Meeting Highlights
American College of Rheumatology and
Transcatheter Cardiovascular Therapeutics Walter Alexander
ACR 2013: Rheumatoid Arthritis, Psoriatic Arthritis, and Behçet’s Syndrome ACR 2013 hosted 11,800 professionals from October 25–30 in San Diego. This was the third highest attendance figure in the 77 years of ACR annual meetings. Key presentations included rheumatoid arthritis; psoriatic arthritis, with two cases reported in the PALACE I–IV trials; and Behçet’s disease.
Tofacitinib (Xeljanz) After Adalimumab (Humira) for Rheumatoid Arthritis: Phase 3 • Mark C. Genovese, MD, Stanford University School of Medicine, Immunology and Rheumatology Clinic, Stanford, California The main reason patients with rheumatoid arthritis switch from an anti–tumor necrosis factor (TNF) agent to the Janus kinase (JAK) inhibitor tofacitinib (Xeljanz, Pfizer), said Dr. Genovese, “is to get away from an injectable drug to an oral one—or it might be related to inadequacy of clinical response from the TNF-inhibitor.” Dr. Genovese led a phase 3 trial in which patients had received oral tofacitinib or subcutaneous (SC) injections of adalimumab (Humira, AbbVie), both on top of methotrexate. The patients (n = 124) were then moved directly from the phase 3 randomized, placebo-controlled ORAL trial to an open-label extension without a washout period. Investigators looked at the periods 3 months before, at, and 3 months after the time that patients were switched to tofacitinib 10 mg twice daily. Adjustments to 5 mg of tofacitinib or a lower methotrexate dose were allowed. In patients switched from adalimumab to tofacitinib, American College of Rheumatology (ACR) 20 response rates (ACR20) were 74.2% at 4.5 months before the end of the randomized trial, 76.6% at the end of the randomized trial, and 90.5% 4.5 months after the transition to tofacitinib. (ACR20 is defined as disease improvement of at least 20% compared with baseline.) ACR50 response rates (44.4%, 50.8%, and 65.5%, respectively) and ACR70 response rates (16.1%, 21.0%, and 36.2%, respectively) at the same time points showed a similar pattern. The mean change from baseline scores in the Health Assessment Questionnaire–Disability Index (HAQ–DI) was –0.55, –0.60, and –0.70 at the same time points. For patients who had received The author is a freelance medical writer living in New York City.
tofacitinib in the randomized trial and were moved to the openlabel extension with tofacitinib, results were similar at the same time points and showed a similar pattern of increases from the randomized controlled trial to the open-label extension. The incidence of safety-related adverse drug events (ADEs) generally increased in the 3 months after the switch to openlabel administration for the group switching from adalimumab to tofacitinib and for the group going from double-blind tofacitinib to open-label tofacitinib. Dr. Genovese said, “It is unclear whether this is due to longerterm use of the agent or if it is related to the fact that patients now know that they are receiving active drug.” Discontinuations, however, decreased from a total 12-month rate of 13.3 per 100 patient-years for the randomized ORAL trial to 9.1 per 100 patient-years in the ORAL open-label extension. The changes were small, he said, and no further confirmation is required. He added, “We don’t see an increase in risk associated with the transition from adalimumab to tofacitinib.”
Tight-Control Treatment of Early Psoriatic Arthritis: TICOPA
• Philip Heliwell, MD, Leeds Institute of Molecular Medicine, Division of Rheumatic and Musculoskeletal Medicine, University of Leeds, United Kingdom • Laura C. Coates, MD, PhD, Leeds Institute of Molecular Medicine, Division of Rheumatic and Musculoskeletal Medicine, University of Leeds, United Kingdom Joint and skin outcomes improved when patients with early psoriatic arthritis (PsA) in an intensive-management (“tightcontrol”) group followed a strict treatment protocol with escalation of therapy if minimal disease activity (MDA) criteria were not met. The finding was from an analysis of the Tight Control Of Early Psoriatic Arthritis (TICOPA) study, a prospective, multicenter, open-label randomized controlled trial in which the authors compared a strategy of tight, treat-to-target goals with standard care. Dr. Heliwell said at an ACR press conference: Psoriatic arthritis has lagged behind rheumatoid arthritis in treatment paradigms, yet it’s the second commonest inflammatory arthritis. Psoriasis occurs in 2% to 3% of the North American population, and up to a third of people with psoriasis will develop psoriatic arthritis—although up to half of them don’t know they have it. I think this study brings it up to date alongside rheumatoid arthritis.
Dr. Coates, presenting TICOPA data in an oral session, said that the study included 206 patients with early PsA who were
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Meeting Highlights: American College of Rheumatology naive to disease-modifying antirheumatic drugs (DMARDs). Early disease was defined by symptoms lasting less than 24 months. Median patient age was 45 years (range, 18–81 years; 52% male). Polyarthritis was present in 71% of the patients. Patients were randomly assigned to receive, in a 1:1 ratio, either tight control, which entailed a review every 4 weeks, or standard care with a review every 12 weeks. Patients in the tight-control arm were started on methotrexate with rapid dose escalation to 25 mg, if tolerated, after 6 weeks. After 12 weeks, therapy was escalated to combination DMARDs if patients had not achieved the criteria for MDA. This was defined by the presence of five of seven criteria encompassing tender and swollen joint counts, Psoriasis Area and Severity Index (PASI), and body surface area (BSA) scores; patient pain, patient global activity, Health Assessment Questionnaire– Disability Index (HAQ–DI) scores; and tender entheseal points. In patients who had three or more tender and swollen joints, according to the United Kingdom’s National Institute for Care and Excellence (NICE) guidelines, therapy was escalated to anti-TNF agents. If MDA criteria were not met or if there were fewer than three actively swollen joints, patients received an alternative DMARD combined with methotrexate. Patients receiving standard care were treated by a rheumatologist with no set protocol and no limitations. The primary outcome was the achievement of ACR20 (at least a 20% improved response over baseline) by 48 weeks. Key secondary outcomes were ACR50, ACR70, and more than 75% improvement (PASI75). An intention-to-treat (ITT) analysis revealed that the odds of achieving ACR20 at week 48 were higher in the tight-control arm than in the standard-care arm, for an odds ratio (OR) of 1.91 and a 95% confidence interval (CI) of 1.03 to 3.55 (P = 0.0392). The odds of achieving ACR50 (OR, 2.36; 95% CI, 1.25–4.47; P = 0.0081) and ACR70 (OR, 2.64; 95% CI, 1.32–5.26; P = 0.0058) were also greater with tight control than with standard care. Adverse drug events (ADEs) were more common in the tight-control arm (97%) than with standard care (80%). ADEs included nausea, liver function test abnormalities, and infections (e.g., the common cold). Although serious ADEs were more common with tightcontrol therapy (25) than with standard care (eight), no deaths or unexpected serious ADEs were reported. Tight control of PsA disease activity using a treat-to-target approach significantly improves joint and skin outcomes for patients with newly diagnosed PsA without causing unexpected serious ADEs, Dr. Coates concluded. Pfizer and Arthritis Research UK funded this study.
Apremilast Improves Enthesitis and Dactylitis In Psoriatic Arthritis: PALACE 1, 2, and 3
of muscles, tendons, joint capsules, ligaments and fascia to bone) and dactylitis (swelling of a finger or toe). Patients in the PALACE trials had active psoriatic arthritis (PsA) despite prior disease-modifying antirheumatic drugs (DMARDs) and/ or biologics. Dr. Gladman noted, “Enthesitis and dactylitis are distinguishing features of psoriatic arthritis that may be associated with more severe disease and can be difficult to treat.” Patients in the PALACE trials were randomly assigned, in a 1:1:1 fashion, to receive placebo (n = 496), apremilast 20 mg twice daily (n = 500), or apremilast 30 mg twice daily (n = 497). The groups were stratified by their baseline use of DMARDs. At week 16, patients with a 20% reduction or less from baseline in swollen joint count or tender joint count qualified for a protocol-required early escape. Patients receiving placebo were reassigned to receive apremilast at 20 or 30 mg twice daily. At week 24, all remaining placebo patients were reassigned to receive apremilast 20 or 30 mg twice daily through week 52. Patients taking concurrent DMARDs were allowed to continue stable doses of methotrexate, sulfasalazine, leflunomide, or combinations. Enthesopathy was assessed via the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), representing the number of painful entheses out of a possible 13 entheses. The dactylitis count, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis. In patients who were originally assigned to receive apremilast and who had pre-existing enthesopathy (n = 618) and/or dactylitis (n = 412), at week 24 the mean change in MASES was –0.8 for placebo, –1.2 for apremilast 20 mg, and –1.4 for apremilast 30 mg (P = 0.016 for apremilast 30 mg vs. placebo). At week 52, MASES scores of 0 were achieved by 41.4% of patients in the 20-mg group and by 37.4% of patients in the 30-mg group. In response to a question about the clinical significance of the magnitude of the MASES improvements with apremilast, Dr. Gladman said, “I concentrate more on the number of patients who have gone to zero—to me, that’s more important.” At week 24, the mean change in dactylitis count was –1.2 for placebo, –1.5 for apremilast 20 mg, and –1.8 for apremilast 30 mg (P = 0.0121 for apremilast 30 mg vs. placebo). The median reduction in dactylitis count for the apremilast doses was 67.6% at 16 weeks and 100% at both 24 and 52 weeks. No new safety findings were identified in long-term follow-up examinations. Apremilast demonstrated an acceptable safety profile, with diarrhea, nausea, headache, upper respiratory tract infection and nasopharyngitis as the most common ADEs. Over a 52-week period, apremilast continued to demonstrate efficacy in the treatment of PsA, including improvements in enthesitis and dactylitis, Dr. Gladman concluded.
• Dafna Gladman, MD, Toronto Western Hospital, Toronto, Canada
Apremilast in DMARD-Naive Patients With Psoriatic Arthritis: PALACE 4 (Phase 3)
In an analysis of combined results of the PALACE 1, 2, and 3 trials, Celgene’s apremilast, an oral phosphodiesterase-4 (DPP-4) inhibitor, when compared with placebo, led to longterm improvements in enthesitis (inflamed attachment sites
PALACE 4 was one of the first studies to demonstrate efficacy and safety of a novel agent given solely to DMARD-naive
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• Alvin Wells, MD, PhD, Rheumatology and Immunotherapy Center, Oak Creek, Wisconsin
Meeting Highlights: American College of Rheumatology patients with PsA. Apremilast, an oral PPD-4 inhibitor that modulates intracellular inflammatory mediators, produced clinically meaningful improvements in signs and symptoms in treated patients in this 52-week study. Patients had PsA for at least 6 months, had at least three swollen and three tender joints, and had received no previous treatment with conventional DMARDs or biologics. They met the definition of CASPAR (Classification Criteria for Psoriatic Arthritis). Investigators randomly assigned 527 patients with PsA, in a 1:1:1 fashion, to receive apremilast 20 mg twice daily, apremilast 30 mg twice daily, or placebo. At week 16, patients with reduction of 20% or less from baseline in swollen joint count or tender joint count qualified for a protocol-required early escape. Patients receiving placebo were reassigned to receive apremilast at 20 or 30 mg twice daily. At week 24, all remaining placebo patients were reassigned to receive apremilast 20 or 30 mg twice daily through week 52. The primary endpoint was the proportion of patients achieving an ACR20 (improvement of at least 20% compared with baseline). The patients (mean age, 49.4 years) had a mean duration of PsA of 3.41 years. The mean duration of skin psoriasis (present in all patients) was 15.8 years. The baseline mean swollen joint count was 11.2, and the mean tender joint count was 20.1. Sixtyfive percent of the patients had enthesitis (a median MASES score of 3.0; range 0–13), and 50% had dactylitis (finger or toe swelling), with a median severity score of 2.0. At week 16, patients receiving apremilast showed improvements in multiple endpoints, including enthesitis (inflammation at sites where tendons, ligaments, or joint capsule fibers insert into bone), dactylitis, impaired physical function, swollen and tender joint counts, and associated psoriasis. In patients originally receiving apremilast and completing 52 weeks of therapy (n = 273), benefits were maintained or increased. In the 16-week primary endpoint analysis, a significantly greater proportion of apremilast-treated patients achieved ACR20 compared with placebo patients: 29.2% receiving apremilast 20 mg and 32.3% receiving apremilast 30 mg versus 16.9% receiving placebo (P = 0.0076 and P = 0.0011 vs. placebo). At week 52, ACR20 was achieved by 53.4% of the 131 patients receiving apremilast 20 mg and by 58.7% of the 138 patients receiving 30 mg. The median change in swollen joint count at 52 weeks was –89.4% and –100.0% in the 20-mg and 30-mg groups of patients. Tender joint count changes were –67.1% and –66.7%, respectively. Nausea, diarrhea, headache, and upper respiratory tract infections were reported in 5% or more of patients receiving apremilast. Most ADEs were mild to moderate in severity. In the placebo-controlled period of the trial, serious ADE rates were 2.8% for placebo, 1.7% for apremilast 20 mg, and 0.6% for apremilast 30 mg. The rate of therapy discontinuation attributable to ADEs over the 52 weeks was 5.2% in apremilast-exposed patients. Apremilast demonstrated clinical benefits up to week 52 in patients with PsA who had not received DMARDs previously, Dr. Wells concluded.
Apremilast for Behçet’s Syndrome: Phase 2
• Gülen Hatemi, MD, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey Among the estimated 10,000 Americans with Behçet’s syndrome, a type of vasculitis that causes inflammation in the blood vessels throughout the body, mucocutaneous manifestations can be resistant to conventional treatment and may be disabling. Apremilast, an oral phosphodiesterase-4 (PPD-4) inhibitor that modulates inflammatory pathways, effectively reduced oral ulcers and other disease symptoms in a phase 2 multicenter, randomized, placebo-controlled study with an open-label extension. The trial included 111 patients who had two or more oral ulcers but no major organ involvement. The main symptom of Behçet’s is painful mouth ulcers, although genital ulcers may also occur less often. Patients received apremilast 30 mg twice daily or placebo for 12 weeks, followed by a 12-week activetreatment period for all patients and a 28-day post-treatment observational follow-up period. The primary endpoint was the number of oral ulcers at week 12. The mean patient age was 34.5 years (±10.1 years; 69% were women), and the mean duration of Behçet’s syndrome was 5.3 years. In the primary endpoint analysis at week 12, the mean number (± standard deviation) of oral ulcers over time was 0.5 with apremilast and 2.1 with placebo (P < 0.0001). The mean oral ulcer area-under-the-curve (AUC) concentration with apremilast was one-third of that with placebo (P < 0.0001). Dr. Hatemi emphasized that the beneficial effects of apremilast started within 2 weeks and were sustained during treatment—but they soon disappeared after apremilast was stopped at week 24. Among other benefits, oral ulcer pain on a Visual Analogue Scale (VAS) was 9.4 for apremilast and 35.0 for placebo (P < 0.0001). At week 12, significantly more patients receiving apremilast had a complete response (70.9% in 39 of 55 patients vs. 28.6% in 16 of 56 placebo patients; P < 0.0001). For the 16 patients with genital ulcers at baseline, 10 of 10 (100%) receiving apremilast had a complete response at week 12, compared with three of six patients in the placebo group (50%) (P = 0.036). In patients who did not have genital ulcers at baseline, new ulcers developed in five placebo patients and in one apremilasttreated patient. Five placebo patients and four apremilast patients withdrew from treatment because of adverse drug events (ADEs). Two serious ADEs were reported in the apremilast group—diplegia (paralysis of corresponding parts on both sides of the body) and anal fissure with hemorrhoids. Three ADEs were reported in the placebo group (two disease flares and one fever episode). Diplegia was transient and was not thought to be related to treatment. Headache, a common symptom in patients with Behçet’s syndrome, was the most commonly reported ADE (by 47.3% apremilast patients and by 44.6% of placebo patients) during the placebo-controlled period. Apremilast was effective for treating the oral ulcers of Behçet’s syndrome, and it had an acceptable safety profile, Dr. Hatemi added.
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Meeting Highlights: Transcatheter Cardiovascular Therapeutics “It also seems that it is effective in genital ulcers, which is a difficult-to-treat manifestation of Behçet’s syndrome,” she concluded.
Transcatheter Cardiovascular Therapeutics (TCT) The 25th TCT meeting took place in San Francisco from October 28 to November 2, 2013. The gathering focused on catheter-based interventions for cardiovascular disease and was attended by more than 11,500 health care practitioners. Three sessions related to the environment of acute coronary events are reviewed: one on platelet function testing as a guide to antiplatelet therapy and two on the effect of pharmacological strategies in the setting of myocardial infarction.
Impact of Platelet Function Testing on Practice: TRANSLATE–POPS •
Tracy Y. Wang, MD, Duke Clinical Research Institute, Durham, North Carolina
Although high platelet reactivity is known to be associated with a greater cardiovascular risk in patients undergoing percutaneous coronary intervention (PCI) for ST-elevation and non–ST-elevation myocardial infarction (STEMI and NSTEMI), randomized controlled trials have failed to show that altering antiplatelet therapy based on platelet function tests improves outcomes. Research has also shown, Dr. Wang noted at a TCT press conference, that many PCI patients who receive an adenosine diphosphate (ADP) receptor inhibitor still have high platelet reactivity, suggesting the need for stronger platelet inhibition. In TRANSLATE–POPS (Treatment with ADP Receptor Inhibitors–Prospective Open-Label Antiplatelet Therapy Study), Dr. Wang et al. asked this question: Does access to routine, no-cost platelet function testing increase the frequency of therapeutic adjustment of ADP receptor inhibitors? The team hypothesized that access would increase adjustments of ADP receptor inhibitors before hospital discharge and improve 30-day and long-term (12-month) clinical outcomes. Facilities that were not routinely performing platelet testing (less than 30%) for PCI patients were eligible for the clusterrandomized trial. TRANSLATE–POPS was embedded within TRANSLATE–ACS (Treatment with ADP Receptor Inhibitors– Longitudinal Assessment Patterns and Events After Acute Coronary Syndrome), an observational study. Sites were randomly assigned (50 patients in each treatment arm) to receive either free and routine availability of platelet function testing (the device arm) or the standard of care (the usual-care arm). For the device arm, the sites were encouraged to test patients before discharge and at least 12 hours after PCI. For the usual-care arm, the sites were not provided with routine platelet function testing, but the health care team could choose to perform testing if it was judged to be clinically necessary. The primary endpoint was the rate of in-hospital therapeutic adjustments to anticlotting therapy.
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The sites did not uniformly take up the offer of no-cost platelet testing in the device arm. For this arm, Dr. Wang reported, platelet testing was performed 66% of the time, compared with 1.4% of the time for the usual-care arm. The odds ratio (OR) for the primary endpoint of therapeutic adjustment, accounting for a clustering effect within a site, was 1.55 for the device arm versus the usual-care arm (11.6% usual care, 15.9% device (P = 0.01). Switching of antiplatelet agents was more frequent in the device arm (14.5% vs. 10.6% for usual care). In the device arm, therapeutic adjustments occurred in 31% of patients with platelet reactivity units (PRUs) of 235 or more and in 29% of patients with PRUs of 208 or more. Rates for PRUs below 235 and below 208 were 14% and 13%, respectively (P < 0.001 for both). A significantly greater number of patients were switched from clopidogrel (e.g., Plavix, Bristol-Myers Squibb/Sanofi) to the more potent antiplatelet agents prasugrel (Effient, Eli Lilly/Daiichi Sankyo) or ticagrelor (Brilinta, AstraZeneca) in the device arm than in the usual-care arm (P = 0.004). Assessment of outcomes after 30 days failed to show an advantage for patients in the device arm, who experienced a similar percentage of major cardiac ADEs as the usual-care arm (4.5% vs. 5.1%, respectively; P = 0.69). Both groups reported a similar rate of bleeding events (4.2% for the device arm vs. 4.3% for the usual-care arm; P = 0.33). There was no observed impact on early major adverse cardiac ADEs, Dr. Wang said; however, an investigation of long-term outcomes is ongoing. The impact on antiplatelet adjustments, Dr. Wang commented, was modest. Although platelet testing did lead to some higher first-line use of prasugrel, she concluded, “TRANSLATE– POPS showed that current U.S. practice still strongly favors generic clopidogrel.” She added, “If clinicians have already decided what they are going to treat the patients with, then adding a test result is very unlikely to substantially change treatment decisions.” TRANSLATE–POPS was funded by Eli Lilly and Daiichi Sankyo.
Bivalirudin Versus Heparins With or Without Glycoprotein Inhibitors: EUROMAX
• Phillippe Gabriel Steg, MD, Hôpital Bichat, Paris, France • Ori Ben-Yehuda, MD, press conference moderator • Bernard J. Gersh, MB, ChB, DPhil, Mayo Clinic, Rochester, Minnesota, panelist • James B. Hermiller, Jr., MD, St. Vincent Heart Center, Indianapolis, Indiana, panelist The European Ambulance ACS AngioX trial (EUROMAX) is the first study to evaluate anticoagulant therapy options prior to hospital admission and in conjunction with the newer P2Y12 in- hibitors. The study was conducted in response to questions raised by an earlier trial, Harmonizing Outcomes with Revascularization and Stents in Myocardial Infarction (HORIZONS–AMI). That trial showed that bivalirudin (Angiomax, The Medicines Company) reduced mortality and bleeding in patients undergoing primary percutaneous coronary intervention (PCI). The questions, said Dr. Steg, were these: • What role would bivalirudin have in the ambulance?
Meeting Highlights: Transcatheter Cardiovascular Therapeutics • Would a prolonged infusion of bivalirudin reduce the higher risk of acute stent thrombosis shown in HORIZONS– AMI? The international, prospective, open-label EUROMAX trial included 2,218 patients intended for primary PCI with ST-segment elevation myocardial infarction (STEMI) and treated for more than 20 minutes and 12 hours or less from symptom onset. Patients were randomly assigned to an ambulance or a non-PCI hospital to receive unfractionated heparin (UFH)/low-molecularweight (LMW) heparin, with or without a glycoprotein 2b/3a inhibitor (GPI) per standard practice, or bivalirudin (a 0.75-mg/ kg bolus, a 1.75-mg/kg/hour infusion plus prolonged optional infusion) with a rescue GPI only. Aspirin plus a P2Y12 inhibitor such as prasugrel (Effient) or ticagrelor (Brilinta) was given as soon as possible. The primary endpoint was 30-day death or non–coronary artery bypass (CABG)-related major bleeding. For the primary endpoint of death or major bleeding at 30 days, rates were 5.1% with bivalirudin and 8.4% with heparins with an optional GPI (P = 0.002). For the main secondary endpoint of death, re-infarction, or major bleeding at 30 days, rates were 6.7% for bivalirudin and 9.1% for heparins with an optional GPI (P = 0.03). Rates of cardiac and non-cardiac deaths were similar between the groups (P = 0.46, P = 0.10). Non–CABG-related major bleeding at 30 days was significantly lower in the bivalirudin arm than in the heparin arm (2.7% vs. 6.1%, respectively; P < 0.001). Dr. Steg said, “These benefits, which were consistent across subgroups, stemmed from substantial reductions in major bleeding. Also, the results were achieved on a background of contemporary care, with a high rate of radial access, use of novel P2Y12 inhibitors, and optional GPI use in the control arm.” Re-infarction rates at 30 days were similar between groups, but the rate of acute stent thrombosis was higher with bivalirudin than with heparins (1.1% vs. 0.2%, respectively; P = 0.007). The findings, Dr. Steg added, “support a role for bivalirudin in the pre-hospital setting.” Asked by Dr. Ben-Yehuda to comment on the initiation of treatment in the ambulance (an aspect of the trial that he characterized as being part of typical care in Europe but difficult to achieve in the U.S.), Dr. Gersh said, “I think we are the losers, because we have a different, competitive system. I’ve never seen any data to suggest that prehospital administration and diagnosis are not beneficial. But how we are going to achieve that in the United States? I don’t know.” He added, “It’s not that often that you see trials that will change clinical practice—but I think this will. ” Dr. Hermiller said, “It will be very interesting to see how this very large difference in major bleeding translates into mortality down the road.” Trial results were published simultaneously in the New England Journal of Medicine.1 EUROMAX was funded by the Medicines Company.
REFERENCE 1.
Steg PG, van’t Hof A, Hamm CW, et al. Bivalirudin started during emergency transport for primary PCI. N Engl Med J, October 30, 2013 (online).
Cangrelor Versus Clopidogrel in Intraprocedural Stent Thrombosis: CHAMPION PHOENIX
• Philippe Généreux, MD, Angiographic Core Laboratory, Cardiovascular Research Foundation, New York, N.Y. Intraprocedural stent thrombosis (IPST) is defined as a new or worsening thrombus that develops during deployment of a coronary stent. In earlier presentations of CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require PCI), cangrelor reduced the primary efficacy endpoint of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis (5.9% for clopidogrel vs. 4.7% for cangrelor; P = 0.006) as well as periprocedural (48-hour) and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI). Cangrelor (The Medicines Company) is a fast-acting intravenous (IV) adenosine diphosphate (ADP) receptor antagonist with a rapid onset (3–6 minutes) and offset (60 minutes). Although adverse drug events (ADEs) are relatively rare during PCI, affecting fewer than 1% of patients, IPST was associated with an extremely high increase in mortality rates in CHAMPION PHOENIX. To evaluate the clinical impact of IPST, Dr. Généreux’s laboratory conducted a frame-by-frame analysis of angiograms from the trial. Cangrelor was associated with significant reductions in the key secondary endpoints of stent thrombosis (0.8%), compared with clopidogrel (Plavix) (1.4%) (P = 0.01), and in IPST (0.6% with cangrelor vs. 1.0% with clopidogrel; P = 0.04). “Importantly,” Dr. Généreux said, “intraprocedural stent thrombosis was a strong, independent predictor of short-term mortality, with a more than 20-fold increase in 48-hour mortality and more than a 12-fold increase in 30-day mortality” (P < 0.0001 for both). Dr. Généreux further noted that IPST occurred more often in those with non–ST-segment elevation MI (NSTEMI) and ST-segment MI (STEMI) than in those with stable coronary artery disease (1.2%, 1.2%, and 0.5%, respectively; P = 0.0006). Worsening thrombus accounted for 46.1% of IPST, and new thromboses accounted for 46.1%. The detrimental impact of IPST persisted even after normal blood flow was restored at the end of the PCI procedure. Hospital length of stay in patients with IPST was doubled (45.6 vs. 27.0 hours after PCI; P < 0.0001). An analysis identified independent predictors of IPST to include STEMI, unstable angina, thrombus at baseline, and a longer total stent length. Compared with clopidogrel, cangrelor reduced the odds of IPST by 35%, for an odds ratio of 0.65 and a 95% confidence interval of 0.42 to 1.00 (P = 0.048). Dr. Généreux concluded, “These findings may have major implications when selecting the most potent antithrombotic treatment during PCI.” He commented further, in an interview, about the EUROMAX trial, also presented at the TCT meeting. The trial’s finding that bivalirudin, compared with heparin given to STEMI patients in the ambulance, was safe and efficient yet led to increased rates of stent thrombosis at 30 days raised an important question: “Will cangrelor reduce stent thrombosis among these patients treated in the ambulance?” n
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American College of Rheumatology and
Transcatheter Cardiovascular Therapeutics Walter Alexander
ACR 2013: Rheumatoid Arthritis, Psoriatic Arthritis, and Behçet’s Syndrome ACR 2013 hosted 11,800 professionals from October 25–30 in San Diego. This was the third highest attendance figure in the 77 years of ACR annual meetings. Key presentations included rheumatoid arthritis; psoriatic arthritis, with two cases reported in the PALACE I–IV trials; and Behçet’s disease.
Tofacitinib (Xeljanz) After Adalimumab (Humira) for Rheumatoid Arthritis: Phase 3 • Mark C. Genovese, MD, Stanford University School of Medicine, Immunology and Rheumatology Clinic, Stanford, California The main reason patients with rheumatoid arthritis switch from an anti–tumor necrosis factor (TNF) agent to the Janus kinase (JAK) inhibitor tofacitinib (Xeljanz, Pfizer), said Dr. Genovese, “is to get away from an injectable drug to an oral one—or it might be related to inadequacy of clinical response from the TNF-inhibitor.” Dr. Genovese led a phase 3 trial in which patients had received oral tofacitinib or subcutaneous (SC) injections of adalimumab (Humira, AbbVie), both on top of methotrexate. The patients (n = 124) were then moved directly from the phase 3 randomized, placebo-controlled ORAL trial to an open-label extension without a washout period. Investigators looked at the periods 3 months before, at, and 3 months after the time that patients were switched to tofacitinib 10 mg twice daily. Adjustments to 5 mg of tofacitinib or a lower methotrexate dose were allowed. In patients switched from adalimumab to tofacitinib, American College of Rheumatology (ACR) 20 response rates (ACR20) were 74.2% at 4.5 months before the end of the randomized trial, 76.6% at the end of the randomized trial, and 90.5% 4.5 months after the transition to tofacitinib. (ACR20 is defined as disease improvement of at least 20% compared with baseline.) ACR50 response rates (44.4%, 50.8%, and 65.5%, respectively) and ACR70 response rates (16.1%, 21.0%, and 36.2%, respectively) at the same time points showed a similar pattern. The mean change from baseline scores in the Health Assessment Questionnaire–Disability Index (HAQ–DI) was –0.55, –0.60, and –0.70 at the same time points. For patients who had received The author is a freelance medical writer living in New York City.
tofacitinib in the randomized trial and were moved to the openlabel extension with tofacitinib, results were similar at the same time points and showed a similar pattern of increases from the randomized controlled trial to the open-label extension. The incidence of safety-related adverse drug events (ADEs) generally increased in the 3 months after the switch to openlabel administration for the group switching from adalimumab to tofacitinib and for the group going from double-blind tofacitinib to open-label tofacitinib. Dr. Genovese said, “It is unclear whether this is due to longerterm use of the agent or if it is related to the fact that patients now know that they are receiving active drug.” Discontinuations, however, decreased from a total 12-month rate of 13.3 per 100 patient-years for the randomized ORAL trial to 9.1 per 100 patient-years in the ORAL open-label extension. The changes were small, he said, and no further confirmation is required. He added, “We don’t see an increase in risk associated with the transition from adalimumab to tofacitinib.”
Tight-Control Treatment of Early Psoriatic Arthritis: TICOPA
• Philip Heliwell, MD, Leeds Institute of Molecular Medicine, Division of Rheumatic and Musculoskeletal Medicine, University of Leeds, United Kingdom • Laura C. Coates, MD, PhD, Leeds Institute of Molecular Medicine, Division of Rheumatic and Musculoskeletal Medicine, University of Leeds, United Kingdom Joint and skin outcomes improved when patients with early psoriatic arthritis (PsA) in an intensive-management (“tightcontrol”) group followed a strict treatment protocol with escalation of therapy if minimal disease activity (MDA) criteria were not met. The finding was from an analysis of the Tight Control Of Early Psoriatic Arthritis (TICOPA) study, a prospective, multicenter, open-label randomized controlled trial in which the authors compared a strategy of tight, treat-to-target goals with standard care. Dr. Heliwell said at an ACR press conference: Psoriatic arthritis has lagged behind rheumatoid arthritis in treatment paradigms, yet it’s the second commonest inflammatory arthritis. Psoriasis occurs in 2% to 3% of the North American population, and up to a third of people with psoriasis will develop psoriatic arthritis—although up to half of them don’t know they have it. I think this study brings it up to date alongside rheumatoid arthritis.
Dr. Coates, presenting TICOPA data in an oral session, said that the study included 206 patients with early PsA who were
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Meeting Highlights: American College of Rheumatology naive to disease-modifying antirheumatic drugs (DMARDs). Early disease was defined by symptoms lasting less than 24 months. Median patient age was 45 years (range, 18–81 years; 52% male). Polyarthritis was present in 71% of the patients. Patients were randomly assigned to receive, in a 1:1 ratio, either tight control, which entailed a review every 4 weeks, or standard care with a review every 12 weeks. Patients in the tight-control arm were started on methotrexate with rapid dose escalation to 25 mg, if tolerated, after 6 weeks. After 12 weeks, therapy was escalated to combination DMARDs if patients had not achieved the criteria for MDA. This was defined by the presence of five of seven criteria encompassing tender and swollen joint counts, Psoriasis Area and Severity Index (PASI), and body surface area (BSA) scores; patient pain, patient global activity, Health Assessment Questionnaire– Disability Index (HAQ–DI) scores; and tender entheseal points. In patients who had three or more tender and swollen joints, according to the United Kingdom’s National Institute for Care and Excellence (NICE) guidelines, therapy was escalated to anti-TNF agents. If MDA criteria were not met or if there were fewer than three actively swollen joints, patients received an alternative DMARD combined with methotrexate. Patients receiving standard care were treated by a rheumatologist with no set protocol and no limitations. The primary outcome was the achievement of ACR20 (at least a 20% improved response over baseline) by 48 weeks. Key secondary outcomes were ACR50, ACR70, and more than 75% improvement (PASI75). An intention-to-treat (ITT) analysis revealed that the odds of achieving ACR20 at week 48 were higher in the tight-control arm than in the standard-care arm, for an odds ratio (OR) of 1.91 and a 95% confidence interval (CI) of 1.03 to 3.55 (P = 0.0392). The odds of achieving ACR50 (OR, 2.36; 95% CI, 1.25–4.47; P = 0.0081) and ACR70 (OR, 2.64; 95% CI, 1.32–5.26; P = 0.0058) were also greater with tight control than with standard care. Adverse drug events (ADEs) were more common in the tight-control arm (97%) than with standard care (80%). ADEs included nausea, liver function test abnormalities, and infections (e.g., the common cold). Although serious ADEs were more common with tightcontrol therapy (25) than with standard care (eight), no deaths or unexpected serious ADEs were reported. Tight control of PsA disease activity using a treat-to-target approach significantly improves joint and skin outcomes for patients with newly diagnosed PsA without causing unexpected serious ADEs, Dr. Coates concluded. Pfizer and Arthritis Research UK funded this study.
Apremilast Improves Enthesitis and Dactylitis In Psoriatic Arthritis: PALACE 1, 2, and 3
of muscles, tendons, joint capsules, ligaments and fascia to bone) and dactylitis (swelling of a finger or toe). Patients in the PALACE trials had active psoriatic arthritis (PsA) despite prior disease-modifying antirheumatic drugs (DMARDs) and/ or biologics. Dr. Gladman noted, “Enthesitis and dactylitis are distinguishing features of psoriatic arthritis that may be associated with more severe disease and can be difficult to treat.” Patients in the PALACE trials were randomly assigned, in a 1:1:1 fashion, to receive placebo (n = 496), apremilast 20 mg twice daily (n = 500), or apremilast 30 mg twice daily (n = 497). The groups were stratified by their baseline use of DMARDs. At week 16, patients with a 20% reduction or less from baseline in swollen joint count or tender joint count qualified for a protocol-required early escape. Patients receiving placebo were reassigned to receive apremilast at 20 or 30 mg twice daily. At week 24, all remaining placebo patients were reassigned to receive apremilast 20 or 30 mg twice daily through week 52. Patients taking concurrent DMARDs were allowed to continue stable doses of methotrexate, sulfasalazine, leflunomide, or combinations. Enthesopathy was assessed via the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), representing the number of painful entheses out of a possible 13 entheses. The dactylitis count, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis. In patients who were originally assigned to receive apremilast and who had pre-existing enthesopathy (n = 618) and/or dactylitis (n = 412), at week 24 the mean change in MASES was –0.8 for placebo, –1.2 for apremilast 20 mg, and –1.4 for apremilast 30 mg (P = 0.016 for apremilast 30 mg vs. placebo). At week 52, MASES scores of 0 were achieved by 41.4% of patients in the 20-mg group and by 37.4% of patients in the 30-mg group. In response to a question about the clinical significance of the magnitude of the MASES improvements with apremilast, Dr. Gladman said, “I concentrate more on the number of patients who have gone to zero—to me, that’s more important.” At week 24, the mean change in dactylitis count was –1.2 for placebo, –1.5 for apremilast 20 mg, and –1.8 for apremilast 30 mg (P = 0.0121 for apremilast 30 mg vs. placebo). The median reduction in dactylitis count for the apremilast doses was 67.6% at 16 weeks and 100% at both 24 and 52 weeks. No new safety findings were identified in long-term follow-up examinations. Apremilast demonstrated an acceptable safety profile, with diarrhea, nausea, headache, upper respiratory tract infection and nasopharyngitis as the most common ADEs. Over a 52-week period, apremilast continued to demonstrate efficacy in the treatment of PsA, including improvements in enthesitis and dactylitis, Dr. Gladman concluded.
• Dafna Gladman, MD, Toronto Western Hospital, Toronto, Canada
Apremilast in DMARD-Naive Patients With Psoriatic Arthritis: PALACE 4 (Phase 3)
In an analysis of combined results of the PALACE 1, 2, and 3 trials, Celgene’s apremilast, an oral phosphodiesterase-4 (DPP-4) inhibitor, when compared with placebo, led to longterm improvements in enthesitis (inflamed attachment sites
PALACE 4 was one of the first studies to demonstrate efficacy and safety of a novel agent given solely to DMARD-naive
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• Alvin Wells, MD, PhD, Rheumatology and Immunotherapy Center, Oak Creek, Wisconsin
Meeting Highlights: American College of Rheumatology patients with PsA. Apremilast, an oral PPD-4 inhibitor that modulates intracellular inflammatory mediators, produced clinically meaningful improvements in signs and symptoms in treated patients in this 52-week study. Patients had PsA for at least 6 months, had at least three swollen and three tender joints, and had received no previous treatment with conventional DMARDs or biologics. They met the definition of CASPAR (Classification Criteria for Psoriatic Arthritis). Investigators randomly assigned 527 patients with PsA, in a 1:1:1 fashion, to receive apremilast 20 mg twice daily, apremilast 30 mg twice daily, or placebo. At week 16, patients with reduction of 20% or less from baseline in swollen joint count or tender joint count qualified for a protocol-required early escape. Patients receiving placebo were reassigned to receive apremilast at 20 or 30 mg twice daily. At week 24, all remaining placebo patients were reassigned to receive apremilast 20 or 30 mg twice daily through week 52. The primary endpoint was the proportion of patients achieving an ACR20 (improvement of at least 20% compared with baseline). The patients (mean age, 49.4 years) had a mean duration of PsA of 3.41 years. The mean duration of skin psoriasis (present in all patients) was 15.8 years. The baseline mean swollen joint count was 11.2, and the mean tender joint count was 20.1. Sixtyfive percent of the patients had enthesitis (a median MASES score of 3.0; range 0–13), and 50% had dactylitis (finger or toe swelling), with a median severity score of 2.0. At week 16, patients receiving apremilast showed improvements in multiple endpoints, including enthesitis (inflammation at sites where tendons, ligaments, or joint capsule fibers insert into bone), dactylitis, impaired physical function, swollen and tender joint counts, and associated psoriasis. In patients originally receiving apremilast and completing 52 weeks of therapy (n = 273), benefits were maintained or increased. In the 16-week primary endpoint analysis, a significantly greater proportion of apremilast-treated patients achieved ACR20 compared with placebo patients: 29.2% receiving apremilast 20 mg and 32.3% receiving apremilast 30 mg versus 16.9% receiving placebo (P = 0.0076 and P = 0.0011 vs. placebo). At week 52, ACR20 was achieved by 53.4% of the 131 patients receiving apremilast 20 mg and by 58.7% of the 138 patients receiving 30 mg. The median change in swollen joint count at 52 weeks was –89.4% and –100.0% in the 20-mg and 30-mg groups of patients. Tender joint count changes were –67.1% and –66.7%, respectively. Nausea, diarrhea, headache, and upper respiratory tract infections were reported in 5% or more of patients receiving apremilast. Most ADEs were mild to moderate in severity. In the placebo-controlled period of the trial, serious ADE rates were 2.8% for placebo, 1.7% for apremilast 20 mg, and 0.6% for apremilast 30 mg. The rate of therapy discontinuation attributable to ADEs over the 52 weeks was 5.2% in apremilast-exposed patients. Apremilast demonstrated clinical benefits up to week 52 in patients with PsA who had not received DMARDs previously, Dr. Wells concluded.
Apremilast for Behçet’s Syndrome: Phase 2
• Gülen Hatemi, MD, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey Among the estimated 10,000 Americans with Behçet’s syndrome, a type of vasculitis that causes inflammation in the blood vessels throughout the body, mucocutaneous manifestations can be resistant to conventional treatment and may be disabling. Apremilast, an oral phosphodiesterase-4 (PPD-4) inhibitor that modulates inflammatory pathways, effectively reduced oral ulcers and other disease symptoms in a phase 2 multicenter, randomized, placebo-controlled study with an open-label extension. The trial included 111 patients who had two or more oral ulcers but no major organ involvement. The main symptom of Behçet’s is painful mouth ulcers, although genital ulcers may also occur less often. Patients received apremilast 30 mg twice daily or placebo for 12 weeks, followed by a 12-week activetreatment period for all patients and a 28-day post-treatment observational follow-up period. The primary endpoint was the number of oral ulcers at week 12. The mean patient age was 34.5 years (±10.1 years; 69% were women), and the mean duration of Behçet’s syndrome was 5.3 years. In the primary endpoint analysis at week 12, the mean number (± standard deviation) of oral ulcers over time was 0.5 with apremilast and 2.1 with placebo (P < 0.0001). The mean oral ulcer area-under-the-curve (AUC) concentration with apremilast was one-third of that with placebo (P < 0.0001). Dr. Hatemi emphasized that the beneficial effects of apremilast started within 2 weeks and were sustained during treatment—but they soon disappeared after apremilast was stopped at week 24. Among other benefits, oral ulcer pain on a Visual Analogue Scale (VAS) was 9.4 for apremilast and 35.0 for placebo (P < 0.0001). At week 12, significantly more patients receiving apremilast had a complete response (70.9% in 39 of 55 patients vs. 28.6% in 16 of 56 placebo patients; P < 0.0001). For the 16 patients with genital ulcers at baseline, 10 of 10 (100%) receiving apremilast had a complete response at week 12, compared with three of six patients in the placebo group (50%) (P = 0.036). In patients who did not have genital ulcers at baseline, new ulcers developed in five placebo patients and in one apremilasttreated patient. Five placebo patients and four apremilast patients withdrew from treatment because of adverse drug events (ADEs). Two serious ADEs were reported in the apremilast group—diplegia (paralysis of corresponding parts on both sides of the body) and anal fissure with hemorrhoids. Three ADEs were reported in the placebo group (two disease flares and one fever episode). Diplegia was transient and was not thought to be related to treatment. Headache, a common symptom in patients with Behçet’s syndrome, was the most commonly reported ADE (by 47.3% apremilast patients and by 44.6% of placebo patients) during the placebo-controlled period. Apremilast was effective for treating the oral ulcers of Behçet’s syndrome, and it had an acceptable safety profile, Dr. Hatemi added.
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Meeting Highlights: Transcatheter Cardiovascular Therapeutics “It also seems that it is effective in genital ulcers, which is a difficult-to-treat manifestation of Behçet’s syndrome,” she concluded.
Transcatheter Cardiovascular Therapeutics (TCT) The 25th TCT meeting took place in San Francisco from October 28 to November 2, 2013. The gathering focused on catheter-based interventions for cardiovascular disease and was attended by more than 11,500 health care practitioners. Three sessions related to the environment of acute coronary events are reviewed: one on platelet function testing as a guide to antiplatelet therapy and two on the effect of pharmacological strategies in the setting of myocardial infarction.
Impact of Platelet Function Testing on Practice: TRANSLATE–POPS •
Tracy Y. Wang, MD, Duke Clinical Research Institute, Durham, North Carolina
Although high platelet reactivity is known to be associated with a greater cardiovascular risk in patients undergoing percutaneous coronary intervention (PCI) for ST-elevation and non–ST-elevation myocardial infarction (STEMI and NSTEMI), randomized controlled trials have failed to show that altering antiplatelet therapy based on platelet function tests improves outcomes. Research has also shown, Dr. Wang noted at a TCT press conference, that many PCI patients who receive an adenosine diphosphate (ADP) receptor inhibitor still have high platelet reactivity, suggesting the need for stronger platelet inhibition. In TRANSLATE–POPS (Treatment with ADP Receptor Inhibitors–Prospective Open-Label Antiplatelet Therapy Study), Dr. Wang et al. asked this question: Does access to routine, no-cost platelet function testing increase the frequency of therapeutic adjustment of ADP receptor inhibitors? The team hypothesized that access would increase adjustments of ADP receptor inhibitors before hospital discharge and improve 30-day and long-term (12-month) clinical outcomes. Facilities that were not routinely performing platelet testing (less than 30%) for PCI patients were eligible for the clusterrandomized trial. TRANSLATE–POPS was embedded within TRANSLATE–ACS (Treatment with ADP Receptor Inhibitors– Longitudinal Assessment Patterns and Events After Acute Coronary Syndrome), an observational study. Sites were randomly assigned (50 patients in each treatment arm) to receive either free and routine availability of platelet function testing (the device arm) or the standard of care (the usual-care arm). For the device arm, the sites were encouraged to test patients before discharge and at least 12 hours after PCI. For the usual-care arm, the sites were not provided with routine platelet function testing, but the health care team could choose to perform testing if it was judged to be clinically necessary. The primary endpoint was the rate of in-hospital therapeutic adjustments to anticlotting therapy.
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The sites did not uniformly take up the offer of no-cost platelet testing in the device arm. For this arm, Dr. Wang reported, platelet testing was performed 66% of the time, compared with 1.4% of the time for the usual-care arm. The odds ratio (OR) for the primary endpoint of therapeutic adjustment, accounting for a clustering effect within a site, was 1.55 for the device arm versus the usual-care arm (11.6% usual care, 15.9% device (P = 0.01). Switching of antiplatelet agents was more frequent in the device arm (14.5% vs. 10.6% for usual care). In the device arm, therapeutic adjustments occurred in 31% of patients with platelet reactivity units (PRUs) of 235 or more and in 29% of patients with PRUs of 208 or more. Rates for PRUs below 235 and below 208 were 14% and 13%, respectively (P < 0.001 for both). A significantly greater number of patients were switched from clopidogrel (e.g., Plavix, Bristol-Myers Squibb/Sanofi) to the more potent antiplatelet agents prasugrel (Effient, Eli Lilly/Daiichi Sankyo) or ticagrelor (Brilinta, AstraZeneca) in the device arm than in the usual-care arm (P = 0.004). Assessment of outcomes after 30 days failed to show an advantage for patients in the device arm, who experienced a similar percentage of major cardiac ADEs as the usual-care arm (4.5% vs. 5.1%, respectively; P = 0.69). Both groups reported a similar rate of bleeding events (4.2% for the device arm vs. 4.3% for the usual-care arm; P = 0.33). There was no observed impact on early major adverse cardiac ADEs, Dr. Wang said; however, an investigation of long-term outcomes is ongoing. The impact on antiplatelet adjustments, Dr. Wang commented, was modest. Although platelet testing did lead to some higher first-line use of prasugrel, she concluded, “TRANSLATE– POPS showed that current U.S. practice still strongly favors generic clopidogrel.” She added, “If clinicians have already decided what they are going to treat the patients with, then adding a test result is very unlikely to substantially change treatment decisions.” TRANSLATE–POPS was funded by Eli Lilly and Daiichi Sankyo.
Bivalirudin Versus Heparins With or Without Glycoprotein Inhibitors: EUROMAX
• Phillippe Gabriel Steg, MD, Hôpital Bichat, Paris, France • Ori Ben-Yehuda, MD, press conference moderator • Bernard J. Gersh, MB, ChB, DPhil, Mayo Clinic, Rochester, Minnesota, panelist • James B. Hermiller, Jr., MD, St. Vincent Heart Center, Indianapolis, Indiana, panelist The European Ambulance ACS AngioX trial (EUROMAX) is the first study to evaluate anticoagulant therapy options prior to hospital admission and in conjunction with the newer P2Y12 in- hibitors. The study was conducted in response to questions raised by an earlier trial, Harmonizing Outcomes with Revascularization and Stents in Myocardial Infarction (HORIZONS–AMI). That trial showed that bivalirudin (Angiomax, The Medicines Company) reduced mortality and bleeding in patients undergoing primary percutaneous coronary intervention (PCI). The questions, said Dr. Steg, were these: • What role would bivalirudin have in the ambulance?
Meeting Highlights: Transcatheter Cardiovascular Therapeutics • Would a prolonged infusion of bivalirudin reduce the higher risk of acute stent thrombosis shown in HORIZONS– AMI? The international, prospective, open-label EUROMAX trial included 2,218 patients intended for primary PCI with ST-segment elevation myocardial infarction (STEMI) and treated for more than 20 minutes and 12 hours or less from symptom onset. Patients were randomly assigned to an ambulance or a non-PCI hospital to receive unfractionated heparin (UFH)/low-molecularweight (LMW) heparin, with or without a glycoprotein 2b/3a inhibitor (GPI) per standard practice, or bivalirudin (a 0.75-mg/ kg bolus, a 1.75-mg/kg/hour infusion plus prolonged optional infusion) with a rescue GPI only. Aspirin plus a P2Y12 inhibitor such as prasugrel (Effient) or ticagrelor (Brilinta) was given as soon as possible. The primary endpoint was 30-day death or non–coronary artery bypass (CABG)-related major bleeding. For the primary endpoint of death or major bleeding at 30 days, rates were 5.1% with bivalirudin and 8.4% with heparins with an optional GPI (P = 0.002). For the main secondary endpoint of death, re-infarction, or major bleeding at 30 days, rates were 6.7% for bivalirudin and 9.1% for heparins with an optional GPI (P = 0.03). Rates of cardiac and non-cardiac deaths were similar between the groups (P = 0.46, P = 0.10). Non–CABG-related major bleeding at 30 days was significantly lower in the bivalirudin arm than in the heparin arm (2.7% vs. 6.1%, respectively; P < 0.001). Dr. Steg said, “These benefits, which were consistent across subgroups, stemmed from substantial reductions in major bleeding. Also, the results were achieved on a background of contemporary care, with a high rate of radial access, use of novel P2Y12 inhibitors, and optional GPI use in the control arm.” Re-infarction rates at 30 days were similar between groups, but the rate of acute stent thrombosis was higher with bivalirudin than with heparins (1.1% vs. 0.2%, respectively; P = 0.007). The findings, Dr. Steg added, “support a role for bivalirudin in the pre-hospital setting.” Asked by Dr. Ben-Yehuda to comment on the initiation of treatment in the ambulance (an aspect of the trial that he characterized as being part of typical care in Europe but difficult to achieve in the U.S.), Dr. Gersh said, “I think we are the losers, because we have a different, competitive system. I’ve never seen any data to suggest that prehospital administration and diagnosis are not beneficial. But how we are going to achieve that in the United States? I don’t know.” He added, “It’s not that often that you see trials that will change clinical practice—but I think this will. ” Dr. Hermiller said, “It will be very interesting to see how this very large difference in major bleeding translates into mortality down the road.” Trial results were published simultaneously in the New England Journal of Medicine.1 EUROMAX was funded by the Medicines Company.
REFERENCE 1.
Steg PG, van’t Hof A, Hamm CW, et al. Bivalirudin started during emergency transport for primary PCI. N Engl Med J, October 30, 2013 (online).
Cangrelor Versus Clopidogrel in Intraprocedural Stent Thrombosis: CHAMPION PHOENIX
• Philippe Généreux, MD, Angiographic Core Laboratory, Cardiovascular Research Foundation, New York, N.Y. Intraprocedural stent thrombosis (IPST) is defined as a new or worsening thrombus that develops during deployment of a coronary stent. In earlier presentations of CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require PCI), cangrelor reduced the primary efficacy endpoint of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis (5.9% for clopidogrel vs. 4.7% for cangrelor; P = 0.006) as well as periprocedural (48-hour) and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI). Cangrelor (The Medicines Company) is a fast-acting intravenous (IV) adenosine diphosphate (ADP) receptor antagonist with a rapid onset (3–6 minutes) and offset (60 minutes). Although adverse drug events (ADEs) are relatively rare during PCI, affecting fewer than 1% of patients, IPST was associated with an extremely high increase in mortality rates in CHAMPION PHOENIX. To evaluate the clinical impact of IPST, Dr. Généreux’s laboratory conducted a frame-by-frame analysis of angiograms from the trial. Cangrelor was associated with significant reductions in the key secondary endpoints of stent thrombosis (0.8%), compared with clopidogrel (Plavix) (1.4%) (P = 0.01), and in IPST (0.6% with cangrelor vs. 1.0% with clopidogrel; P = 0.04). “Importantly,” Dr. Généreux said, “intraprocedural stent thrombosis was a strong, independent predictor of short-term mortality, with a more than 20-fold increase in 48-hour mortality and more than a 12-fold increase in 30-day mortality” (P < 0.0001 for both). Dr. Généreux further noted that IPST occurred more often in those with non–ST-segment elevation MI (NSTEMI) and ST-segment MI (STEMI) than in those with stable coronary artery disease (1.2%, 1.2%, and 0.5%, respectively; P = 0.0006). Worsening thrombus accounted for 46.1% of IPST, and new thromboses accounted for 46.1%. The detrimental impact of IPST persisted even after normal blood flow was restored at the end of the PCI procedure. Hospital length of stay in patients with IPST was doubled (45.6 vs. 27.0 hours after PCI; P < 0.0001). An analysis identified independent predictors of IPST to include STEMI, unstable angina, thrombus at baseline, and a longer total stent length. Compared with clopidogrel, cangrelor reduced the odds of IPST by 35%, for an odds ratio of 0.65 and a 95% confidence interval of 0.42 to 1.00 (P = 0.048). Dr. Généreux concluded, “These findings may have major implications when selecting the most potent antithrombotic treatment during PCI.” He commented further, in an interview, about the EUROMAX trial, also presented at the TCT meeting. The trial’s finding that bivalirudin, compared with heparin given to STEMI patients in the ambulance, was safe and efficient yet led to increased rates of stent thrombosis at 30 days raised an important question: “Will cangrelor reduce stent thrombosis among these patients treated in the ambulance?” n
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