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American Heart Association Scientific Sessions 2014
This year’s American Heart Association (AHA) Scientific Sessions drew an estimated 17,835 cardiologists, researchers, and other health care professionals to Chicago from November 15 to 19, with 6,421 international visitors among them. Sessions of particular interest covered the thorny issue of duration of anticoagulation therapy during procedures, a novel alternative to statins, and the risks of endocarditis when dental antibiotic prophylaxis is dropped.
ODYSSEY ALTERNATIVE: Efficacy and Safety of Alirocumab Versus Ezetimibe, in Patients With Statin Intolerance Defined by Placebo Run-In And Statin Rechallenge Arm
- Patrick M. Moriarty, MD, Director of Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas
In clinical practice, statin intolerance limits the ability of about 10% to 25% of patients to meet goals for low-density lipoprotein-cholesterol (LDL-C). Myalgia is the most common complaint among these patients. While alternative statin-lowering drugs are available, large-scale, well-controlled randomized trials with those drugs are lacking, Dr. Moriarty said at an AHA press conference.
Ezetimibe is a recommended option for statin-intolerant patients. ODYSSEY ALTERNATIVE, a multinational study, compared the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 monoclonal antibody, to that of ezetimibe in patients with statin intolerance.
Patients with coronary heart disease or other cardiovascular risk factors were first given a four-week placebo challenge and excluded if they experienced muscle-related adverse events. Continuing patients were randomized 2:2:1 to alirocumab 75 mg self-administered via a 1-mL prefilled pen every two weeks (n = 126), ezetimibe 10 mg/day (n = 122), or atorvastatin 20 mg/day for 24 weeks (n = 63, safety analysis only). Their mean age was approximately 63 years; about 55% were male. The alirocumab dose was increased to 150 mg at week 12 depending on cardiovascular risk and week 8 LDL-C levels. The primary endpoint was the percent change in LDL-C from baseline to week 24. Patients could enter an open-label extension and receive alirocumab 75 mg or 150 mg every two weeks.
Mean LDL-C was 191.1 mg/dL in the alirocumab group, 193.5 mg/dL in the ezetimibe group, and 187.3 mg/dL in the atorvastatin group. After the placebo run-in, 6.9% of patients discontinued because of muscle-related adverse events.
At 24 weeks, the mean LDL-C level was 108.5 mg/dL in the alirocumab group, with about 42% of alirocumab patients achieving their LDL-C goals compared with 4% in the ezetimibe group (P < 0.001). Alirocumab reduced LDL-C from baseline by 45.0%, compared with a 14.6% reduction with ezetimibe (P < 0.0001). About half of the alirocumab patients who had received at least one injection by week 12 did not need dose increases.
Myalgia was reported in 24.6%, 23.4%, and 27.0% of patients receiving alirocumab, ezetimibe, and atorvastatin, respectively, while discontinuations for adverse events occurred at rates of 23.8%, 33.6%, and 33.3%, respectively. Only two patients discontinued because of myalgia among the 89.5% of patients who entered the open-label extension.
Dr. Moriarty concluded, “Alirocumab may be considered a good alternative therapy in patients with a history of statin intolerance.”
Is 6 Months DAPT Post-Coronary Stenting Non-Inferior to 24 months? The Italic/Italic+ Randomized Trial: Results of the One-Year Primary Endpoint
- Martine Gilard, MD, University of Brest, Brest Cedex, France
Currently, the recommended duration of dual antiplatelet therapy (DAPT) for reducing the risk of late stent thrombosis in drug-eluting stent recipients is 12 months, especially in those with acute coronary syndromes. However, DAPT is associated with increased bleeding that may affect outcomes, especially in patients who have comorbidities or require surgical treatment.
A meta-analysis of extended DAPT after percutaneous coronary intervention (PCI) by Cassese et al,5 Dr. Gilard noted at an AHA late-breaking clinical trial press conference, showed lower cerebrovascular accident and Thrombolysis in Myocardial Infarction (TIMI) major bleeding rates for controls than for extended DAPT. The ITALIC trial hypothesized that antiplatelet treatment with aspirin alone six months after drug-eluting stent implantation may be noninferior to DAPT in patients who are not resistant to aspirin.
ITALIC was conducted at 55 sites in Europe and the Middle East among 2,031 patients eligible for PCI who received at least one Xience V drug-eluting stent. All patients were pretreated with aspirin plus clopidogrel, prasugrel, or ticagrelor. Individuals pretreated with abciximab and those receiving primary PCI for acute myocardial infarction or treatment of the left main artery were excluded.
The actual randomization occurred among the 1,850 patients who experienced no events during the first six months after PCI. Their mean age was 61.6 years; about 80% were male. About 15% had prior myocardial infarction. Half received aspirin alone and half received another 18 months of DAPT, followed subsequently by aspirin alone. The primary endpoint was the composite of death, myocardial infarction, emergency target-vessel revascularization, stroke, or major bleeding (TIMI criteria) within 12 months.
Rates of the primary endpoint and all death favored 24-month DAPT in the subgroup of patients with acute coronary syndromes (ACSs) (HRs, 1.773 and 4.041, respectively). In the non-ACS group, the primary endpoint, all death, and cardiac death favored six-month DAPT (HRs, 0.79, 0.660, and 0.661), and myocardial infarction and minor bleeding favored 24-month DAPT (HRs, 1.990 and 3.981). Analysis, Dr. Gilard said, confirmed the overall noninferiority of six-month DAPT (P = 0.0002).
“I think this is very important because this trial showed that with six months of DAPT there is no problem at all,” Dr. Gilard commented. “In our daily practice with the new generation of drug-eluting stents we can shorten the duration of DAPT and give aspirin alone.” While he concluded that six-month DAPT was noninferior to 24-month DAPT in patients who responded well to aspirin, he added that confirming optimal DAPT duration for ACS patients will require further trials.
Increased Risk of Ischemic Events Upon Discontinuation of Prasugrel After 12 or 30 Months of Therapy Following Placement of the Taxus Liberté Paclitaxel-Eluting Coronary Stent
- Kirk N Garratt, MD, Associate Chair of Research & Quality, Interventional Cardiology, Lenox Hill Heart and Vascular Institute, New York, New York
Patients undergoing drug-eluting stent procedures face late risks of both ischemia and bleeding. The optimal prolonged antiplatelet therapy balancing these risks is unknown, Dr. Garratt said at an AHA press conference.
The TAXUS Liberté Post-Approval Study was an international, randomized, double-blind, placebo-controlled trial comparing 30 versus 12 months of dual antiplatelet therapy (DAPT) with a thienopyridine (prasugrel) plus aspirin for 30 months. It was a broadly inclusive trial powered for stent thrombosis, cardiovascular events, and bleeding. The coprimary effectiveness endpoints were stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE) over the 12 to 30 months after the index procedure. The primary safety endpoint was the incidence of major bleeding (moderate or severe GUSTO, or Global Utilization of Streptokinase and tPA for Occluded Arteries). Subjects with very low body mass or advanced age were excluded from the study.
In the randomized population of 2,191 patients receiving drug-eluting stents (out of 25,682 in the larger DAPT study), 51% had at least one risk factor for stent thrombosis at the index procedure (26% with ACSs, 11% with acute ST elevation myocardial infarction, and 12% with a thrombus-containing lesion).
The rate of MACCE at 540 days for patients receiving 12 months of prasugrel plus aspirin was 8.8%, significantly higher (P < 0.001) than that for those receiving prasugrel and aspirin for 30 months (3.7%; HR = 0.407; 95% CI, 0.261–0.589). The MACCE difference was driven entirely by a higher rate of ARC (Academic Research Consortium) myocardial infarction in the 12-month group (7.1% versus 1.9%; HR, 0.255; 95% CI, 0.156–0.417; P < 0.001).
The 12-month prasugrel coprimary endpoint rate for definite or probable stent thrombosis at 540 days was again significantly higher (2.9% versus 0.2%; HR, 0.063; CI, 0.015–0.264; P < 0.001) than the 30-month rate. GUSTO moderate or severe bleeding was higher in the 30-month prasugrel group (2.4% versus 1.7%), but not significantly so (P = 0.234).
The Data Monitoring Committee, Dr. Garratt noted, recommended discussion of continuing open-label prasugrel based on the early increase in ischemic events following withdrawal of active prasugrel therapy in both groups.
“Whether the reduction in late ischemic events demonstrated with prasugrel plus aspirin and the TAXUS Liberté paclitaxel-eluting coronary stent would be observed with other dual antiplatelet regimens and/or other drug-eluting stents will require further study including insights from the larger DAPT Study,” Dr. Garratt said.
The Incidence of Infective Endocarditis in England Is Increasing: An Assessment of the Impact of Cessation of Antibiotic Prophylaxis Using Population Statistics
- Mark J. Dayer, Consultant Cardiologist, Taunton and Somerset NHS Trust, Taunton, United Kingdom (UK)
The fact that invasive dental procedures can result in viridans streptococci being released into the circulation has been known for many years, Dr. Dayer said in an AHA press conference. “It is believed,” he added, “that infective endocarditis can develop as a consequence of this in susceptible individuals.”
Since the National Institute for Health and Care Excellence (NICE) in England withdrew its recommendation for antibiotic prophylaxis before invasive dental procedures, there has been a documented rise in endocarditis cases. There has been no change in current practice recommendations, but after Dr. Dayer’s analysis, NICE will review its guidance.
Subsequent to issuance of the first AHA guidelines on antibiotic prophylaxis in 1955, guideline-recommended antibiotic doses have progressively become lower with shorter duration of administration and fewer patients indicated as being at risk. However, NICE surprised the health community in March 2008, Dr. Dayer said, when it recommended a cessation of antibiotic prophylaxis in the UK due to the lack of supportive evidence for efficacy. It specifically listed individuals undergoing dental, gastrointestinal, genitourinary, and respiratory tract procedures as being exempt from prophylaxis.
To evaluate the effects of the guideline change, Dr. Dayer and colleagues reviewed all single-dose prescriptions for amoxicillin 3 g or clindamycin 600 mg between January 2004 and March 2013; they reviewed 19,804 cases in the UK with primary diagnoses of infective endocarditis in the same period.
The 2008 guideline change did indeed have an effect, based on a 90% decline in prescriptions. By March 2013, the number of infective endocarditis cases per month had risen by 25% (from 140 to 175) more than would have been expected. Increases were in both the highest and lowest risk groups, but were nearly doubled in the latter. The change was observed to begin just three months after the new guideline was introduced. However, a slight upward shift in death rates in the infective endocarditis population since the guideline change is not significant, Dr. Dayer said.
“We want to emphasize that although we have demonstrated a temporal association, we have not demonstrated a cause–effect relationship, and other explanations for the change are possible,” Dr. Dayer said. A prospective, randomized controlled trial is necessary to determine whether or not the association is in fact causal, he added.
The AHA discussant, Dhruv S. Kazi, MD, of the University of California at San Francisco, concurred: “As presented, these data are inadequate to alter the weight of evidence on which the prophylaxis guidelines are based, and should not prompt changes in prescribing practice at this time.”
Dr. Dayer’s study was published concurrently in The Lancet.6
- Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367(18):1694–1703.
- Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371(20):1877–1888.
- Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2014. doi:10.1056/NEJMoa1412690.
- Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014;371(20):1867–1876.
- Cassese S, Byrne RA, Tada T, et al. Clinical impact of extended dual antiplatelet therapy after percutaneous coronary interventions in the drug-eluting stent era: a meta-analysis of randomized trials. Eur Heart J 2012;33(24):3078–3087.
- Dayer MJ, Jones S, Prendergast B, et al. Incidence of infective endocarditis in England, 2000–13: a secular trend, interrupted time-series analysis. Lancet 2014. doi:10.1016/S0140-6736(14)62007-9.