NEJM online first articles for American College Cardiology meeting 3/15: summaries and comments

Trial of Early, Goal-Directed Resuscitation for Septic Shock
P.R. Mouncey and Others
Published Online: March 17, 2015 (DOI: 10.1056/NEJMoa1500896)

Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains.We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome.
Comment: ICU sepsis care is now done using bedside ultrasound for IVC size with liberal fluid administration (at least 2 L). Every ICU fellows and Internal Medicine residents are learning ultrasound as diagnostic tool in addition to stethoscope. We are shifting from using lines to using ultrasound on daily rounds in MICU.

 

 
Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Disease
S. Bangalore and Others
Published Online: March 16, 2015 (DOI: 10.1056/NEJMoa1412168)

In a contemporary clinical-practice registry study, the risk of death associated with PCI with everolimus-eluting stents was similar to that associated with CABG. PCI was associated with a higher risk of myocardial infarction (among patients with incomplete revascularization) and repeat revascularization but a lower risk of stroke.
Trial of Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease
S.-J. Park and Others
Published Online: March 16, 2015 (DOI: 10.1056/NEJMoa1415447)

We conducted a randomized noninferiority trial at 27 centers in East Asia. We planned to randomly assign 1776 patients with multivessel coronary artery disease to PCI with everolimus-eluting stents or to CABG. The primary end point was a composite of death, myocardial infarction, or target-vessel revascularization at 2 years after randomization. Event rates during longer-term follow-up were also compared between groups. Among patients with multivessel coronary artery disease, the rate of major adverse cardiovascular events was higher among those who had undergone PCI with the use of everolimus-eluting stents than among those who had undergone CABG.
Comment: In combination with SYNTAX and FREEDOM trials, we now have the tools to make better decisions on CABG vs PCI. In general, CABG is favored for patients with SYNTAX score (anatomical score) of 24 or higher or DM; PCI is favored in patients with high stroke risk or high comorbidities with lower SYNTAX score and no DM. 

Randomized Trial of Primary PCI with or without Routine Manual Thrombectomy
S.S. Jolly and Others
Published Online: March 16, 2015 (DOI: 10.1056/NEJMoa1415098)

During primary percutaneous coronary intervention (PCI), manual thrombectomy may reduce distal embolization and thus improve microvascular perfusion. Small trials have suggested that thrombectomy improves surrogate and clinical outcomes, but a larger trial has reported conflicting results.We randomly assigned 10,732 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI to a strategy of routine upfront manual thrombectomy versus PCI alone. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days. The key safety outcome was stroke within 30 days.In patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days. (Funded by Medtronic and the Canadian Institutes of Health Research;

Comment: In STEMI care, clot aspiration is no longer mandatory.


Surgical Ablation of Atrial Fibrillation during Mitral-Valve Surgery
A.M. Gillinov and Others
Published Online: March 16, 2015 (DOI: 10.1056/NEJMoa1500528)
Among patients undergoing mitral-valve surgery, 30 to 50% present with atrial fibrillation, which is associated with reduced survival and increased risk of stroke. Surgical ablation of atrial fibrillation has been widely adopted, but evidence regarding its safety and effectiveness is limited.  We randomly assigned 260 patients with persistent or long-standing persistent atrial fibrillation who required mitral-valve surgery to undergo either surgical ablation (ablation group) or no ablation (control group) during the mitral-valve operation. Patients in the ablation group underwent further randomization to pulmonary-vein isolation or a biatrial maze procedure. All patients underwent closure of the left atrial appendage. The primary end point was freedom from atrial fibrillation at both 6 months and 12 months (as assessed by means of 3-day Holter monitoring).The addition of atrial fibrillation ablation to mitral-valve surgery significantly increased the rate of freedom from atrial fibrillation at 1 year among patients with persistent or long-standing persistent atrial fibrillation, but the risk of implantation of a permanent pacemaker was also increased.

Comment: atrial fib ablation does not decrease A fib or CV events post mitral surgery, but is associated with pacemaker implantation. We all know cases that this happened. This means in future we will ask our surgeon to keep the surgery simple.
 

Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events
M.S. Sabatine and Others
Published Online: March 15, 2015 (DOI: 10.1056/NEJMoa1500858)

Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data.
In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies (“parent trials”) of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined. During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880 and NCT01854918.)

Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events
J.G. Robinson and Others
Published Online: March 15, 2015 (DOI: 10.1056/NEJMoa1501031)
Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy. We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24.Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM

Comment: These two trials usher in the new era of PCSK9 inhbitors for cholesterol: both the AMGEN and Sanofi agents are bi-weekly; both reduced cardiac events by 50% when added to standard therapy, if LDL is > 70.


Outcomes of Anatomical versus Functional Testing for Coronary Artery Disease
P.S. Douglas and Others
Published Online: March 14, 2015 (DOI: 10.1056/NEJMoa1415516)

We randomly assigned 10,003 symptomatic patients to a strategy of initial anatomical testing with the use of coronary computed tomographic angiography (CTA) or to functional testing (exercise electrocardiography, nuclear stress testing, or stress echocardiography). The composite primary end point was death, myocardial infarction, hospitalization for unstable angina, or major procedural complication. Secondary end points included invasive cardiac catheterization that did not show obstructive CAD and radiation exposure. In symptomatic patients with suspected CAD who required noninvasive testing, a strategy of initial CTA, as compared with functional testing, did not improve clinical outcomes over a median follow-up of 2 years. (Funded by the National Heart, Lung, and Blood Institute; PROMISE ClinicalTrials.gov number, NCT01174550.)
Comment: This suggests that both coronary CTA or Nuclear stress approaches are similar in median term outcome. Thus, the decision of which approach to use will be based on availability (is it covered by insurance.) In our patients, for Medicaid patients nuclear stress is easily available; for most Medicare plans (AARP, Fidelis), also nuclear; for private insurances, CTA may be accessible.



Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction
M.P. Bonaca and Others
Published Online: March 14, 2015 (DOI: 10.1056/NEJMoa1500857)
We randomly assigned, in a double-blind 1:1:1 fashion, 21,162 patients who had had a myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed for a median of 33 months. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. In patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased the risk of major bleeding. (Funded by AstraZeneca; PEGASUS-TIMI 54 ClinicalTrials.gov number, NCT01225562.)
Comment: the so-call “PEGASUS” trial is a hot dinner topic among cardiologists. The feeling is that this study applies to older generation drug eluting stents (Cypher and Taxus) and may not be as applicable with Everolimus stents (the new generation stents with thin struts), which are much safer. Other studies in JACC this month suggest that ASA/Plavix is only needed for 6 months for Everolimus stents. Thus, it becomes more important to figure out (1) what generation of stents the patients had: Everolimus stents require 12 months of ASA/Plavix. (2) was the PCI complex? complex PCI would require longer term ASA/Plavix. (3) Bleeding risk: most elderly patients bled rather than having stent thrombosis, thus 12 months is appropriate.  

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