Journal Scan 2019

We have personally selected four papers, 1 each from various cardiac specialties such as cardiovascular diseases and interventions, valvular heart disease, and cardiovascular medicine from indexed journals, and reviewed them between January 2019 and June 2019. The selected studies are believed to have an impact in clinical practice

Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in Low-Risk Patients (PARTNER 3 Trail)

N Engl J Med. 2019;380:1695-1705

May 2, 2019

Abstract

Background: Among patients with aortic stenosis who are at intermediate or high risk for death with surgery, major outcomes are similar to transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. There is insufficient evidence regarding the comparison of the 2 procedures in patients who are at low risk.

Methods: We randomly assigned patients with severe aortic stenosis and low surgical risk to undergo either TAVR with transfemoral placement of a balloon-expandable valve or surgery. The primary end point was a composite of death, stroke, or rehospitalization at 1 year. Both noninferiority testing (with a prespecified margin of 6 percentage points) and superiority testing were performed in the as-treated population.

Results: At 71 centers, 1000 patients underwent randomization. The mean age of the patients was 73 years, and the mean Society of Thoracic Surgeons risk score was 1.9% (with scores ranging from 0% to 100% and higher scores indicating a greater risk of death within 30 days after the procedure). The Kaplan–Meier estimate of the rate of the primary composite end point at 1 year was significantly lower in the TAVR group than in the surgery group (8.5% versus 15.1%; absolute difference, −6.6 percentage points; 95% confidence interval [CI], −10.8 to −2.5; P < .001 for noninferiority; hazard ratio, 0.54; 95% CI, 0.37 to 0.79; P = .001 for superiority). At 30 days, TAVR resulted in a lower rate of stroke than surgery (P = .02) and in lower rates of death or stroke (P = .01) and new-onset atrial fibrillation (P < .001). TAVR also resulted in a shorter index hospitalization than surgery (P < .001) and in a lower risk of a poor treatment outcome (death or a low Kansas City Cardiomyopathy Questionnaire [KCCQ] score) at 30 days (P < .001). There were no significant between-group differences in major vascular complications, new permanent pacemaker insertions, or moderate or severe paravalvular regurgitation.

Conclusions: Among patients with severe aortic stenosis who were at low surgical risk, the rate of the composite of death, stroke, or rehospitalization at 1 year was significantly lower with TAVR than with surgery.

Perspective

TAVR was first performed in the early 21st century by Cribier and colleagues in 2002 as a treatment of high-risk patients with severe aortic stenosis. 6 randomized controlled trails subsequently demonstrated safety and efficacy comparable to or better than surgery in patients with high or intermediate surgical risk. Now, 2 trails (PARTNER 3 and EVOLUT) in low-risk patients with symptomatic severe aortic stenosis were presented at American College of Cardiology in New Orleans in 2019.

PARTNER 3 is a randomized, parallel study done by Mack and colleagues in patients with low-risk symptomatic high-gradient aortic stenosis (Society of Thoracic Surgeons risk of 30-day mortality: <4.0%), with suitable transfemoral access. Patients undergoing AVR were randomized to TAVR using the SAPIEN 3 valve (n = 503) versus Surgical Aortic Valve Replacement (SAVR) (n = 497). 1000 patients were enrolled in study with duration of follow-up of 1 year, mean patient age of 73 years. Patients with bicuspid aortic valve, anatomical features that increased the risk of complications, severe left ventricular dysfunction, myocardial infarction within the last month, stroke or transient ischemic attack within the last 90 days, complex coronary artery disease including unprotected left main disease, symptomatic carotid or vertebral artery disease, bleeding predisposition, severe lung disease or severe pulmonary artery hypertension, and body mass index > 50 kg/m² were excluded from the study.

On analysis of results, TAVR compared to surgery had (a) Less primary combined end points (all causes: mortality, stroke, and rehospitalization) at 1 year. (b) Shorter duration of hospital stay. (c) Rapid improvement in quality of life. (d) Similar rate of requirement for new pacemakers. (e) Higher rate of left bundle branch block and paravalvular regurgitation.

Most important limitation of this trial is that it reflects only 1-year outcomes and does not address issues like long-term structural valve deterioration. Several other limitations are as follows: First, in this trial, as in previous TAVR trials, adjudication of end points was not blinded, which could have resulted in bias in outcome assessment. Second, the results apply only to the defined trial population, which excluded patients with poor transfemoral access, bicuspid aortic valves, or other anatomical or clinical factors that increased the risk of complications associated with either TAVR or surgery. Third, missing data regarding NYHA class, 6-minute walk-test distance, KCCQ score, and follow-up echocardiograms were not fully accounted for with multiple imputation. Fourth, this analysis did not examine the rate and relevance of asymptomatic valve thrombosis

This study is game-changing and opens the door to TAVR as the default approach for most patients. But there are concerns regarding long-term results. The current studies will publish 10-year follow-up data to help answer this concern. TAVR will likely be quickly approved as an alternative for low-risk patients who will prefer the less-invasive approach. Physicians will need a reason to refer for surgery.

Antithrombotic Therapy After Acute Coronary Syndrome or PCI in Atrial Fibrillation (AUGUSTUS trail)

N Engl J Med. 2019;380:1509-1524

April 18, 2019

Abstract

Background: Appropriate antithrombotic regimens for patients with atrial fibrillation (AF) who have an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) are unclear.

Methods: In an international trial with a 2-by-2 factorial design, we randomly assigned patients with AF who had an ACS or had undergone PCI and were planning to take a P2Y12 inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events.

Results: Enrollment included 4614 patients from 33 countries. There were no significant interactions between the 2 randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P < .001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P < .001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = .002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group.

Conclusions: In patients with AF and a recent ACS or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both.

Perspective

Approximately 5% to 8% of patients who undergo PCI have AF. Dual antiplatelet therapy (DAPT) with P2Y12 inhibitors and aspirin is superior to oral anticoagulant in reducing risk of stent thrombosis in patients undergoing PCI, but oral anticoagulation (OAC) is superior to DAPT in reducing ischemic strokes in patients with AF. There must be optimum balance in treatment strategy for patients with AF who undergo PCI or have an episode of ACS. Triple therapy is a common guideline-based practice (OAC + DAPT), but this approach may result in major bleeds (2.2% in first month of treatment, 4% to 12% in first year of treatment).

Regimes including nonvitamin K antagonists offer a number of advantages over vitamin k antagonists (VKA). Two trails (PIONEER AF and REDUCE PCI) showed lower bleeding risk in group using novel oral anticoagulants (NOACs) without aspirin compared to group VKA with aspirin. However, they couldn’t conclude whether use of NOAC or removal of aspirin from the regime has reduced the bleeding risk.

AUGUSTUS, a randomized controlled trail compared two groups of patients with AF and recent ACS or PCI. In this trail 4614 patients (median age 70.7 years; 29 percent women) were enrolled and randomized within 14 days (mean 6.6 days) of an ACS episode or stent insertion to apixaban (5 mg twice daily) or VKA and to either a daily low dose aspirin or placebo. All patients were on clopidogrel (90%) or another P2Y12 inhibitor. The study’s primary end point was major or clinically relevant nonmajor bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) definition. Secondary end points included a composite of death or hospitalization and a composite of death or stroke, heart attack, stent thrombosis or urgent revascularization.

After 6 months, the bleeding risk was less in the group taking apixiban and placebo compared to group taking warfarin and aspirin. The number needed to treat to avoid 1 primary event was 24 with apixaban versus VKA.

Deaths and hospitalizations were highest in patients taking VKA and aspirin, and lowest for those taking apixaban and placebo. Patients in the apixaban group had lower risk of stroke compared with those taking VKA.

Limitations of trial are (a) Patients receiving VKA were in therapeutic range only 59% of the time. (b) Trial was not adequately powered to detect small differences in ischemic events, which are likely to increase with early discontinuation of aspirin.

Combination of apixaban and a clopidogrel—without aspirin—is the safest treatment regimen for this difficult-to-treat group of patients, without significantly increasing ischemic events.

Coronary Angiography after Cardiac Arrest without ST-Segment Elevation (COACT Trail)

N Engl J Med. 2019;380:1397-1407

April 11, 2019

Abstract

Background: Ischemic heart disease is a major cause of out-of-hospital cardiac arrests. The role of immediate coronary angiography (CAG) and percutaneous coronary intervention (PCI) in the treatment of patients who have been successfully resuscitated after cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) remains uncertain.

Methods: In this multicenter trial, we randomly assigned 552 patients who had cardiac arrest without signs of STEMI to undergo immediate CAG or CAG that was delayed until after neurologic recovery. All patients underwent PCI if indicated. The primary end point was survival at 90 days. Secondary end points included survival at 90 days with good cerebral performance or mild or moderate disability, myocardial injury, duration of catecholamine support, markers of shock, recurrence of ventricular tachycardia, duration of mechanical ventilation, major bleeding, occurrence of acute kidney injury, need for renal-replacement therapy, time to target temperature, and neurologic status at discharge from the intensive care unit.

Results: At 90 days, 176 of 273 patients (64.5%) in the immediate angiography group and 178 of 265 patients (67.2%) in the delayed angiography group were alive (odds ratio, 0.89; 95% confidence interval [CI], 0.62 to 1.27; P = .51). The median time to target temperature was 5.4 hours in the immediate angiography group and 4.7 hours in the delayed angiography group (ratio of geometric means, 1.19; 95% CI, 1.04 to 1.36). No significant differences between the groups were found in the remaining secondary end points.

Conclusions: Among patients who had been successfully resuscitated after out-of-hospital cardiac arrest and had no signs of STEMI, a strategy of immediate angiography was not found to be better than a strategy of delayed angiography with respect to overall survival at 90 days.

Perspective

Out-of-hospital cardiac arrest is the leading cause of death all over the world. Ventricular fibrillation or pulseless ventricular tachycardia is observed in 40% of patients who have survived the event. Coronary artery disease was the cause in 70% of such cardiac arrest cases. Current European and American guidelines recommend immediate CAG with PCI in cardiac arrest patients who present with STEMI, but in those who do not have ST-segment elevation, the role of immediate CAG is controversial.

Coronary Angiography after Cardiac Arrest trail (COACT) was designed to compare the safety and efficacy of emergent CAG with PCI if indicated as compared with delayed angiography among patients presenting with out-of-hospital cardiac arrest who did not have ST-segment elevation on electrocardiogram (ECG) post-return of spontaneous circulation (ROSC)

A total of 538 patients with initial shockable rhythm (mean patient age is 65 years), unconscious after ROSC, without ST-segment elevation on ECG post-ROSC are randomized in a 1:1 fashion to either emergent angiography (n = 273) or delayed angiography (n = 265). CAG was performed after neurological recovery in delayed arm. Median times to CAG post-arrest were 2.3 hours for emergent versus 121.9 hours for delayed angiography. The intent of angiography was to revascularize any possible culprit lesions, either with PCI or coronary artery bypass grafting. Targeted temperate management was initiated as soon as possible. Patients are followed-up for 90 days. Patients STEMI, shock, and noncoronary cause of the arrest were excluded from study

On analysis, results of the trail did not show a significant difference between the two treatment groups in the primary end point of survival at 90 days nor in the secondary outcomes such as cerebral performance, survival to hospital discharge, major bleeding, and need for RRT (Renal Replacement Therapy). The reason for no significant difference in survival outcomes could be explained by the low rate of occlusive thrombus and the fact that neurologic injury was the most common cause of death. Limitations noted in the trial are (a) Data was collected only in the final phase of the trail (b) patients with shock, severe renal dysfunction, or persistent ST segment elevation were excluded.

Finally, COACT trail concludes that there is no survival benefit to the patients with immediate angiography compared to delayed angiography, who were successfully resuscitated after out-of-hospital cardiac arrest and who had a shockable rhythm and no signs of STEMI or a noncoronary cause of the arrest.

Antibacterial Envelope to Prevent Cardiac Implantable Device Infection (WRAP–IT trail)

N Engl J Med. 2019;380:1895-1905

May 16, 2019

Abstract

Background: Infections after placement of cardiac implantable electronic devices (CIEDs) are associated with substantial morbidity and mortality. There is limited evidence on prophylactic strategies, other than the use of preoperative antibiotics, to prevent such infections.

Methods: We conducted a randomized, controlled clinical trial to assess the safety and efficacy of an absorbable, antibiotic-eluting envelope in reducing the incidence of infection associated with CIED implantations. Patients who were undergoing a CIED pocket revision, generator replacement, or system upgrade or an initial NNN implantation of a cardiac resynchronization therapy defibrillator (CRT-D) were randomly assigned, in a 1:1 ratio, to receive the envelope or not. Standard-of-care strategies to prevent infection were used in all patients. The primary end point was infection resulting in system extraction or revision, long-term antibiotic therapy with infection recurrence, or death, within 12 months after the CIED implantation procedure. The secondary end point for safety was procedure-related or system-related complications within 12 months.

Results: A total of 6983 patients underwent randomization: 3495 to the envelope group and 3488 to the control group. The primary end point occurred in 25 patients in the envelope group and 42 patients in the control group (12-month Kaplan–Meier estimated event rate, 0.7% and 1.2%, respectively; hazard ratio, 0.60; 95% confidence interval [CI], 0.36 to 0.98; P = .04). The safety end point occurred in 201 patients in the envelope group and 236 patients in the control group (12-month Kaplan–Meier estimated event rate, 6.0% and 6.9%, respectively; hazard ratio, 0.87; 95% CI, 0.72 to 1.06; P < .001 for noninferiority). The mean (±SD) duration of follow-up was 20.7±8.5 months. Major CIED-related infections through the entire follow-up period occurred in 32 patients in the envelope group and 51 patients in the control group (hazard ratio, 0.63; 95% CI, 0.40 to 0.98).

Conclusions: Adjunctive use of an antibacterial envelope resulted in a significantly lower incidence of major CIED infections than standard-of-care infection-prevention strategies alone, without a higher incidence of complications.

Perspective

Approximately 1.5 million patients receive CIEDs worldwide every year. Infections after CIED implantation is a major complication and is associated with substantial morbidity, mortality and health care utilization. Currently there is limited evidence on prophylactic strategies and there are no randomized control trails. Worldwide Randomized Antibiotic Envelope Infection Prevention Trial (WRAP-IT) is a multicenter, randomized, controlled, prospective, single blind, post marketing, interventional clinical trial designed to evaluate the safety and effectiveness of the envelope in reducing CIED infection as adjunctive therapy to standard infection-prevention strategies. TYRX envelope is an absorbable single-use envelope designed to hold a CIED when the device is implanted in the body. The envelope is constructed from a multifilament knitted mesh and coated with an absorbable polymer mixed with minocycline and rifampin, which elutes the antibiotics into the local tissue for a minimum of 7 days; envelope is fully absorbed in approximately 9 weeks

In the WRAP–IT trail, 6983 patients enrolled for CIED pocket revision, generator placement, or system upgrade or an initial implantation of a CRT-D were randomized to an absorbable antibiotic-eluting envelope (n = 3495) versus control (n = 3488). All patients received preprocedure intravenous antibiotics and sterile technique. In this study, duration of follow-up was 20.7 months and the mean patient age was 70.1 years. The primary end point of this trial was implantable cardioverter defibrillator (ICD) infection within 12 months after implantation.

Analysis showed a significantly higher rate of infection among patients in the control group, which was mainly pocket related and not due to endocarditis or bacteremia. There were fewer system revisions in the envelope group than in the control group and no complications were noted due to allergy to the envelope mesh polymer. Beneficial effects of the envelope in preventing major CIED infection in 12 months were more pronounced in patients with high-power devices (ICD/CRT-D) than in those with low-power devices (pacemaker/CRT-P) or an initial CRT-D. Use of the envelope requires dissection of a slightly larger CIED pocket, but there were no significant differences in procedure time or procedure-related complications (eg hematoma)

WRAP-IT trail demonstrated 40% lower incidence of major CIED infection with TYRX envelope than standard-of-care infection-prevention strategies alone. However, the number needed to treat is large (200 patients to be treated to prevent 1 infection). The additional costs incurred were not discussed, and the impact on antimicrobial resistance was not evaluated. Further, bacteremia and endocarditis, the most feared infectious complications of ICDs, were numerically (but not statistically) higher in the envelope group. To conclude use of absorbable envelope with ICD placement may be best reserved for patients at highest risk of infectious complications, such as those with staphylococcus aureus colonization, diabetes mellitus, or other immunocompromising conditions.