Meeting Highlights
European Society of Cardiology Congress 2013 Walter Alexander
More than 29,000 cardiologists and other health professionals from more than 150 countries attended the European Society of Cardiology (ESC) 2013 meeting in Amsterdam from August 31 to September 4. The meeting included more than 4,000 presentations. This article includes key sessions on the pharmacological treatment of venous thromboembolism; the prevention of stent thrombosis; hypertension; and plaque regression.
Clinical Trials • ACUITY: Acute Catheterization and Urgent Intervention Triage Strategy • ASPIRANT–EXT: Addition of Spironolactone in Patients with Resistant Arterial Hypertension Trial • ASSURE: ApoA1 Synthesis Simulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation • CHAMPION–PCI: Cangrelor Up Front Versus Clopidogrel Up Front • CHAMPION–PHOENIX: A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention (PCI) • CHAMPION–PLATFORM: Cangrelor Up Front Versus Delayed Clopidogrel • GUSTO: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries • TIMI: Thrombosis in Myocardial Infarction
Edoxaban (Lixiana) Versus Warfarin for Venous Thromboembolism: Hokusai–VTE Study • Harry R. Büller, MD, Professor of Medicine, Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands Administered once daily after initial treatment with heparin, edoxaban (Lixiana, Daiichi Sankyo) was found to be non-inferior to standard therapy, and it caused significantly less bleeding. The results suggested that this investigative oral factor Xa inhibitor is an effective alternative to warfarin for preventing recurring acute venous thromboembolism (VTE). In the randomized, double-blind, non-inferiority Hokusai– VTE Study, researchers enrolled 4,921 subjects with deepvein thrombosis (DVT) and 3,319 subjects with a pulmonary embolism (PE). All subjects had been previously treated with heparin. They received either warfarin (n = 4,122) or edoxaban (n = 4,118) 60 mg once daily or 30 mg once daily. Subjects had a creatinine clearance (CrCl) of 30 to 50 mL/minute and weighed less than 60 kg. The primary efficacy outcome was recurrent symptomatic VTE. The principal safety outcome was major or clinically relevant non-major bleeding. Patients received the study drug for 3 to 12 months. Recurrent symptomatic VTE, Dr. Büller said in a Hotline oral session, occurred in 130 edoxaban subjects (3.2%) and in 146 warfarin subjects (3.5%), for a hazard ratio (HR) of 0.89 and a 95% confidence interval (CI) of 0.70 to 1.13 (P < 0.001 for non-inferiority), thereby fulfilling criteria for non-inferiority to warfarin. Among the 938 subjects with right ventricular dysfunction, the rate of recurrent VTE was 3.3% in the edoxaban group and 6.2% in the warfarin group (HR = 0.52; 95% CI, 0.28–0.98). In safety reporting, major or clinically relevant non-major bleeding occurred in 349 edoxaban subjects (8.5%) and in 423 warfarin subjects (10.3%) (HR = 0.81; 95% CI, 0.71–0.94; P = 0.004 for superiority). Other adverse-event rates were comparable between the groups. Dr. Büller concluded, “Edoxaban administered once daily after initial treatment with heparin was non-inferior to highquality standard therapy and caused significantly less bleeding The author is a freelance medical writer living in New York City.
in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism.” The study was published online in September.1 In July 2011, edoxaban was approved in Japan for preventing VTE following lower-limb orthopedic surgery. Filing for FDA approval in the U.S. is expected this year. The Hokusai-VTE trial was funded by Daiichi Sankyo (ClinicalTrials.gov No. NCT00986154.)
REFERENCE 1.
Büller H, Hokusai–VTE investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med, September 1, 2013.
Risk of Stent Thrombosis After Discontinuation of Clopidogrel (Plavix) • Thea C. Godschalk, MS, St. Antonius Center for Platelet Function Research, St. Antonius Hospital, Department of Cardiology, Nieuwegein, The Netherlands • Jurriën Maria Ten Berg, MD, PhD, St. Antonius Center for Platelet Function Research, St. Antonius Hospital, Department of Cardiology, Nieuwegein, The Netherlands • Patrick W. Serruys, MD, PhD, Head, Inter ventional Cardiology Department of the Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands Product labels for P2Y12 platelet inhibitors include a warning of thrombotic cardiac events after premature discontinuation of these agents. Stopping clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi) prematurely is the leading risk factor for stent thrombosis. That vulnerability, said Thea Godschalk in a poster session, is strongest in the first 7 days after clopidogrel discontinuation.
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Meeting Highlights: European Society of Cardiology Congress 2013 Dr. Goldschalk conducted her research under Professor Jurriën ten Berg, a coauthor of the poster. However, the product labels, as well as treatment guidelines, recommend discontinuation of these same P2Y12 inhibitors 5 to 7 days before surgery. The authors sought to determine the absolute risk of stent thrombosis after post-PCI premature discontinuation of clopidogrel. They analyzed 437 cases of stent thrombosis from the 21,009-patient Dutch Percutaneous [Coronary] Intervention Registry and compared them with 866 matched controls. They looked at various time points after discontinuation (7 days or less, 8–14 days, and 15–30 days) and the risk of stent thrombosis within 7 days after discontinuation with varying durations of post-PCI clopidogrel treatment (30 days or less, 31–180 days, and 181–365 days). The stent thrombosis rate was 37.3% at 7 days or less after clopidogrel was stopped; 15.7% at 8 to 14 days after discontinuation; and 6.0% at 15 to 30 days after discontinuation. For the entire registry, the absolute stent thrombosis risk was 4.6%. Length of clopidogrel treatment before post-PCI discontinuation correlated inversely with stent thrombosis rates. When patients had received clopidogrel for 30 days or less, the stent thrombosis rate was 41.0%; for 31 to 180 days, the rate was 25.2%; and for 181 to 365 days, the rate was 5.9%. “Patients who prematurely discontinue clopidogrel are at increased risk of stent thrombosis within 180 days after PCI, especially within 7 days after discontinuation,” the researchers concluded. The risk, Ms. Godschalk said in an interview, might be reduced among patients awaiting surgery after PCI with the use of a rapidly reversible platelet inhibitor to sustain P2Y12 inhibition until surgery. She said that intravenous (IV) cangrelor (The Medicines Company), an investigational platelet inhibitor, may be given until surgery and then restarted after surgery until oral P2Y12 inhibitors take effect. The same strategy, she suggested, might apply with stenting of coronary artery bifurcated lesions, which are predictors of stent thrombosis. Commenting in an interview on cangrelor’s potential in PCI, Dr. Serruys said, “I think it’s a very elegant way to control stent thrombosis risks for a short period of time.”
Cangrelor Versus Clopidogrel in Percutaneous Coronary Intervention: CHAMPION Trials
• Christian W. Hamm, MD, Kerckhoff Heart Center, Bad Nauheim, Germany • Stephen James, MD, Director, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, Discussant Three phase 3 trials of the intravenous (IV) adenosine diphosphate (ADP) receptor (P2Y12) antagonist cangrelor (The Medicines Company) enrolled a total of more than 25,000 patients. The trials were CHAMPION–PCI, CHAMPION– PLATFORM, and CHAMPION–PHOENIX. Neither one of the first two studies met its primary endpoint, but positive effects on stent thrombosis, ischemia-driven revascularization, and Q-wave myocardial infarction (MI) were evident.
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CHAMPION–PHOENIX demonstrated a 21% reduction in thrombotic events with cangrelor compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi) (P = 0.0055). A meta-analysis of all three trials led Dr. Hamm to conclude, “Intravenous cangrelor may be an attractive option across the full spectrum of percutaneous intervention: stable angina, non–ST-segment elevation MI, and ST-segment MI.” Particular promise for IV cangrelor, Dr. Hamm said in a Hotline session, comes from its short half-life of 3 to 6 minutes. Available oral agents are limited by a long duration of action and limited bioavailability. IV glycoprotein 2b/3a inhibition reduces ischemic events but also increases bleeding significantly. The primary endpoint for the meta-analysis was a combination of death, MI, ischemia-driven revascularization, and stent thrombosis at 48 hours after percutaneous coronary intervention (PCI). The primary safety endpoint was GUSTO severe bleeding at 48 hours. The mean age in the entire patient cohort (cangrelor, N = 12,475; clopidogrel, N = 12,435) was 63 years; men made up 72% of the cohort. Patients received either a 300-mg loading dose of clopidogrel (11%) or 600 mg of clopidogrel (89%). The primary endpoint was reduced by 19% (3.8% with cangrelor vs. 4.7% with clopidogrel, P = 0.0007). Among secondary efficacy outcomes, cangrelor benefits were significant for stent thrombosis, as follows: • 0.5% vs. 0.8% with clopidogrel (P = 0.0008) • death, MI, and ischemia-driven revascularization (3.6% vs. 4.4% for clopidogrel; P = 0.001) • MI (3.1% vs. 3.6% with clopidogrel; P = 0.018) • Q-wave MI (0.2% vs. 0.3% with clopidogrel; P = 0.021) • ischemia-driven revascularization (0.5% vs. 0.7% with clopidogrel; P = 0.036) The efficacy and safety benefits of cangrelor were consistent across all subgroups, including in stratifications according to clopidogrel loading dose, aspirin dose, glycoprotein 2b/3a, and previous use of thienopyridine. The same benefits seen at 48 hours also generally continued at 30 days. Non-coronary artery bypass graft (CABG) surgery bleeding rates were higher with cangrelor. However, differences from clopidogrel were not significant for severe bleeding in the GUSTO trial (0.2% for both cangrelor and clopidogrel), for GUSTO moderate bleeding (0.6% for cangrelor and 0.4% for clopidogrel; P = 0.083), or for TIMI major bleeding (0.3% vs. 0.2%, respectively; P = 0.610). With more sensitive definitions, Dr. Hamm said—TIMI minor bleeding (P = 0.022), TIMI major plus minor bleeding (P = 0.029), ACUITY major bleeding (P < 0.001), and ACUITY without hematoma (P = 0.007)—bleeding rates were higher with cangrelor. However, the need for transfusions was not significantly higher with cangrelor (0.7% vs. 0.6% with clopidogrel, respectively; P = 0.115). Dr. James commented that among cangrelor’s attractive properties for PCI patients—particularly individuals with acute coronary syndrome (ACS)—are its consistent, reliable platelet inhibition and its fast onset and offset of action. These create a balance between efficacy and safety, he said. He posed this question to Dr. Hamm: “What would the results
Meeting Highlights: European Society of Cardiology Congress 2013 have been if a more potent agent, such as prasugrel [Effient, Eli Lilly/Daiichi Sankyo] or ticagrelor [Brilinta, AstraZeneca], had been used as a comparator?” The answer remains unknown, Dr. Hamm acknowledged, but he added that there is a drawback of the higher-potency antiplatelet agents: a loading dose of these drugs induces several days of antiplatelet activity, creating problems in the event of bleeding. “The unique feature of cangrelor is that you can turn off its effects within 60 minutes if there is bleeding or if there is a need to proceed with surgery,” he responded. All three CHAMPION trials were funded by The Medicines Company. A meta-analysis of phase 3 trial data was presented at the ESC and were published simultaneously in The Lancet.1
REFERENCE 1.
Steg PG, Bhatt DL, Hamm CW, et al. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: A pooled analysis of patient-level data. Lancet, September 3, 2013.
Spironolactone in Resistant Arterial Hypertension: ASPIRANT–EXT • Jan Václavík, MD, PhD, Internal Cardiology Department, University Hospital Olomouc, and Palacký University School of Medicine, Olomouc, Czech Republic In a trial of patients with resistant arterial hypertension, spironolactone lowered systolic blood pressure effectively. Patients enrolled in the multicenter ASPIRANT–EXT trial, said lead author Dr. Václavík, had been treated with at least three antihypertensive drugs, including a diuretic. The patients (n = 161) had office systolic blood pressures (BPs) above 140 mm Hg or diastolic BPs above 90 mm Hg. The patients were randomly assigned to receive spironolactone (n = 81) or placebo (n = 80). The primary endpoint was the difference in reductions in mean daytime systolic BP and diastolic BP, assessed by ambulatory BP monitoring (ABPM) after 8 weeks of treatment. Significantly more patients in the placebo group (47.4%) had type-2 diabetes than those in the spironolactone group (26.4%) (P = 0.019). Among 150 evaluable subjects (74 receiving spironolactone and 76 receiving placebo), decreases in mean daytime BP, as assessed by ABPM, were significantly greater with spironolactone for both systolic and diastolic BP after 8 weeks. The systolic BP difference was –9.8 mm Hg (P < 0.001), and the diastolic BP difference was –3.3 mm Hg (P = 0.013). Assessment of nighttime pressures via ABPM, 24-hour ABPM systolic BP, and office measures of systolic BP revealed benefits of spironolactone as well (P = 0.001 for all categories). The pattern persisted for diastolic BP measurements in the same three categories (P < 0.001, P = 0.005, and P = 0.003, respectively). Adverse-event rates were similar in both groups. Dr. Václavík concluded, “Spironolactone is an effective drug for lowering systolic blood pressure in patients with resistant arterial hypertension.”
RVX-208 Fails to Surpass Placebo for Plaque Regression: ASSURE
• Stephen Nicholls, MD, Professor of Cardiology, University of Adelaide, Adelaide, Australia • M. John Chapman, MD, BSc, PhD, DSc, Director, Dyslipidemia and Atherosclerosis Research Unit, National Institute for Health and Medical Research (INSERM), PitiéSalpétrière Hospital, Paris, France, Discussant RVX-208 (Resverlogix Corp.) is an investigational smallmolecule, oral bromodomain and extraterminal (BET) protein inhibitor that induces apolipoprotein A1 (apoA1) synthesis and subsequent favorable effects on high-density lipoprotein (HDL)-related measures and cholesterol efflux. Enrolling 323 patients with symptomatic coronary artery disease, angiographic stenosis exceeding 20%, and low HDLcholesterol (HDL-C) levels (defined as less than 40 mg/dL in men and less than 45 mg/dL in women), investigators in the ASSURE trial evaluated the early effects of RVX-208 100 mg (twice daily for 26 weeks) on the progression of coronary atherosclerosis compared with baseline values. Participants, Dr. Nicholls said in a Hotline session, were randomly assigned to receive, in a 1:3 ratio, either placebo (n = 80) or RVX-208 (n = 243). The patients’ mean age was about 58 years, and the mean HDL-C level was 39.0 mg/dL in both groups. Analyses of biochemical parameters showed significant positive changes in low-density lipoprotein-cholesterol (LDL-C), HDL-C, apoA1, apoB, total cholesterol, large HDL particles, and high-sensitivity C-reactive protein (hsCRP) (P = 0.08 for placebo) in both groups. Differences between the groups were not significant. Although the percentage of atheroma volume was similar in both groups (36.2% for placebo and 38.1% for RVX-208; P = 0.11) after 26 weeks, total atheroma volume (in mm3) and atheroma volume in the most diseased 10-mm segment (in mm3) were significantly higher in the RVX-208 group (P < 0.001 and P = 0.05, respectively). Follow-up was completed in 281 patients who had intravascular ultrasound (IVUS)-imaged target vessels. Among these patients, the primary IVUS efficacy parameter of the median change in percentage of atheroma volume reflected no difference between groups (–0.30% with placebo vs. –0.40% with RVX-208; P = 0.81). The change for placebo from baseline was not significant (P = 0.23), and the change for RVX-208 showed a favorable trend (P = 0.08). Looking separately at the whole segment and at the most diseased 10-mm segment (the secondary IVUS efficacy endpoint), investigators found no difference between the groups (P = 0.86 for the whole segment and P = 0.79 for the most diseased 10-mm segment). Changes from baseline, however, were significant for the whole segment (–2.8% with placebo, P = 0.01; –4.2% with RVX-208, P < 0.001) and for the most diseased 10-mm segment (–1.3% for placebo; P = 0.01; –2.2% for RVX-208; P < 0.001). The percentage of patients with plaque regression (assessed by the percentage of atheroma volume) was similar in both groups (56.2% for placebo vs. 56.3% for RVX-208; P = 0.99). Findings were also similar for total atheroma volume (54.8% for placebo vs. 55.3% for the study drug; P = 0.94). Cardiovascular events were somewhat more common in the
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Meeting Highlights: ESC 2013 placebo group (13.8% vs. 7.4% for RVX-208; P = 0.09), but liver abnormalities, including transaminases more than three times the upper limit of normal (ULN), as observed in a previous study, were more common in the RVX-208 group (0% vs. 7.1%, respectively; P = 0.009). Creatine kinase elevations exceeding three times the ULN were more numerous with RVX-208 (0% vs. 1.3%, respectively; P = 0.58). Dr. Nicholls concluded, “Administration of RVX-208 for 26 weeks did not produce an incremental benefit on atherosclerotic plaque compared with placebo.” Asked in an interview to account for the substantial placebo benefits, Dr. Nicholls did not have a definitive answer but responded, “Keep in mind that these were very-well-treated patients who were seen by a physician 11 times over 26 weeks. This is as good as a placebo group ever does.” Commenting on RVX-208’s potential, ESC Discussant Dr. Chapman said, “Insights from HDL infusion trials suggest that the low absolute magnitude of the increases in apoA1 and HDL with this agent would remain largely inadequate to warrant its development as an anti-atherosclerotic agent.” But he was quick to emphasize, “The quest for agents that modulate apoA1 and HDL metabolism and function in cardiometabolic disease must be maintained despite this setback.” He pointed out that ASSURE did not directly evaluate the so-called HDL hypothesis, which states that high HDL-C levels are protective. n
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European Society of Cardiology Congress 2013 Walter Alexander
More than 29,000 cardiologists and other health professionals from more than 150 countries attended the European Society of Cardiology (ESC) 2013 meeting in Amsterdam from August 31 to September 4. The meeting included more than 4,000 presentations. This article includes key sessions on the pharmacological treatment of venous thromboembolism; the prevention of stent thrombosis; hypertension; and plaque regression.
Clinical Trials • ACUITY: Acute Catheterization and Urgent Intervention Triage Strategy • ASPIRANT–EXT: Addition of Spironolactone in Patients with Resistant Arterial Hypertension Trial • ASSURE: ApoA1 Synthesis Simulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation • CHAMPION–PCI: Cangrelor Up Front Versus Clopidogrel Up Front • CHAMPION–PHOENIX: A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention (PCI) • CHAMPION–PLATFORM: Cangrelor Up Front Versus Delayed Clopidogrel • GUSTO: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries • TIMI: Thrombosis in Myocardial Infarction
Edoxaban (Lixiana) Versus Warfarin for Venous Thromboembolism: Hokusai–VTE Study • Harry R. Büller, MD, Professor of Medicine, Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands Administered once daily after initial treatment with heparin, edoxaban (Lixiana, Daiichi Sankyo) was found to be non-inferior to standard therapy, and it caused significantly less bleeding. The results suggested that this investigative oral factor Xa inhibitor is an effective alternative to warfarin for preventing recurring acute venous thromboembolism (VTE). In the randomized, double-blind, non-inferiority Hokusai– VTE Study, researchers enrolled 4,921 subjects with deepvein thrombosis (DVT) and 3,319 subjects with a pulmonary embolism (PE). All subjects had been previously treated with heparin. They received either warfarin (n = 4,122) or edoxaban (n = 4,118) 60 mg once daily or 30 mg once daily. Subjects had a creatinine clearance (CrCl) of 30 to 50 mL/minute and weighed less than 60 kg. The primary efficacy outcome was recurrent symptomatic VTE. The principal safety outcome was major or clinically relevant non-major bleeding. Patients received the study drug for 3 to 12 months. Recurrent symptomatic VTE, Dr. Büller said in a Hotline oral session, occurred in 130 edoxaban subjects (3.2%) and in 146 warfarin subjects (3.5%), for a hazard ratio (HR) of 0.89 and a 95% confidence interval (CI) of 0.70 to 1.13 (P < 0.001 for non-inferiority), thereby fulfilling criteria for non-inferiority to warfarin. Among the 938 subjects with right ventricular dysfunction, the rate of recurrent VTE was 3.3% in the edoxaban group and 6.2% in the warfarin group (HR = 0.52; 95% CI, 0.28–0.98). In safety reporting, major or clinically relevant non-major bleeding occurred in 349 edoxaban subjects (8.5%) and in 423 warfarin subjects (10.3%) (HR = 0.81; 95% CI, 0.71–0.94; P = 0.004 for superiority). Other adverse-event rates were comparable between the groups. Dr. Büller concluded, “Edoxaban administered once daily after initial treatment with heparin was non-inferior to highquality standard therapy and caused significantly less bleeding The author is a freelance medical writer living in New York City.
in a broad spectrum of patients with venous thromboembolism, including those with severe pulmonary embolism.” The study was published online in September.1 In July 2011, edoxaban was approved in Japan for preventing VTE following lower-limb orthopedic surgery. Filing for FDA approval in the U.S. is expected this year. The Hokusai-VTE trial was funded by Daiichi Sankyo (ClinicalTrials.gov No. NCT00986154.)
REFERENCE 1.
Büller H, Hokusai–VTE investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med, September 1, 2013.
Risk of Stent Thrombosis After Discontinuation of Clopidogrel (Plavix) • Thea C. Godschalk, MS, St. Antonius Center for Platelet Function Research, St. Antonius Hospital, Department of Cardiology, Nieuwegein, The Netherlands • Jurriën Maria Ten Berg, MD, PhD, St. Antonius Center for Platelet Function Research, St. Antonius Hospital, Department of Cardiology, Nieuwegein, The Netherlands • Patrick W. Serruys, MD, PhD, Head, Inter ventional Cardiology Department of the Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands Product labels for P2Y12 platelet inhibitors include a warning of thrombotic cardiac events after premature discontinuation of these agents. Stopping clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi) prematurely is the leading risk factor for stent thrombosis. That vulnerability, said Thea Godschalk in a poster session, is strongest in the first 7 days after clopidogrel discontinuation.
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Meeting Highlights: European Society of Cardiology Congress 2013 Dr. Goldschalk conducted her research under Professor Jurriën ten Berg, a coauthor of the poster. However, the product labels, as well as treatment guidelines, recommend discontinuation of these same P2Y12 inhibitors 5 to 7 days before surgery. The authors sought to determine the absolute risk of stent thrombosis after post-PCI premature discontinuation of clopidogrel. They analyzed 437 cases of stent thrombosis from the 21,009-patient Dutch Percutaneous [Coronary] Intervention Registry and compared them with 866 matched controls. They looked at various time points after discontinuation (7 days or less, 8–14 days, and 15–30 days) and the risk of stent thrombosis within 7 days after discontinuation with varying durations of post-PCI clopidogrel treatment (30 days or less, 31–180 days, and 181–365 days). The stent thrombosis rate was 37.3% at 7 days or less after clopidogrel was stopped; 15.7% at 8 to 14 days after discontinuation; and 6.0% at 15 to 30 days after discontinuation. For the entire registry, the absolute stent thrombosis risk was 4.6%. Length of clopidogrel treatment before post-PCI discontinuation correlated inversely with stent thrombosis rates. When patients had received clopidogrel for 30 days or less, the stent thrombosis rate was 41.0%; for 31 to 180 days, the rate was 25.2%; and for 181 to 365 days, the rate was 5.9%. “Patients who prematurely discontinue clopidogrel are at increased risk of stent thrombosis within 180 days after PCI, especially within 7 days after discontinuation,” the researchers concluded. The risk, Ms. Godschalk said in an interview, might be reduced among patients awaiting surgery after PCI with the use of a rapidly reversible platelet inhibitor to sustain P2Y12 inhibition until surgery. She said that intravenous (IV) cangrelor (The Medicines Company), an investigational platelet inhibitor, may be given until surgery and then restarted after surgery until oral P2Y12 inhibitors take effect. The same strategy, she suggested, might apply with stenting of coronary artery bifurcated lesions, which are predictors of stent thrombosis. Commenting in an interview on cangrelor’s potential in PCI, Dr. Serruys said, “I think it’s a very elegant way to control stent thrombosis risks for a short period of time.”
Cangrelor Versus Clopidogrel in Percutaneous Coronary Intervention: CHAMPION Trials
• Christian W. Hamm, MD, Kerckhoff Heart Center, Bad Nauheim, Germany • Stephen James, MD, Director, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, Discussant Three phase 3 trials of the intravenous (IV) adenosine diphosphate (ADP) receptor (P2Y12) antagonist cangrelor (The Medicines Company) enrolled a total of more than 25,000 patients. The trials were CHAMPION–PCI, CHAMPION– PLATFORM, and CHAMPION–PHOENIX. Neither one of the first two studies met its primary endpoint, but positive effects on stent thrombosis, ischemia-driven revascularization, and Q-wave myocardial infarction (MI) were evident.
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CHAMPION–PHOENIX demonstrated a 21% reduction in thrombotic events with cangrelor compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi) (P = 0.0055). A meta-analysis of all three trials led Dr. Hamm to conclude, “Intravenous cangrelor may be an attractive option across the full spectrum of percutaneous intervention: stable angina, non–ST-segment elevation MI, and ST-segment MI.” Particular promise for IV cangrelor, Dr. Hamm said in a Hotline session, comes from its short half-life of 3 to 6 minutes. Available oral agents are limited by a long duration of action and limited bioavailability. IV glycoprotein 2b/3a inhibition reduces ischemic events but also increases bleeding significantly. The primary endpoint for the meta-analysis was a combination of death, MI, ischemia-driven revascularization, and stent thrombosis at 48 hours after percutaneous coronary intervention (PCI). The primary safety endpoint was GUSTO severe bleeding at 48 hours. The mean age in the entire patient cohort (cangrelor, N = 12,475; clopidogrel, N = 12,435) was 63 years; men made up 72% of the cohort. Patients received either a 300-mg loading dose of clopidogrel (11%) or 600 mg of clopidogrel (89%). The primary endpoint was reduced by 19% (3.8% with cangrelor vs. 4.7% with clopidogrel, P = 0.0007). Among secondary efficacy outcomes, cangrelor benefits were significant for stent thrombosis, as follows: • 0.5% vs. 0.8% with clopidogrel (P = 0.0008) • death, MI, and ischemia-driven revascularization (3.6% vs. 4.4% for clopidogrel; P = 0.001) • MI (3.1% vs. 3.6% with clopidogrel; P = 0.018) • Q-wave MI (0.2% vs. 0.3% with clopidogrel; P = 0.021) • ischemia-driven revascularization (0.5% vs. 0.7% with clopidogrel; P = 0.036) The efficacy and safety benefits of cangrelor were consistent across all subgroups, including in stratifications according to clopidogrel loading dose, aspirin dose, glycoprotein 2b/3a, and previous use of thienopyridine. The same benefits seen at 48 hours also generally continued at 30 days. Non-coronary artery bypass graft (CABG) surgery bleeding rates were higher with cangrelor. However, differences from clopidogrel were not significant for severe bleeding in the GUSTO trial (0.2% for both cangrelor and clopidogrel), for GUSTO moderate bleeding (0.6% for cangrelor and 0.4% for clopidogrel; P = 0.083), or for TIMI major bleeding (0.3% vs. 0.2%, respectively; P = 0.610). With more sensitive definitions, Dr. Hamm said—TIMI minor bleeding (P = 0.022), TIMI major plus minor bleeding (P = 0.029), ACUITY major bleeding (P < 0.001), and ACUITY without hematoma (P = 0.007)—bleeding rates were higher with cangrelor. However, the need for transfusions was not significantly higher with cangrelor (0.7% vs. 0.6% with clopidogrel, respectively; P = 0.115). Dr. James commented that among cangrelor’s attractive properties for PCI patients—particularly individuals with acute coronary syndrome (ACS)—are its consistent, reliable platelet inhibition and its fast onset and offset of action. These create a balance between efficacy and safety, he said. He posed this question to Dr. Hamm: “What would the results
Meeting Highlights: European Society of Cardiology Congress 2013 have been if a more potent agent, such as prasugrel [Effient, Eli Lilly/Daiichi Sankyo] or ticagrelor [Brilinta, AstraZeneca], had been used as a comparator?” The answer remains unknown, Dr. Hamm acknowledged, but he added that there is a drawback of the higher-potency antiplatelet agents: a loading dose of these drugs induces several days of antiplatelet activity, creating problems in the event of bleeding. “The unique feature of cangrelor is that you can turn off its effects within 60 minutes if there is bleeding or if there is a need to proceed with surgery,” he responded. All three CHAMPION trials were funded by The Medicines Company. A meta-analysis of phase 3 trial data was presented at the ESC and were published simultaneously in The Lancet.1
REFERENCE 1.
Steg PG, Bhatt DL, Hamm CW, et al. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: A pooled analysis of patient-level data. Lancet, September 3, 2013.
Spironolactone in Resistant Arterial Hypertension: ASPIRANT–EXT • Jan Václavík, MD, PhD, Internal Cardiology Department, University Hospital Olomouc, and Palacký University School of Medicine, Olomouc, Czech Republic In a trial of patients with resistant arterial hypertension, spironolactone lowered systolic blood pressure effectively. Patients enrolled in the multicenter ASPIRANT–EXT trial, said lead author Dr. Václavík, had been treated with at least three antihypertensive drugs, including a diuretic. The patients (n = 161) had office systolic blood pressures (BPs) above 140 mm Hg or diastolic BPs above 90 mm Hg. The patients were randomly assigned to receive spironolactone (n = 81) or placebo (n = 80). The primary endpoint was the difference in reductions in mean daytime systolic BP and diastolic BP, assessed by ambulatory BP monitoring (ABPM) after 8 weeks of treatment. Significantly more patients in the placebo group (47.4%) had type-2 diabetes than those in the spironolactone group (26.4%) (P = 0.019). Among 150 evaluable subjects (74 receiving spironolactone and 76 receiving placebo), decreases in mean daytime BP, as assessed by ABPM, were significantly greater with spironolactone for both systolic and diastolic BP after 8 weeks. The systolic BP difference was –9.8 mm Hg (P < 0.001), and the diastolic BP difference was –3.3 mm Hg (P = 0.013). Assessment of nighttime pressures via ABPM, 24-hour ABPM systolic BP, and office measures of systolic BP revealed benefits of spironolactone as well (P = 0.001 for all categories). The pattern persisted for diastolic BP measurements in the same three categories (P < 0.001, P = 0.005, and P = 0.003, respectively). Adverse-event rates were similar in both groups. Dr. Václavík concluded, “Spironolactone is an effective drug for lowering systolic blood pressure in patients with resistant arterial hypertension.”
RVX-208 Fails to Surpass Placebo for Plaque Regression: ASSURE
• Stephen Nicholls, MD, Professor of Cardiology, University of Adelaide, Adelaide, Australia • M. John Chapman, MD, BSc, PhD, DSc, Director, Dyslipidemia and Atherosclerosis Research Unit, National Institute for Health and Medical Research (INSERM), PitiéSalpétrière Hospital, Paris, France, Discussant RVX-208 (Resverlogix Corp.) is an investigational smallmolecule, oral bromodomain and extraterminal (BET) protein inhibitor that induces apolipoprotein A1 (apoA1) synthesis and subsequent favorable effects on high-density lipoprotein (HDL)-related measures and cholesterol efflux. Enrolling 323 patients with symptomatic coronary artery disease, angiographic stenosis exceeding 20%, and low HDLcholesterol (HDL-C) levels (defined as less than 40 mg/dL in men and less than 45 mg/dL in women), investigators in the ASSURE trial evaluated the early effects of RVX-208 100 mg (twice daily for 26 weeks) on the progression of coronary atherosclerosis compared with baseline values. Participants, Dr. Nicholls said in a Hotline session, were randomly assigned to receive, in a 1:3 ratio, either placebo (n = 80) or RVX-208 (n = 243). The patients’ mean age was about 58 years, and the mean HDL-C level was 39.0 mg/dL in both groups. Analyses of biochemical parameters showed significant positive changes in low-density lipoprotein-cholesterol (LDL-C), HDL-C, apoA1, apoB, total cholesterol, large HDL particles, and high-sensitivity C-reactive protein (hsCRP) (P = 0.08 for placebo) in both groups. Differences between the groups were not significant. Although the percentage of atheroma volume was similar in both groups (36.2% for placebo and 38.1% for RVX-208; P = 0.11) after 26 weeks, total atheroma volume (in mm3) and atheroma volume in the most diseased 10-mm segment (in mm3) were significantly higher in the RVX-208 group (P < 0.001 and P = 0.05, respectively). Follow-up was completed in 281 patients who had intravascular ultrasound (IVUS)-imaged target vessels. Among these patients, the primary IVUS efficacy parameter of the median change in percentage of atheroma volume reflected no difference between groups (–0.30% with placebo vs. –0.40% with RVX-208; P = 0.81). The change for placebo from baseline was not significant (P = 0.23), and the change for RVX-208 showed a favorable trend (P = 0.08). Looking separately at the whole segment and at the most diseased 10-mm segment (the secondary IVUS efficacy endpoint), investigators found no difference between the groups (P = 0.86 for the whole segment and P = 0.79 for the most diseased 10-mm segment). Changes from baseline, however, were significant for the whole segment (–2.8% with placebo, P = 0.01; –4.2% with RVX-208, P < 0.001) and for the most diseased 10-mm segment (–1.3% for placebo; P = 0.01; –2.2% for RVX-208; P < 0.001). The percentage of patients with plaque regression (assessed by the percentage of atheroma volume) was similar in both groups (56.2% for placebo vs. 56.3% for RVX-208; P = 0.99). Findings were also similar for total atheroma volume (54.8% for placebo vs. 55.3% for the study drug; P = 0.94). Cardiovascular events were somewhat more common in the
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Meeting Highlights: ESC 2013 placebo group (13.8% vs. 7.4% for RVX-208; P = 0.09), but liver abnormalities, including transaminases more than three times the upper limit of normal (ULN), as observed in a previous study, were more common in the RVX-208 group (0% vs. 7.1%, respectively; P = 0.009). Creatine kinase elevations exceeding three times the ULN were more numerous with RVX-208 (0% vs. 1.3%, respectively; P = 0.58). Dr. Nicholls concluded, “Administration of RVX-208 for 26 weeks did not produce an incremental benefit on atherosclerotic plaque compared with placebo.” Asked in an interview to account for the substantial placebo benefits, Dr. Nicholls did not have a definitive answer but responded, “Keep in mind that these were very-well-treated patients who were seen by a physician 11 times over 26 weeks. This is as good as a placebo group ever does.” Commenting on RVX-208’s potential, ESC Discussant Dr. Chapman said, “Insights from HDL infusion trials suggest that the low absolute magnitude of the increases in apoA1 and HDL with this agent would remain largely inadequate to warrant its development as an anti-atherosclerotic agent.” But he was quick to emphasize, “The quest for agents that modulate apoA1 and HDL metabolism and function in cardiometabolic disease must be maintained despite this setback.” He pointed out that ASSURE did not directly evaluate the so-called HDL hypothesis, which states that high HDL-C levels are protective. n
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