, with an average 22 hours a day of use at the start of treatment that subsequently dipped to 21 hours a day near the end of the 90-day treatment period, Dr. Olgin reported.
The most likely explanation for the disparity between the significant effect on total mortality and the insignificant effect on arrhythmia mortality is misclassification of some deaths. “Any small number of misclassified sudden deaths would have dramatically reduced our power to see a difference” in arrhythmia deaths, Dr. Olgin noted.
VEST was sponsored by Zoll, the company that markets the tested device. Dr. Olgin has no personal disclosures. Dr. Al-Khatib and Dr. Lakkireddy had no disclosures. Dr. Wilber is a consultant to Biosense Webster and Medtronic.
[email protected]
SOURCE: Olgin J et al. ACC 18.
ORLANDO – Wearable cardioverter defibrillator vests failed to significantly cut the rate of arrhythmic death in at-risk post-MI patients but succeeded in significantly dropping total mortality during a median of 84 days of use in the first randomized trial of nonimplanted defibrillators in such patients.
But despite this overall mortality benefit, the 1,524 patients randomized to the WCD group failed to show a significant improvement in the rate of sudden and ventricular tachycardia death, the primary endpoint for the study, said Dr. Olgin, chief of cardiology at the University of California, San Francisco. Total mortality was a secondary endpoint in the study. Based on the total mortality benefit observed and the “totality of evidence” from prior, uncontrolled observational studies, Dr. Olgin concluded that it is now “reasonable” to protect post-MI patients with ejection fractions of 35% or less during the first 40-90 days following an MI when patients can then be assessed for receiving an implantable cardioverter defibrillator.
That would be an upgrade from the current American College of Cardiology/American Heart Association guidelines on managing ventricular arrhythmias and preventing sudden cardiac death, issued in 2017, that classified WCDs as a class IIb recommendations – “may be reasonable” – for post-MI patients with a reduced left ventricular ejection fraction (Circulation. 2017 Oct 30;doi:10.1161/CIR.0000000000000549).
WCDs are currently approved for routine prescribing by U.S. physicians, but their use is very variable in post-MI patients. Just before Dr. Olgin delivered his report at the meeting, a poll of the several thousand meeting attendees who heard his talk showed that roughly a third reported routinely prescribing WCDs, with the other two thirds saying they did not.
Several electrophysiologists who heard the report agreed that further research needs to better tease out which post-MI patients get the most benefit from this treatment.
The patients enrolled in the study “were not a sick population; they had a low event rate,” commented Sana M. Al-Khatib, MD, professor of medicine at Duke University in Durham, N.C. and chair of the panel that wrote the 2017 ventricular arrhythmia guidelines. She suggested testing the efficacy of WCDs in post-MI patients with lower ejection fractions or those with a greater history of heart disease prior to their index MI. Nearly half of the patients enrolled in the study had New York Heart Association class I symptoms, indicating that they had mild heart disease, she noted in an interview. Another issue left unresolved by the results Dr. Olgin reported was how much of the mortality benefit was attributable to the shocks delivered by the tested WCDs and how much derived from the arrhythmia monitoring that the WCDs provided.
Another way to better target WCDs to post-MI patients who could derive the most benefit might be to focus on patients with frequent premature ventricular contractions and nonsustained ventricular tachycardia, suggested Dhanunjaya Lakkireddy, MD, professor of medicine and director of the Center for Excellence in AF and Complex Arrhythmias at the University of Kansas Medical Center in Kansas City. But Dr. Lakkireddy acknowledged that currently left ventricular ejection fraction is the primary surrogate marker cardiologists rely on to identify post-MI patients who are at increased risk for ventricular arrhythmia.
Dr. Olgin countered that the total mortality rate seen among the control, usual care patients in his study, 4.9% during the median 84 day follow-up, closely matched the 5% rate reported in prior trials of at-risk patients who received implantable cardioverter defibrillators.
During follow-up, total mortality occurred in 3.1% of the patients randomized to WCD use and 4.9% among the control patients.
The results also showed that 19% of the patients randomized to the WCD arm failed to ever use the device, and that over the course of follow-up the usage rate fell below 50%. Patients who used the device generally wore it as directed, however, with an average 22 hours a day of use at the start of treatment that subsequently dipped to 21 hours a day near the end of the 90-day treatment period, Dr. Olgin reported.
The most likely explanation for the disparity between the significant effect on total mortality and the insignificant effect on arrhythmia mortality is misclassification of some deaths. “Any small number of misclassified sudden deaths would have dramatically reduced our power to see a difference” in arrhythmia deaths, Dr. Olgin noted.
VEST was sponsored by Zoll, the company that markets the tested device. Dr. Olgin has no personal disclosures. Dr. Al-Khatib and Dr. Lakkireddy had no disclosures. Dr. Wilber is a consultant to Biosense Webster and Medtronic.
[email protected]
SOURCE: Olgin J et al. ACC 18.
ORLANDO – Wearable cardioverter defibrillator vests failed to significantly cut the rate of arrhythmic death in at-risk post-MI patients but succeeded in significantly dropping total mortality during a median of 84 days of use in the first randomized trial of nonimplanted defibrillators in such patients.
But despite this overall mortality benefit, the 1,524 patients randomized to the WCD group failed to show a significant improvement in the rate of sudden and ventricular tachycardia death, the primary endpoint for the study, said Dr. Olgin, chief of cardiology at the University of California, San Francisco. Total mortality was a secondary endpoint in the study. Based on the total mortality benefit observed and the “totality of evidence” from prior, uncontrolled observational studies, Dr. Olgin concluded that it is now “reasonable” to protect post-MI patients with ejection fractions of 35% or less during the first 40-90 days following an MI when patients can then be assessed for receiving an implantable cardioverter defibrillator.
That would be an upgrade from the current American College of Cardiology/American Heart Association guidelines on managing ventricular arrhythmias and preventing sudden cardiac death, issued in 2017, that classified WCDs as a class IIb recommendations – “may be reasonable” – for post-MI patients with a reduced left ventricular ejection fraction (Circulation. 2017 Oct 30;doi:10.1161/CIR.0000000000000549).
WCDs are currently approved for routine prescribing by U.S. physicians, but their use is very variable in post-MI patients. Just before Dr. Olgin delivered his report at the meeting, a poll of the several thousand meeting attendees who heard his talk showed that roughly a third reported routinely prescribing WCDs, with the other two thirds saying they did not.
Several electrophysiologists who heard the report agreed that further research needs to better tease out which post-MI patients get the most benefit from this treatment.
The patients enrolled in the study “were not a sick population; they had a low event rate,” commented Sana M. Al-Khatib, MD, professor of medicine at Duke University in Durham, N.C. and chair of the panel that wrote the 2017 ventricular arrhythmia guidelines. She suggested testing the efficacy of WCDs in post-MI patients with lower ejection fractions or those with a greater history of heart disease prior to their index MI. Nearly half of the patients enrolled in the study had New York Heart Association class I symptoms, indicating that they had mild heart disease, she noted in an interview. Another issue left unresolved by the results Dr. Olgin reported was how much of the mortality benefit was attributable to the shocks delivered by the tested WCDs and how much derived from the arrhythmia monitoring that the WCDs provided.
Another way to better target WCDs to post-MI patients who could derive the most benefit might be to focus on patients with frequent premature ventricular contractions and nonsustained ventricular tachycardia, suggested Dhanunjaya Lakkireddy, MD, professor of medicine and director of the Center for Excellence in AF and Complex Arrhythmias at the University of Kansas Medical Center in Kansas City. But Dr. Lakkireddy acknowledged that currently left ventricular ejection fraction is the primary surrogate marker cardiologists rely on to identify post-MI patients who are at increased risk for ventricular arrhythmia.
Dr. Olgin countered that the total mortality rate seen among the control, usual care patients in his study, 4.9% during the median 84 day follow-up, closely matched the 5% rate reported in prior trials of at-risk patients who received implantable cardioverter defibrillators.
During follow-up, total mortality occurred in 3.1% of the patients randomized to WCD use and 4.9% among the control patients.
The results also showed that 19% of the patients randomized to the WCD arm failed to ever use the device, and that over the course of follow-up the usage rate fell below 50%. Patients who used the device generally wore it as directed, however, with an average 22 hours a day of use at the start of treatment that subsequently dipped to 21 hours a day near the end of the 90-day treatment period, Dr. Olgin reported.
The most likely explanation for the disparity between the significant effect on total mortality and the insignificant effect on arrhythmia mortality is misclassification of some deaths. “Any small number of misclassified sudden deaths would have dramatically reduced our power to see a difference” in arrhythmia deaths, Dr. Olgin noted.
VEST was sponsored by Zoll, the company that markets the tested device. Dr. Olgin has no personal disclosures. Dr. Al-Khatib and Dr. Lakkireddy had no disclosures. Dr. Wilber is a consultant to Biosense Webster and Medtronic.
[email protected]
SOURCE: Olgin J et al. ACC 18.
REPORTING FROM ACC18
Key clinical point: The first RCT of a wearable defibrillator in post-MI patients showed reduced total mortality.
Major finding: Total mortality was 3.2% in patients treated with a wearable cardioverter defibrillator and 4.9% in controls after a median of 84 days.
Study details: VEST, a multicenter, randomized trial with 2,302 patients.
Disclosures: VEST was sponsored by Zoll, the company that markets the tested device. Dr. Olgin has no personal disclosures.
Source: Olgin J. ACC 18.
Ticagrelor noninferior to clopidogrel in terms of major bleeds in STEMI
For patients under age 75 years with ST-segment elevation myocardial infarction, switching from clopidogrel to ticagrelor was noninferior to continuing clopidogrel in terms of 30-day rates of major bleeding, investigators reported at the annual meeting of the American College of Cardiology.
Rates of thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days were 0.73% in the ticagrelor group and 0.69% in the clopidogrel group, for an absolute difference of 0.04% (95% confidence interval, −0.49% to 0.58%; P less than .001 for noninferiority). “However, minor bleeding was increased with ticagrelor, and there was no benefit on efficacy outcomes,” Otavio Berwanger, MD, PhD, wrote simultaneously in JAMA Cardiology, on behalf of the writing committee for the randomized, phase 3, open-label TREAT trial.
Abundant, robust data support prompt revascularization in ST-elevation myocardial infarction (STEMI), but the real world doesn’t always meet this standard, and lytics remain in wide use in many countries, noted Dr. Berwanger, Director of the Research Institute at the Heart Hospital of Sao Paulo (Brazil). In the early 2000s, two large trials showed that dual antiplatelet therapy with aspirin and clopidogrel reduced major adverse cardiovascular events in patients receiving fibrinolytics for STEMI. More recently, the Platelet Inhibition and Patient Outcomes (PLATO) study favored ticagrelor over clopidogrel for reducing cardiovascular or stroke-related death, with no increase in the risk of major bleeding, despite ticagrelor’s boxed warning.
However, PLATO excluded patients who received fibrinolytics in the 24 hours before treatment because of concerns that ticagrelor might contribute to serious or fatal bleeding. To assess this risk, Dr. Berwanger and his associates from 10 countries randomly assigned 3,799 patients with STEMI to receive either ticagrelor (180-mg loading dose; 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose; 75 mg daily thereafter) a median of 11.4 hours after fibrinolysis. Patients averaged 58 years in age (standard deviation, 9.5 years), 77% were men, and 57% were white.
Because about 90% of patients had been pretreated with clopidogrel, the study primarily compared the effect of staying on clopidogrel with switching to ticagrelor, the investigators noted. “Our trial was an investigator- initiated trial with limited funding that did not allow a double-dummy design,” they added. “We attempted to minimize the risk of bias associated with the open-label nature of the study by performing blinded outcome adjudication.”
In terms of secondary endpoints, 23 patients (1.2%) on ticagrelor developed major bleeding according to PLATO criteria and Bleeding Academic Research Consortium (BARC) criteria, as did 26 patients (1.4%) on clopidogrel at 30-day follow-up (absolute difference, −0.18%; 95% CI, −0.89% to 0.54; P = .001 for noninferiority). Ticagrelor and clopidogrel also resembled each other in terms of fatal bleeds (0.16% versus 0.11%, respectively; P = .67) and intracranial bleeds (0.42% versus 0.37%; P = .82).
However, minimal PLATO bleeding was significantly more common with ticagrelor (3.2%) than with clopidogrel (2%; P = .02), the researchers reported. Clinically significant TIMI bleeding requiring medical attention occurred in 2% of the ticagrelor group and 1.2% of the clopidogrel group (P = .06), and ticagrelor was no more effective than clopidogrel in terms of preventing death from vascular causes, myocardial infarction, or stroke, with a composite rate of 4% in each arm and a statistically insignificant hazard ratio of (0.91; 95% CI, 0.67 to 1.25; P = .57).
Additionally, while similar proportions of patients stopped treatment because of adverse events, dyspnea was more common with ticagrelor (13.9%) than clopidogrel (7.6%). “Based on our findings, patients with STEMI younger than 75 years who initially received clopidogrel can be safely switched to ticagrelor in the first 24 hours after fibrinolysis,” the researchers wrote. “Whether this strategy will result in fewer cardiovascular events in the long term remains to be determined.”
AstraZeneca makes ticagrelor and funded the trial. Dr. Berwanger disclosed grants and personal fees from AstraZeneca and several other pharmaceutical companies.
Source: JAMA Cardiol. doi:10.1001/jamacardio.2018.0612
The TREAT trial “answers some questions, but critical others remain,” Clyde W. Yancy, MD, MSc, and Robert A. Harrington, MD, write in a brief accompanying editorial in JAMA Cardiology.
Perhaps most notably, the trial does not answer the “crucial” question on concomitant ticagrelor-lytic therapy for acute revascularization, they write. “Given the worldwide burden of acute coronary syndromes and the recognized exigencies which preclude the ubiquitous availability of PCI, we believe this question needs urgent attention. We await future trials.”
Dr. Yancy is at Feinberg School of Medicine, Northwestern University, Chicago. Dr. Harrington is at the department of medicine, Stanford University, Stanford, Calif. Dr. Harrington disclosed ties to Astra, Amgen, Bayer, Bristol-Myers Squibb, and several other pharmaceutical companies, and reported having served on the board of directors of the American Heart Association and Stanford Health Care. Dr. Yancy had no disclosures.
The TREAT trial “answers some questions, but critical others remain,” Clyde W. Yancy, MD, MSc, and Robert A. Harrington, MD, write in a brief accompanying editorial in JAMA Cardiology.
Perhaps most notably, the trial does not answer the “crucial” question on concomitant ticagrelor-lytic therapy for acute revascularization, they write. “Given the worldwide burden of acute coronary syndromes and the recognized exigencies which preclude the ubiquitous availability of PCI, we believe this question needs urgent attention. We await future trials.”
Dr. Yancy is at Feinberg School of Medicine, Northwestern University, Chicago. Dr. Harrington is at the department of medicine, Stanford University, Stanford, Calif. Dr. Harrington disclosed ties to Astra, Amgen, Bayer, Bristol-Myers Squibb, and several other pharmaceutical companies, and reported having served on the board of directors of the American Heart Association and Stanford Health Care. Dr. Yancy had no disclosures.
The TREAT trial “answers some questions, but critical others remain,” Clyde W. Yancy, MD, MSc, and Robert A. Harrington, MD, write in a brief accompanying editorial in JAMA Cardiology.
Perhaps most notably, the trial does not answer the “crucial” question on concomitant ticagrelor-lytic therapy for acute revascularization, they write. “Given the worldwide burden of acute coronary syndromes and the recognized exigencies which preclude the ubiquitous availability of PCI, we believe this question needs urgent attention. We await future trials.”
Dr. Yancy is at Feinberg School of Medicine, Northwestern University, Chicago. Dr. Harrington is at the department of medicine, Stanford University, Stanford, Calif. Dr. Harrington disclosed ties to Astra, Amgen, Bayer, Bristol-Myers Squibb, and several other pharmaceutical companies, and reported having served on the board of directors of the American Heart Association and Stanford Health Care. Dr. Yancy had no disclosures.
For patients under age 75 years with ST-segment elevation myocardial infarction, switching from clopidogrel to ticagrelor was noninferior to continuing clopidogrel in terms of 30-day rates of major bleeding, investigators reported at the annual meeting of the American College of Cardiology.
Rates of thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days were 0.73% in the ticagrelor group and 0.69% in the clopidogrel group, for an absolute difference of 0.04% (95% confidence interval, −0.49% to 0.58%; P less than .001 for noninferiority). “However, minor bleeding was increased with ticagrelor, and there was no benefit on efficacy outcomes,” Otavio Berwanger, MD, PhD, wrote simultaneously in JAMA Cardiology, on behalf of the writing committee for the randomized, phase 3, open-label TREAT trial.
Abundant, robust data support prompt revascularization in ST-elevation myocardial infarction (STEMI), but the real world doesn’t always meet this standard, and lytics remain in wide use in many countries, noted Dr. Berwanger, Director of the Research Institute at the Heart Hospital of Sao Paulo (Brazil). In the early 2000s, two large trials showed that dual antiplatelet therapy with aspirin and clopidogrel reduced major adverse cardiovascular events in patients receiving fibrinolytics for STEMI. More recently, the Platelet Inhibition and Patient Outcomes (PLATO) study favored ticagrelor over clopidogrel for reducing cardiovascular or stroke-related death, with no increase in the risk of major bleeding, despite ticagrelor’s boxed warning.
However, PLATO excluded patients who received fibrinolytics in the 24 hours before treatment because of concerns that ticagrelor might contribute to serious or fatal bleeding. To assess this risk, Dr. Berwanger and his associates from 10 countries randomly assigned 3,799 patients with STEMI to receive either ticagrelor (180-mg loading dose; 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose; 75 mg daily thereafter) a median of 11.4 hours after fibrinolysis. Patients averaged 58 years in age (standard deviation, 9.5 years), 77% were men, and 57% were white.
Because about 90% of patients had been pretreated with clopidogrel, the study primarily compared the effect of staying on clopidogrel with switching to ticagrelor, the investigators noted. “Our trial was an investigator- initiated trial with limited funding that did not allow a double-dummy design,” they added. “We attempted to minimize the risk of bias associated with the open-label nature of the study by performing blinded outcome adjudication.”
In terms of secondary endpoints, 23 patients (1.2%) on ticagrelor developed major bleeding according to PLATO criteria and Bleeding Academic Research Consortium (BARC) criteria, as did 26 patients (1.4%) on clopidogrel at 30-day follow-up (absolute difference, −0.18%; 95% CI, −0.89% to 0.54; P = .001 for noninferiority). Ticagrelor and clopidogrel also resembled each other in terms of fatal bleeds (0.16% versus 0.11%, respectively; P = .67) and intracranial bleeds (0.42% versus 0.37%; P = .82).
However, minimal PLATO bleeding was significantly more common with ticagrelor (3.2%) than with clopidogrel (2%; P = .02), the researchers reported. Clinically significant TIMI bleeding requiring medical attention occurred in 2% of the ticagrelor group and 1.2% of the clopidogrel group (P = .06), and ticagrelor was no more effective than clopidogrel in terms of preventing death from vascular causes, myocardial infarction, or stroke, with a composite rate of 4% in each arm and a statistically insignificant hazard ratio of (0.91; 95% CI, 0.67 to 1.25; P = .57).
Additionally, while similar proportions of patients stopped treatment because of adverse events, dyspnea was more common with ticagrelor (13.9%) than clopidogrel (7.6%). “Based on our findings, patients with STEMI younger than 75 years who initially received clopidogrel can be safely switched to ticagrelor in the first 24 hours after fibrinolysis,” the researchers wrote. “Whether this strategy will result in fewer cardiovascular events in the long term remains to be determined.”
AstraZeneca makes ticagrelor and funded the trial. Dr. Berwanger disclosed grants and personal fees from AstraZeneca and several other pharmaceutical companies.
Source: JAMA Cardiol. doi:10.1001/jamacardio.2018.0612
For patients under age 75 years with ST-segment elevation myocardial infarction, switching from clopidogrel to ticagrelor was noninferior to continuing clopidogrel in terms of 30-day rates of major bleeding, investigators reported at the annual meeting of the American College of Cardiology.
Rates of thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days were 0.73% in the ticagrelor group and 0.69% in the clopidogrel group, for an absolute difference of 0.04% (95% confidence interval, −0.49% to 0.58%; P less than .001 for noninferiority). “However, minor bleeding was increased with ticagrelor, and there was no benefit on efficacy outcomes,” Otavio Berwanger, MD, PhD, wrote simultaneously in JAMA Cardiology, on behalf of the writing committee for the randomized, phase 3, open-label TREAT trial.
Abundant, robust data support prompt revascularization in ST-elevation myocardial infarction (STEMI), but the real world doesn’t always meet this standard, and lytics remain in wide use in many countries, noted Dr. Berwanger, Director of the Research Institute at the Heart Hospital of Sao Paulo (Brazil). In the early 2000s, two large trials showed that dual antiplatelet therapy with aspirin and clopidogrel reduced major adverse cardiovascular events in patients receiving fibrinolytics for STEMI. More recently, the Platelet Inhibition and Patient Outcomes (PLATO) study favored ticagrelor over clopidogrel for reducing cardiovascular or stroke-related death, with no increase in the risk of major bleeding, despite ticagrelor’s boxed warning.
However, PLATO excluded patients who received fibrinolytics in the 24 hours before treatment because of concerns that ticagrelor might contribute to serious or fatal bleeding. To assess this risk, Dr. Berwanger and his associates from 10 countries randomly assigned 3,799 patients with STEMI to receive either ticagrelor (180-mg loading dose; 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose; 75 mg daily thereafter) a median of 11.4 hours after fibrinolysis. Patients averaged 58 years in age (standard deviation, 9.5 years), 77% were men, and 57% were white.
Because about 90% of patients had been pretreated with clopidogrel, the study primarily compared the effect of staying on clopidogrel with switching to ticagrelor, the investigators noted. “Our trial was an investigator- initiated trial with limited funding that did not allow a double-dummy design,” they added. “We attempted to minimize the risk of bias associated with the open-label nature of the study by performing blinded outcome adjudication.”
In terms of secondary endpoints, 23 patients (1.2%) on ticagrelor developed major bleeding according to PLATO criteria and Bleeding Academic Research Consortium (BARC) criteria, as did 26 patients (1.4%) on clopidogrel at 30-day follow-up (absolute difference, −0.18%; 95% CI, −0.89% to 0.54; P = .001 for noninferiority). Ticagrelor and clopidogrel also resembled each other in terms of fatal bleeds (0.16% versus 0.11%, respectively; P = .67) and intracranial bleeds (0.42% versus 0.37%; P = .82).
However, minimal PLATO bleeding was significantly more common with ticagrelor (3.2%) than with clopidogrel (2%; P = .02), the researchers reported. Clinically significant TIMI bleeding requiring medical attention occurred in 2% of the ticagrelor group and 1.2% of the clopidogrel group (P = .06), and ticagrelor was no more effective than clopidogrel in terms of preventing death from vascular causes, myocardial infarction, or stroke, with a composite rate of 4% in each arm and a statistically insignificant hazard ratio of (0.91; 95% CI, 0.67 to 1.25; P = .57).
Additionally, while similar proportions of patients stopped treatment because of adverse events, dyspnea was more common with ticagrelor (13.9%) than clopidogrel (7.6%). “Based on our findings, patients with STEMI younger than 75 years who initially received clopidogrel can be safely switched to ticagrelor in the first 24 hours after fibrinolysis,” the researchers wrote. “Whether this strategy will result in fewer cardiovascular events in the long term remains to be determined.”
AstraZeneca makes ticagrelor and funded the trial. Dr. Berwanger disclosed grants and personal fees from AstraZeneca and several other pharmaceutical companies.
Source: JAMA Cardiol. doi:10.1001/jamacardio.2018.0612
FROM ACC 2018
Key clinical point: Ticagrelor was noninferior to clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction.
Major finding: Rates of thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days were 0.73% and 0.69%, respectively (absolute difference, 0.04%; 95% confidence interval, −0.49% to 0.58%; P less than .001 for noninferiority).
Data source: A phase 3, international, randomized, open-label trial with blinded outcomes assessments of 3,799 patients with ST-elevation myocardial infarction (TREAT).
Disclosures: AstraZeneca makes ticagrelor and funded the trial. Dr. Berwanger disclosed grants and personal fees from AstraZeneca and several other pharmaceutical companies.
Source: JAMA Cardiol. doi:10.1001/jamacardio.2018.0612
