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American College of Cardiology, 2014
The American College of Cardiology (ACC) 63rd Scientific Sessions took place in Washington, D.C., from March 29 to 31. About 19,000 people attended, including 4,000 cardiologists and 9,000 physicians, nurses, and other medical professionals. Among the many high-interest sessions this year, some surprising results were not without their controversies. The clear superiority of heparin over bivalirudin in HEAT PPCI, in contrast to findings in the EUROMAX and HORIZONS-AMI trials, and opposing findings in the two SYMPLICITY trials of renal denervation, are presented below and are fueling active discussion.
HEAT PPCI (How Effective Are Antithrombotic Therapies in PPCI [Primary Percutaneous Coronary Intervention])
In primary percutaneous coronary interventions (PPCIs) for ST-elevation myocardial infarction (STEMI), bivalirudin and heparin appear to have similar anti-ischemic efficacy and similar rates of major adverse cardiac events (MACE). Guideline-recommended use of selective “bailout” glycoprotein IIb/IIIa inhibitors (GPIs) is increasingly the norm as part of antithrombotic therapy. Bivalirudin plus selective GPI use is an established treatment option (7% to 15% of cases).
It is known, Dr. Stables said in an ACC press briefing, that bleeding is associated with less favorable outcomes and that increased GPI use results in increased bleeding with both bivalirudin and heparin. However, determining the relative performance of bivalirudin and heparin with respect to bleeding with differential GPI use requires a direct comparison.
HEAT PPCI, a single-center, randomized, open-label trial of 1,829 patients (median age, approximately 63 years) with suspected myocardial infarction (MI), compared bivalirudin (bolus of 0.75 mg/kg, followed by an infusion of 1.75 mg/kg per hour) plus a selective GPI to heparin (bolus of unfractionated heparin 70 units/kg) plus a selective GPI. Patients were followed for 28 days and assessed for the primary endpoint of combined all-cause death, stroke, repeat MI, or unplanned repeat procedure.
The endpoint was reported in 8.7% of patients receiving bivalirudin and in 5.7% of patients receiving heparin (P = 0.01; relative risk [RR] = 1.52; 95% CI, 1.1–2.1). A larger difference between treatment arms was noted for stent thrombosis, with a rate of 3.4% for bivalirudin compared with 0.9% for heparin (P = 0.001; RR = 3.91; 95% CI, 1.6–9.5). Stent thrombosis differences between the two arms, Dr. Stables said, drove the MACE disparity.
Major bleeding, the primary safety outcome, was similar between groups (3.5% for bivalirudin, 3.1% for heparin).
Dr. Stables concluded that preferential use of heparin would reduce MACE, stent thrombosis, and reinfarction events without an increase in bleeding complications.
“In the UK,” Dr. Stables said, “bivalirudin costs approximately 400 times as much as heparin.” He noted that some critics of the trial suggested the bivalirudin dose was too low. “If we use additional vials of bivalirudin with prolonged infusions … we may approximate heparin, but the cost differential could then be 1,500 times.”
A Phase 3 Double-Blind, Randomized Study to Assess the Safety and Efficacy of Evolocumab (AMG 145) in Hypercholesterolemic Subjects Unable to Tolerate an Effective Dose of Statin
Cardiovascular risk and mortality risk are reduced by about 22% and 10%, respectively, for every decrease in low-density lipoprotein-cholesterol (LDL-C) of 39 mg/dL.3 Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin 9 (PCSK9), yielded potent reductions in LDL-C among statin-intolerant patients in the GAUSS-2 (Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin intolerant Subjects [NCT01763905]) study.
GAUSS-2, a 12-week, randomized, double-blind, placebo- and ezetimibe-controlled, multicenter phase 3 study, aimed to evaluate the efficacy and safety of evolocumab in statin-intolerant hypercholesterolemic patients.
Investigators enrolled 307 patients (mean age approximately 62 years, 46% women), assigning them to one of two subcutaneous evolocumab doses (140 mg every two weeks or 420 mg per month, plus daily placebo) or one of two oral ezetimibe groups (a placebo injection every two weeks or monthly, plus 10 mg oral ezetimibe daily).
More than 94% of all enrolled patients completed the study. Dr. Stroes reported that the primary efficacy endpoint of percentage change from baseline in LDL-C at mean of weeks 10 and 12 and at week 12 was –18% and –56% for the biweekly ezetimibe and evolocumab patients, respectively. For monthly ezetimibe and evolocumab, it was –15% and –53%. The treatment differences for evolocumab versus ezetmibe, for both the 10/12 week averages and at week 12 (–37% and –38%) were highly significant (P < 0.001). Differences were similar for monthly administration of evolocumab (–39% and –38%, P < 0.001).
Musculoskeletal side effects were reported in 12% of patients on evolocumab compared to 23% on ezetimibe. Discontinuations for treatment-related side effects occurred in 8% of evolocumab patients and 13% of ezetimibe patients. The most commonly reported adverse events for evolocumab versus ezetimibe included headache (8% vs. 9%), muscle pain (8% vs. 18%), pain in extremities (7% vs. 1%), and muscle spasms (6% vs. 4%).
Dr. Stroes concluded, “The LDL-C–lowering efficacy combined with good tolerability make evolocumab a promising option to address the unmet clinical need in high-risk hypercholesterolemic patients with statin intolerance.”
Renal Denervation in Patients With Uncontrolled Hypertension: Results of the SYMPLICITY HYPERTENSION 3 Trial
Among the 250 patients with severe resistant hypertension enrolled in the SYMPLICITY HTN-3 trial, renal denervation failed to meet its primary and secondary efficacy endpoints. The trial, the largest and most rigorously designed evaluation of renal denervation, was blinded and included a sham procedure, said Dr. Bhatt. While renal denervation for the treatment of uncontrolled hypertension is approved in more than 80 countries, it is still investigational in the U.S.
Trial investigators randomly assigned 535 patients at 88 U.S. centers with resistant hypertension and systolic blood pressure of 160 mm Hg or higher (135 mm Hg or higher ambulatory blood pressure) to renal denervation or angiography alone. Patients in both groups continued their regimens of three or more antihypertensive drugs, including a diuretic at the highest tolerated doses. The primary efficacy endpoint was the decrease in office systolic blood pressure from baseline to six months. Mean age was about 57 years (approximately 62% male).
With systolic blood pressure reductions at –14.1 mm Hg in the renal denervation arm versus –11.7 mm Hg in the sham procedure arm, the absolute reduction between groups of 2.39 mm Hg was not significant (P = 0.26). The secondary endpoint, change from baseline to six-month follow-up in mean systolic 24-hour ambulatory blood pressure, was also statistically nonsignificant at 1.96 mm Hg (P = 0.98), with a systolic blood pressure reduction of 6.8 mm Hg in the renal denervation arm versus 4.8 mm Hg reduction in the control arm.
Reductions in systolic blood pressure as compared with baseline were significant in both groups.
Analysis of blood pressure changes by tertile revealed no significant differences among groups. There was a strong trend (interaction P value, 0.09) toward differences in response between African-Americans and non-African-Americans. Among African-Americans there was a 2.25 mm Hg increase in systolic blood pressure (P = 0.53) as compared with –6.63 mm Hg for non-African-Americans (P = 0.01).
The safety goal of a 9.8% or lower adverse event rate was easily met, with an event rate of 1.4% for renal denervation and 0.3% for the sham control arm. Only one case of renal stenosis, in the renal denervation arm, was reported. Major adverse event rates were 1.4% for the renal denervation arm and 0.6% for the sham procedure (P = 0.67).
In this population of patients with severe resistant hypertension who were receiving optimal pharmacological therapy and who were closely monitored, SYMPLICITY HTN-3 revealed no added treatment benefit for renal denvervation, Dr. Bhatt said.
With respect to prior trials without sham controls showing renal denervation benefits, Dr. Bhatt added, “These results underscore the importance of blinding and sham controls in evaluations of new devices.” He also noted the need for further rigorously designed clinical trials.
The Global SYMPLICITY Registry: Safety and Effectiveness of Renal Artery Denervation In Real-World Patients With Uncontrolled Hypertension
Analysis of the first 1,000 patients in the largest-to-date real-world registry of uncontrolled hypertension patients treated with renal denervation revealed significant blood pressure lowering and low adverse events at six months, Dr. Böhm said in a late-breaking trial presentation of Global SYMPLICITY Registry results. The trial was conducted at 231 international sites in 37 countries. Included patients were on three or more antihypertensive medications at baseline. Patients had baseline systolic office pressures of at least 160 mm Hg and baseline ambulatory systolic blood pressures of at least 135 mm Hg.
Mean office systolic blood pressure dropped 11.9 mm Hg at six months for the overall population of 751 patients. It increased by 14.2 mm Hg in patients whose baseline systolic blood pressures were below 140 mm Hg at baseline, decreased by 4.6 mm Hg in those with baseline systolic blood pressures of 140–159 mm Hg, and decreased by 21.4 mm Hg in those with baseline systolic blood pressures of 160 mm Hg or more. Decreases of more than 10 mm Hg were reported in 68% of patients.
Only five adverse events were attributed to the procedure; four (0.34%) were access site complications and the other was a successfully treated renal artery dissection.
When Dr. Böhm presented the Global SYMPLICITY results, findings from another renal denervation trial, SYMPLICITY HTN-3, had already taken center stage at the ACC meeting. That randomized trial among 250 patients found no benefit for renal denervation versus a sham procedure. The finding led some experts to suggest that the invasive SYMPLICITY renal denervation technique—which uses radiofrequency radiation to ablate the sympathetic nerves in the renal artery—may be producing no more than a placebo effect.
Responding in an interview, Dr. Böhm listed factors in SYMPLICITY HTN-3 that make a placebo response unlikely as the sole effect: Patients had been pushed to their highest tolerated doses of antihypertensive medications before the renal denervation treatment (raising the bar to show responses), African-Americans did not respond at all to the procedure (lowering the overall response rate), and most of the procedures were performed by operators completely new to the technique, increasing chances of less than optimal results. Dr. Böhm emphasized that the registry procedures were performed by operators who had conducted at least 30 procedures. (In an e-mail response, Deepak Bhatt, MD, the lead investigator of SYMPLICITY HTN-3, replied that the experience of the operators did not affect the magnitude of the responses.)
While acknowledging the limitations of comparing a registry with a randomized, blinded, controlled study, Dr. Böhm stated: “The reduction in blood pressure is numerically larger in the global registry at six months after treatment.”
The stark differences between the findings of SYMPLICITY HTN-3 and the Global SYMPLICITY Registry reflect the investigational status of renal denervation in the United States and its widespread approval and use in Europe (with some application in patients with less severely resistant hypertension).
The impact of the failure to show benefit in SYMPLICITY HTN-3 was clear in an interview with Dr. Böhm. “I think the hype is over. Of course, we had a little bit of hype in Europe, not only in Germany.”
- Cholesterol Treatment Trialists’ Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376(9753):1670–1681.