Important Interventional Trials From ACC.20/WCC Virtual
The American College of Cardiology did a remarkable job of preserving the open and discussed availability of new cardiovascular science this spring despite the major disruptions caused by the novel coronavirus. In short time, the ACC's annual meeting became the ACC Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC) Virtual, an online experience that broadcast important new information around the world. The response was amazing in terms of participants. Congratulations to all the professionals and ACC staff who showed amazing dedication and skill to produce this first-rate meeting.
Thanks also to the dedicated contributors who have summarized and provided personal insight on a selected number of trials chosen for interventionalists' interests. This is an important adjunct to the presentations themselves. As always, comments are appreciated.
Sub-Analyses of ISCHEMIA
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Results of ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) were presented at the American Heart Association's Scientific Sessions 2019 this past November, but the publications for both the primary trial1 and the chronic kidney disease (CKD)2 study were released just after ACC.20/WCC Virtual with more detailed analyses. As published, ISCHEMIA was designed to test whether an initial invasive strategy plus optimal medical management or optical medical management alone is the best strategy for stable ischemic heart disease (SIHD).1 Based on noninvasive assessment, 5,179 patients with moderate or severe ischemia were randomized to an initial invasive strategy versus optimal medical therapy. At follow-up (medial 3.3 years), a composite endpoint of cardiovascular death, myocardial infarction (MI), hospitalization for unstable angina, hospitalization for heart failure (HF), or resuscitated cardiac arrest was not different for the invasive group (13.3%) versus the medical group (15.5%; p = 0.34). Mortality was 6.4% for each group at 4 years.
The controversial results relate to the combined endpoint of increased risk of death or MI in the conservative group (13.9%) compared with the invasive group (11.7%) at 4 years (p = not significant [NS]), the result of a secondary analysis of early, procedure-related MI. Over late follow-up, the incidence of the spontaneous MI increased, raising the question of whether there would be a late advantage to the invasive strategy if the follow-up were extended. Importantly, in a separate analysis by Dr. John Spertus et al.,2 more symptomatic patients showed a reduction in angina for the revascularization strategy, which persisted throughout 4-year follow-up.
Additional sub-analyses of ISCHEMIA were presented at ACC.20/WCC Virtual, further expanding our understanding of the trial results and potential implications on the optimal management of SIHD. Dr. Harmony Reynolds presented an analysis of the interrelationship of coronary artery disease (CAD) severity and extent as well as ischemia and extent of angina symptoms on clinical outcomes. Screening coronary computed tomography (CT) angiography was performed in 4,050 patients who also had stress testing. Seattle Angina Questionnaire angina frequency scores were obtained in patients with no change in baseline angina medications for 3 months. Coronary CT angiography and stress tests were blindly analyzed at independent core laboratories. The modified Duke prognostic score was used to categorize the extent/severity of CAD.
The analysis showed a weak association among ischemia severity, angina frequency, and the extent and severity of CAD. Ischemia and clinical factors were more predictive of the extent/severity, ischemia severity, and angina frequency. On multivariate analysis, worse Seattle Angina Questionnaire angina frequency was not related to extent/severity of CAD but was more common with younger age, females, baseline angina medications, and severe ischemia. These results challenge some of the basic concepts of SIHD related to extent of CAD and ischemia as predictive of clinical outcomes. More data and possible later follow-up will likely further add to our clinical predictive ability.
In a separate presentation, Dr. Sripal Bangalore presented an analysis of medical versus invasive treatment of CKD from ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches–Chronic Kidney Disease) on comparative health effectiveness.3 A total of 777 patients with CKD was randomized to a medical or an invasive strategy. The primary outcome (death/MI) was not significantly different between the invasive (36.4%) and medical group (36.7%; p = 0.95) at 2.3 years but was significantly increased with advancing kidney failure; it was not different between treatment strategy at higher levels of kidney failure. In addition, patients with moderate or severe ischemia had no clinically important difference in angina health status. Overall, there is no important impact on outcome by an invasive strategy in renal failure.
With these updated analyses, how do the results impact treatment? In patients with moderate/severe angina symptoms, there is a persistent symptomatic benefit for the invasive strategy. But overall outcomes are similar between treatment strategies with the current trend toward increasing frequency of spontaneous MIs in the medical therapy group, which has not reached statistical significance. A request for continued follow-up funding is in progress to determine if there might be an advantage of the invasive strategy to reduce Mis over longer time.
Importantly, there are still no data on the completeness or type of revascularization on outcome. Extent of revascularization could be an important factor determining late benefits, and an analysis of 50-70% lesion treatment on outcomes could further define the quality of revascularization necessary to achieve optimal late clinical results. Hopefully this analysis will be available for Transcatheter Cardiovascular Therapeutics 2020 in September.
Lastly it must be remembered that these results apply only to patients without uncontrolled angina, recent MI, percutaneous coronary intervention (PCI) or coronary artery bypass grafting in last year, left main disease >50%, New York Heart Association (NYHA) Class III-IV HF, and/or left ventricular ejection fraction <35%. It is difficult to identify the defined ISCHEMIA population applicable to an initial medical strategy; this is an important issue to address to avoid underdiagnosis and inadequate treatment of higher risk groups by assuming an ISCHEMIA strategy.
The UK TAVI (United Kingdom Transcatheter Aortic Valve Implantation) trial was a randomized study designed to compare transcatheter aortic valve replacement (TAVR) with surgical aortic valve replacement (SAVR) among patients with symptomatic severe aortic stenosis in a non-inferiority analysis. Individuals over the age of 80 years irrespective of their surgical risk and those over the age of 70 with an intermediate or high surgical risk were enrolled. A life expectancy of <1 year, previous aortic valve replacement, concomitant CAD deemed unsuitable for percutaneous revascularization, primary aortic regurgitation, and concomitant severe mitral regurgitation (MR) were exclusion criteria. The primary endpoint was all-cause mortality at 12 months.
A total of 913 patients was enrolled and assigned to TAVR (n = 458) and SAVR (n = 455). The follow up was 12 months. The mean age was 81 years, and 46% were female. The mean Society of Thoracic Surgeons (STS) score was 2.6%, mean left ventricular ejection fraction was 57%, transfemoral TAVR was performed in 92%, and conscious sedation was employed for 70% of the TAVR group. SAPIEN 3 (Edwards Lifesciences; Irvine, CA) was used in 45%, Evolut/Evolut R (Medtronic; Dublin, Ireland) was used in 14%, LOTUS (Boston Scientific; Marlborough, MA) was used in 10%, other valves were used in the remaining 30%. It is also noteworthy that 30% included older generations of Edwards SAPIEN and Medtronic CoreValve. The median length of stay for the TAVR group was 3 days and was 8 days for the SAVR group. The primary outcome, all-cause mortality at 12 months, occurred in 4.6% of the TAVR group compared with 6.6% of the SAVR group (p = 0.23), meeting the pre-specified non-inferiority threshold. The absolute difference in mortality at 1 year was 2% favoring TAVR (4.6% vs. 6.6%; hazard ratio 0.69; 95% confidence interval [CI], 0.38-1.26). In a subgroup analyses by age, STS score, frailty, and CAD requiring revascularization, the treatment effect persisted in favor of TAVR.
The secondary endpoints at 12 months included the following:
- Cardiovascular death: 2.8% for TAVR and 3.3% for SAVR (p = 0.69)
- Stroke: 5.0% for TAVR and 2.9% for SAVR (p = 0.13)
- Permanent pacemaker: 12.2% for TAVR and 6.6% for SAVR (p < 0.001)
- Moderate aortic insufficiency: 2.3% for TAVR and 0.6% for SAVR
- Vascular complications: 4.8% for TAVR and 1.3% for SAVR (p < 0.001)
- Major bleeding: 6.3% for TAVR and 17.1% for SAVR (p < 0.001)
This study concluded that TAVR was non-inferior to SAVR in elderly patients with symptomatic severe aortic stenosis with respect to all-cause mortality. TAVR was also associated with less major bleeding and shorter hospital stay. However, more permanent pacemakers and vascular complications were noted in the TAVR group. Given the age of the patients, a higher rate of permanent pacemaker is not unexpected. Stroke and paravalvular aortic regurgitation were similar statistically but numerically higher in the TAVR group. Moderate aortic regurgitation at 52 weeks was higher in the TAVR group compared with the SAVR group (2.3% vs. 0.6%). Therefore, sustainable results need to be confirmed by long-term follow-up, particularly with respect to paravalvular regurgitation, valve durability, and other clinical endpoints such as stroke. The strength of this study is that it is multicenter, with more than 34 enrolling sites that used several different types of TAVR valves, making it representative of real-life practice. These results cannot be extended to younger patients or those with a low STS score.
As more evidence is generated from studies in lower-risk individuals, we know that both TAVR and SAVR are very safe procedures. But we remain in need of a study of all-comers over the age of 70 years to determine whether life expectancy and durability are offset by a safe procedure in an older population. This multicenter trial adds to the growing evidence from PARTNER 3 (Placement of Aortic Transcatheter Valves 3) and Evolut Low Risk (Evolut Surgical Replacement and Transcatheter Aortic Valve Implantation in Low Risk Patients) (mean age 74 years) trials that suggest a low-risk TAVR procedure in the elderly is not only non-inferior but also may be preferable to SAVR given the shorter life expectancy and lower impact of pacemakers and moderate regurgitation in the long term.
The PARTNER 3 trial was designed to evaluate TAVR using an Edwards SAPIEN 3 valve (TAVR) compared with (SAVR) among low-risk patients with symptomatic severe aortic stenosis. Low risk was defined by an STS risk of 30-day mortality <4.0%. Only those suitable for transfemoral access were included. Bicuspid valves, impaired left ventricular systolic function (<30%), recent stroke, concomitant mitral valve disease, obesity (body mass index >50 kg/m2), severe lung disease, and complex CAD were all excluded. The trial had a randomized parallel design in which the TAVR group received aspirin and clopidogrel 300 mg prior to the procedure and dual antiplatelet for ≥1 month after the procedure. The follow-up period was 1 year. The primary outcome was defined as all-cause mortality, stroke, or re-hospitalization (related to the procedure, valve, or HF) at 1 year.
A total of 503 patients was included in the TAVR arm and 497 patients in the SAVR arm. The mean age was 73 years, and women were 30% of the total cohort. The mean STS score for 30-day mortality was 1.9%. Conscious sedation was employed for 65% of the TAVR group. The primary outcome, all-cause mortality, stroke, or re-hospitalization (related to the procedure, valve, or HF) at 1 year, occurred in 8.5% of the TAVR group compared with 15.1% of the SAVR group (p < 0.001 for non-inferiority; p = 0.001 for superiority). Findings were the same in all pre-specified subgroups. As for the secondary endpoints at 1 year:
- Stroke at 30 days: 0.6% for TAVR and 2.4% for SAVR (p = 0.02)
- New-onset atrial fibrillation (AF) at 30 days: 5.0% for TAVR and 39.5% for SAVR (p < 0.001)
- Death or disabling stroke at 1 year: 1.0% for TAVR and 2.9% for SAVR (p < 0.05)
- Moderate to severe paravalvular aortic regurgitation at 1 year: 0.6% for TAVR and 0.5% for SAVR (p = NS)
- Permanent pacemaker within 30 days: 6.5% for TAVR and 4.0% for SAVR (p = NS)
- Low Kansas City Cardiomyopathy Questionnaire summary score at 30 days: 3.9% for TAVR and 30.6% for SAVR (p < 0.001)
These persisted at 2 years. It is notable that there were more deaths and strokes between 1 and 2 years in the TAVR group. There are many interpretations, most important of which is the change in the antiplatelet and anticoagulation regimens at 1 year.
A cardiac CT sub-analysis was conducted on both TAVR (165) and SAVR (119) patients at 30 days and 1 year. The incidence of hypoattenuated leaflet thickening was 13.3% versus 5.0% (p = 0.03) at 30 days and 27.5% versus 20.2% at 1 year. Higher gradients at 30 days (13.2 vs. 11.7 mmHg; p = 0.08) and at 1 year (13.7 vs. 12.6 mmHg; p = 0.24) were noted in those with hypoattenuated leaflet thickening. At 1 year, 56% of hypoattenuated leaflet thickening at 30 days had resolved without anticoagulation, and 21% without hypoattenuated leaflet thickening at 30 days developed hypoattenuated leaflet thickening. Hypoattenuated leaflet thickening was associated with a numerically higher risk of thromboembolic events (8.6% vs. 2.9%; p = 0.11), albeit insignificant.
The study demonstrated that TAVR was superior to SAVR with respect to death, stroke, and re-hospitalizations at 1 year. These findings persisted at 2 years. Although there was a numerical increase in pacemakers and a statistically significant increase in mild paravalvular regurgitation, neither translated into a worse quality of life or mortality. There was a higher overall incidence of hypoattenuated leaflet thickening in the TAVR group, which was associated with a statistically insignificant higher thromboembolic event rate. However, hypoattenuated leaflet thickening has no predictable pattern and no clear association with the antiplatelet or anticoagulation regimen. The study provides valuable data that allow us to consider TAVR in low-risk patients. It cannot, however, be extended to other low-risk groups such as bicuspid aortic valves. The lower follow-up in the surgical arm (due to withdrawal) is a notable limitation. The VARC-2 definitions for valve thrombosis are outdated. The 2-year follow-up period is inadequate for a low-risk cohort where long-term outcomes and valve durability are imperative and will impact a need for a redo TAVR or SAVR. This study's 10-year clinical and echocardiographic follow-up analysis (especially the clinical relevance of hypoattenuated leaflet thickening) are much anticipated. Until then, a patient-centered decision remains central to any therapy offered.
Stroke Through 24 Months
The Risk/Benefit Tradeoff of Antithrombotic Therapy in Patients With AF Early and Late After an ACS or PCI: Insights From AUGUSTUS
By James Nguyen, MD
St. Francis Hospital, The Heart Center
Allen Jeremias, MD, MSc
St. Francis Hospital, The Heart Center
In patients with acute coronary syndrome (ACS) and AF, the AUGUSTUS (Antithrombotic Therapy After Acute Coronary Syndrome or PCI in Atrial Fibrillation) trial found that P2Y12 inhibitor and novel oral anticoagulants (NOAC) had less bleeding compared with vitamin K antagonists (VKA) and less bleeding with placebo (i.e., dual therapy) compared with aspirin (triple therapy). However, after closely examining the data, the investigators noticed a higher risk of ischemic events among patients assigned to dual anti-thrombotic therapy. Therefore, a post-hoc analysis was done comparing risk (increased bleeding) versus benefit (decreased ischemic events) at two distinct timelines: 0 to 30 days and 30 days to 6 months. In this analysis, after 30 days, there was no benefit of continued aspirin therapy with respect to ischemic events but a ~1% increase in the risk of bleeding. However, within the first 30 days, there was a ~1% absolute increase in ischemic events in the dual therapy group, indicating that dual therapy may be insufficient ischemic protection early on after an ACS event. On the other hand, the absolute increase in bleeding during this timeframe among patients receiving aspirin was also about 1%, demonstrating a roughly equal risk of bleeding and benefit in ischemic protection.
This analysis gives excellent guidance to the duration of dual antiplatelet therapy in conjunction with anticoagulation to reduce the risk of bleeding while decreasing ischemia outcomes in this challenging patient population. Based on these data, it is reasonable to assume that triple therapy for the first 30 days and dual therapy from then on (i.e., without aspirin) is warranted in a low-bleeding-risk population. However, when examining the different study groups in the AUGUSTUS trial, VKA had a 1.01% higher absolute risk of severe ischemic composite outcome compared with NOAC in the first 30 days. Although no interaction between anticoagulation and antiplatelet therapies was reported, this cannot be completely ruled out due to the relatively small outcome sample size. It is therefore possible that the early ischemic risk is largely confined to the VKA group. Based on previous evidence, VKA has not been shown to reduce stent thrombosis; therefore, dual antiplatelet therapy for 30 days is potentially a safer option in combination with VKA.
On the other hand, the combination of a NOAC with single antiplatelet versus VKA and dual antiplatelet therapy in RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) and PIONEER AF-PCI (An Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention), the absolute number of stent thromboses in the triple therapy group was similar to the NOAC plus P2Y12 inhibitor. This may be due to direct thrombin inhibition by the NOAC, which may reduce platelet activation by other pathways. Another potential limitation in the AUGUSTUS trial is the antiplatelet therapy. Clopidogrel was used in over 90% of the patients with up to 30% of patients exhibiting mutations in the CYP2C19 gene, leading to inadequate conversion of clopidogrel into its active metabolite. The open question remains whether prasugrel or ticagrelor, in addition to a NOAC, would confer adequate ischemic protection with an acceptable risk of bleeding, potentially constituting an optimal pharmacologic combination for patients with ACS.
The SPYRAL HTN-OFF MED Pivotal Trial
By Herbert D. Aronow, MD, MPH, FACC
Warren Alpert Medical School of Brown University
Lifespan Cardiovascular Institute
The SPYRAL HTN-OFF MED Pivotal (Efficacy of Catheter-Based Renal Denervation in the Absence of Antihypertensive Medications) trial was a single-blinded, randomized controlled trial comparing catheter-based renal sympathetic denervation with sham therapy among hypertensive patients aged 20-80 years who were not taking antihypertensive agents, had office systolic blood pressure (SBP) 150-179 mmHg, office diastolic blood pressure ≥90 mmHg, and 24-hour ambulatory SBP 140-169 mmHg. It enrolled 331 patients from 44 sites in 9 countries and randomized them 1:1 to each of the 2 treatment arms. Denervation procedures were performed using the Symplicity Spyral multielectrode radiofrequency catheter (Medtronic; Dublin, Ireland). Radiofrequency energy was delivered for 45-60 seconds to all 4 quadrants of renal arteries and their branches with diameters between 3 and 8 mm, including accessory vessels. The primary and secondary efficacy endpoints were change in 24-hour ambulatory SBP and office SBP from baseline to 3 months, respectively. The primary safety endpoint was a 3-month composite of all-cause mortality, end-stage renal disease, embolic event resulting in end-organ damage, perforation or dissection of the renal artery requiring intervention, vascular complications, hospital admission for hypertensive crisis unrelated to medication or protocol nonadherence, or new angiographically confirmed renal artery stenosis of >70%. The primary analysis combined patients from the pilot (n = 80) and pivotal (n = 251) studies using a Bayesian design with an informative prior. Both 24-hour ambulatory and office SBP were significantly reduced by 3.9 mmHg and 6.5 mmHg, respectively. No major procedure-related safety events occurred.
The trial was designed, conducted, and analyzed well, and it addressed many gaps in prior first-generation studies of renal sympathetic denervation. Enrolled patients were young and had few comorbidities, and their blood pressures were similar to those encountered in everyday medical practice. The trial results are consistent with those from other second-generation studies included in our meta-analysis of nearly 1,000 patients from 6 randomized, sham-controlled renal denervation trials.4 That there were no safety concerns at 1-month and 3-month timepoints is also consistent with prior studies. Because this study is much larger than previous trials of renal denervation, it affords one the opportunity to evaluate treatment efficacy in multiple subgroups; it is reassuring that the observed reductions in blood pressure were consistent across all examined subgroups, including age, gender, and ethnicity. The reductions in 24-hour ambulatory SBP and office SBP were similar to those afforded by many commonly used antihypertensive agents, but unlike oral medications, renal denervation is "always on" and is not influenced by adherence, intolerance, or peak-and-trough drug levels. On the surface, observed blood pressure reductions may appear small, but in epidemiological studies, even a 2 mmHg decrease in SBP is associated with a 10% reduction in stroke mortality and a 7% reduction in coronary or other vascular disease mortality. The observed blood pressure reductions in SPYRAL HTN OFF-MED (Investigation of Catheter-Based Renal Denervation in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications) are therefore quite relevant from a public health perspective and should be practice-changing if longer-term efficacy and safety data are consistent. The ongoing SPYRAL HTN-ON MED (Investigation of Catheter-Based Renal Denervation in Patients With Uncontrolled Hypertension in the Presence of Antihypertensive Medications) trial will address short-term safety and efficacy of renal denervation in patients with uncontrolled hypertension who remain on antihypertensive agents.
The Evolut Low Risk Bicuspid Study
By Neal S. Kleiman, MD, FACC
Houston Methodist Hospital
The Evolut Low Risk Bicuspid Study was presented at ACC.20/WCC Virtual. Patients with bicuspid aortic valves constitute a significant proportion of patients with aortic stenosis and are usually younger than those with degenerative tricuspid aortic stenosis and hence at lower risk for SAVR. Randomized trials to date have excluded patients with bicuspid valves, so there are few rigorously obtained data concerning them. Early findings indicated inferior results for TAVR in this group, but more recent series using new valves have suggested that results might be better than previously reported. The CoreValve (Medtronic; Dublin, Ireland) prosthesis was thought to be well-suited for this application because its design permits the frame to assume an ovoid profile at the annular level, which conforms to the profile of a bicuspid valve annulus, while maintaining a circular profile of the supra-annular valve prosthesis. Patients enrolled in the Evolut Low Risk Bicuspid Study were older than 60 years, had symptomatic severe aortic stenosis with CT-confirmed bicuspid morphology in the absence of aortopathy (ascending aorta >4.5 cm), and had STS Predicted Risk of Mortality (PROM) score <3%. Cases were reviewed by a central screening committee. Only one screened patient was excluded on the basis of excessive left ventricular outflow tract calcification. The remaining 150 patients underwent TAVR, which was successful in 149 patients. Only 9% had Sievers Type 0 morphology (no raphe), and the remainder had Type 1 morphology (single raphe). Evolut R (Medtronic; Dublin, Ireland) (43%) or Evolut Pro (Medtronic; Dublin, Ireland) (57%) valves were implanted. The latter design contains an external wrap intended to improve annular sealing. Valve sizing was based on CT measurements of the aortic valve annulus, and predilation was recommended. One patient underwent conversion to SAVR. Follow-up was at 30 days.
The mean age was 71 years; 52% were men, the mean body surface area was 1.9 m2, and the mean STS PROM score was 1.4 +/- 0.6 %, indicating a lower risk population than those previously reported in the pivotal TAVR trials. Iliofemoral access was used in 98.7% of patients, and general anesthesia was used in 63.3%. The primary endpoint, death or disabling stroke, occurred in 1.3% of patients at 30 days (one of each component), and non-disabling stroke occurred in 3.3%. There were no annular ruptures. New permanent pacemakers were implanted in 15.1% of patients without pre-existing pacemakers. At 30 days, as expected, NYHA class improved substantially (75% were NYHA Class I, and 22% were NYHA Class II). Patient-prosthesis mismatch was absent in 87.1% of patients, moderate in 7.6%, and severe in 5.3%. Mean gradient was 7.6 mmHg, and mean effective regurgitant orifice area was 2.3 cm2 at follow-up. No hemodynamic differences were observed between Sievers 0 and Sievers 1 valves. No patient had moderate or severe aortic regurgitation; however, mild aortic regurgitation was present in 59.6% of patients, with a trend toward higher rates in Type 0 valves.
Although these data do not provide a randomized comparison between TAVR and SAVR, they represent the first systematic study of TAVR for patients with bicuspid aortic valves and thus help provide some perspective on these patients. It is important to recognize that the group studied was at lower risk for surgery than those in the randomized trials, and it is extremely important to note that patients with dilated ascending aortas were excluded because aortic replacement is recommended in these patients if SAVR is being considered. Although the safety of the procedure is reassuring (1 death and 1 stroke), the sample size of 150 makes these point estimates less than robust. Because this low-risk group of patients has a prolonged survival horizon, the impact on long-term survival of a 15% pacemaker rate and a 59% rate of mild aortic regurgitation (compared with 39.6% in the randomized low-risk trial) need to be considered and underscore the need for a larger scale randomized trial with dedicated 10-year follow-up.
The POPular TAVI Trial
By Neal S. Kleiman, MD, FACC
Houston Methodist Hospital
The POPular TAVI (Antithrombotic Therapy After Transcatheter Aortic Valve Implantation in Patients With a Long-Term Indication for Oral Anticoagulation) trial was presented at ACC.20/WCC Virtual and published simultaneously in The New England Journal of Medicine. This presentation focused on the second cohort of a larger study examining the use of the antiplatelet drug clopidogrel in patients undergoing TAVR who also had an indication for oral anticoagulants. The trial, sponsored by the Netherlands Organization for Health Research, included patients already on an oral anticoagulant. The design was open label; a total of 313 patients was randomized to continue the oral anticoagulant treatment that was used preoperatively and to receive either the anticoagulant alone or the anticoagulant in combination with clopidogrel added for a period of 3 months. As expected, about 95% of patients had AF as the indication for oral anticoagulation. The average age was 81 years, 45% were women, 9.6% had prior stroke, and the median STS PROM score was 3.1%. The vast majority of patients was on VKA. The two primary outcomes were any bleeding, classified by the VARC-2 criteria, and severe non-procedure-related bleeding distinguished using the BARC (Type 4) criteria. Because the initial proportional hazards assumption was not met, the final analysis was done using a post hoc risk ratio analysis.
At 1 year, the rates of any bleeding were 21.7% for oral anticoagulants alone and 34.6% for oral anticoagulants plus clopidogrel (risk ratio 0.63; 95% CI, 0.43-0.90). For non-procedure-related bleeding, the rates were 21.7% and 34%, respectively (risk ratio [RR] 0.64; 95% CI, 0.44-0.92). Secondary composites of cardiovascular death, non-procedure related bleeding, stroke, or MI, and cardiovascular death, ischemic stroke, or MI also followed a similar pattern: 31.2% versus 45.5% (RR 0.69; 95% CI, 0.51-0.9) and 13.4% versus 17.3% (RR 0.77; 95% CI, 0.46-1.31). The bleeding differences appeared to be most manifest during the early stages of the follow-up. Mortality was 13.4% in the oral anticoagulant group and 15.4% in the combination group; respective rates of ischemic stroke were 5.1% and 5.8%. Neither difference approached statistical significance.
Clinicians caring for patients who undergo TAVR who also need anticoagulants have been faced with a vexing series of choices. The need for oral anticoagulation in the setting of AF is now unassailable, unless a patient has received a left atrial appendage occlusion device more than 6 weeks previously. The use of antiplatelet drugs in patients undergoing TAVR is largely empiric and has largely been derived from earlier experience with intracoronary stents. Current guidelines recommend 3-6 months of dual antiplatelet therapy, although many clinical trials have recommended only a single antiplatelet drug in patients on oral anticoagulants. Both intuition and data from trials of oral anticoagulants in patients undergoing stent placement indicate that compounding antithrombotic medications increases the risk for bleeding. The TAVR population is particularly challenging because the advanced age and frailty of these patients put them at high risk for bleeding. The population studied in the POPular TAVI trial is similar in age to that studied in the high- and extreme-risk studies but is 6-7 years older than those in the low-risk TAVR trials. It is important to keep in mind that a minority of patients in this trial was treated with direct oral anticoagulants, and the trial is not designed to distinguish differences between the anticoagulant chosen. Nonetheless, these data should provide considerable comfort to clinicians who wish to manage post-TAVR patents requiring oral anticoagulants without adding antiplatelet drugs.
The Global EXPAND Study
By Michael N. Young, MD, RPVI
Dartmouth-Hitchcock Medical Center
Geisel School of Medicine at Dartmouth
At the recent ACC.20/WCC Virtual, Dr. Scott Lim presented the results from the Global EXPAND Study (Contemporary Outcomes With MitraClip (NTR/XTR) System in Primary MR). The MitraClip® EXPAND Study is a large, prospective, single-arm observational study of over 1,000 patients undergoing transcatheter mitral valve repair with the MitraClip (Abbott; Abbott Park, IL) in centers across the United States, Europe, and the Middle East. This post-market study, which included subjects with symptomatic >3+ MR, was designed to analyze 30-day, 6-month, and 12-month clinical outcomes in a real-world population of patients undergoing therapy with the next generation MitraClip (i.e., NTR/XTR designs). Both the NTR and XTR clips, introduced in 2018, offered design improvements with respect to the catheter delivery system and clip arm lengths. The current analysis presented by Lim on behalf of the EXPAND investigators was restricted to a subset of 422 patients with primary or mixed mitral valve pathology and focused on their early 30-day outcomes.
As anticipated, the study population was older (mean age 79.5 ± 9.4 years) and medically complex (cardiac arrhythmia in 60.5%, prior HF hospitalization in 1 year in 43.2%, renal failure in 28.2%). There was a comparable distribution of sex (52.1% male and 47.9% female) in the study cohort. With respect to the technical data, the implantation rate was 99.5% (420/422), and the acute procedural success rate—defined as residual MR on discharge 2+ or lower and no requirement for mitral valve surgery—was 94.5% (396/419). The XTR clip was used alone in 46.2% of cases, NTR was used alone in 34.8% of cases, and a combination of the 2 was used in 19.0% of cases. Importantly, the investigators did not find an increased post-implant 30-day mitral valve gradient with the XTR clip compared with the NTR clip. In patients with more complex mitral valve anatomies (e.g., wide flail gaps and calcified landing zones), greater MR reduction was observed with use of the XTR device (p = 0.0383).
Reassuringly, the 30-day major adverse event rates were low (all-cause death 2.4%, MI 0.0%, stroke 1.2%, cardiovascular surgery for device-related complications 0.9%). Single leaflet device attachment and leaflet perforation occurred in 1.9% (n = 8) and 0.2% (n = 1) of cases, respectively. Regarding clinical outcomes, there was sustained improvement across multiple domains: residual MR out to 30 days (MR ≤1+ 86.9%; MR ≤2+ 97.3%), left ventricular remodeling based on echocardiographic-adjudicated dimensions and volumes, and quality of life parameters as assessed by NYHA class and Kansas City Cardiomyopathy Questionnaire scores.
There are several points to this analysis that merit particular emphasis. First, this study was conducted with use of a clinical events committee as well as an echocardiographic core laboratory for data adjudication. Second, the procedural outcomes compared favorably with those from previous trial data, with numerically higher implantation and acute procedural success rates and shorter procedural times and hospital lengths of stay. Notably, the investigators highlight that 30-day MR reduction to ≤1+ was numerically higher than the prohibitive risk cohort of prior iterations of EVEREST (Endovascular Valve Edge-to-Edge Repair Study). Third, the NTR/XTR MitraClip device iterations appear to perform well in terms of echocardiographic and clinical outcomes, both with low and favorable 30-day major adverse event rates.
There are caveats worth mentioning here: 1) only acute procedural and 30-day outcomes are reported, 2) echocardiographic acquisitions may be prone to variability because there was not prospective core laboratory adjudication on enrollment, and 3) there are inherent limitations of attempting to draw comparative inferences between trials (e.g., references to EVEREST results), albeit promising.
To conclude, the key take-home messages from this excellent analysis presented by Lim and colleagues follow:
- The next generation MitraClip NTR/XTR devices are both safe and efficacious for the treatment of symptomatic primary MR in a contemporary, real-world population.
- MitraClip XTR was used more often in patients with a large prolapse or flail gap and demonstrated greater reduction in 30-day residual MR than NTR alone in complex mitral valve anatomies.
- Longer-term data out to 1 year are highly anticipated, as well as data from the functional MR cohort of the EXPAND study.
- Maron DJ, Hochman JS, Reynolds HR, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med 2020;382:1395-407.
- Spertus JA, Jones PG, Maron DJ, et al. Health-Status Outcomes with Invasive or Conservative Care in Coronary Disease. N Engl J Med 2020;382:1408-19.
- Spertus JA, Jones PG, Maron DJ, et al. for the ISCHEMIA-¬CKD Research Group. Health Status after Invasive or Conservative Care in Coronary and Advanced Kidney Disease. N Engl J Med 2020;Mar 30:[Epub ahead of print].
- Sardar P, Bhatt DL, Kirtane AJ, et al. Sham-Controlled Randomized Trials of Catheter-Based Renal Denervation in Patients With Hypertension. J Am Coll Cardiol 2019;73:1633-42.
Keywords: Acute Coronary Syndrome, Angina, Stable, Angina, Unstable, Cardiac Catheterization, Constriction, Pathologic, Coronary Angiography, Coronary Artery Bypass, Coronary Artery Disease, Exercise Test, Heart Arrest, Heart Failure, Magnetic Resonance Imaging, Myocardial Infarction, Myocardial Ischemia, Percutaneous Coronary Intervention, Renal Insufficiency, Chronic, Secondary Prevention, Stroke Volume, Tomography, Acute Coronary Syndrome, Angina Pectoris, Angina, Unstable, Cardiac Catheterization, Coronary Angiography, Coronary Artery Bypass, Coronary Artery Disease, Exercise Test, Heart Arrest, Heart Failure, Kidney Diseases, Magnetic Resonance Imaging, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Percutaneous Coronary Intervention, Renal Dialysis, Renal Insufficiency, Chronic, Secondary Prevention, Stroke, Stroke Volume, Cardiac Surgical Procedures, Aortic Valve Insufficiency, Aortic Valve Stenosis, Conscious Sedation, Geriatrics, Heart Failure, Heart Valve Diseases, Hemorrhage, Pacemaker, Artificial, Stroke, Stroke Volume, Transcatheter Aortic Valve Replacement, Ventricular Function, Left, Vascular Diseases, Aortic Valve Insufficiency, Aortic Valve Stenosis, Aspirin, Atrial Fibrillation, Cardiac Surgical Procedures, Geriatrics, Heart Failure, Heart Valve Diseases, Heart Valve Prosthesis, Pacemaker, Artificial, Stroke, Transcatheter Aortic Valve Replacement, Vascular Diseases, Tomography, Acute Coronary Syndrome, Anticoagulants, Arrhythmias, Cardiac, Aspirin, Atrial Fibrillation, Fibrinolytic Agents, Hemorrhage, Myocardial Revascularization, Percutaneous Coronary Intervention, Secondary Prevention, Thrombosis, Vitamin K, Warfarin, Acute Coronary Syndrome, Antithrombins, Aspirin, Atrial Fibrillation, Coronary Artery Disease, Drug-Eluting Stents, Embolism, Fibrinolytic Agents, Hemorrhage, Myocardial Infarction, Myocardial Revascularization, Purinergic P2Y Receptor Antagonists, Stroke, Thrombosis, Warfarin, Acute Coronary Syndrome, Administration, Oral, Anticoagulants, Aspirin, Atrial Fibrillation, Drug-Eluting Stents, Hemorrhage, Percutaneous Coronary Intervention, Platelet Aggregation Inhibitors, Secondary Prevention, Stents, Thrombosis, Vitamin K, Warfarin, Antihypertensive Agents, Blood Pressure, Blood Pressure Determination, Blood Pressure Monitoring, Ambulatory, Denervation, Diastole, Hypertension, Primary Prevention, Renal Insufficiency, Systole, Antihypertensive Agents, Blood Pressure, Blood Pressure Determination, Blood Pressure Monitoring, Ambulatory, Catheter Ablation, Catheters, Denervation, Hypertension, Primary Prevention, Sympathectomy, Vascular Diseases, Angiography, Antihypertensive Agents, Blood Pressure, Blood Pressure Determination, Blood Pressure Monitoring, Ambulatory, Catheter Ablation, Denervation, Hypertension, Metabolic Syndrome, Primary Prevention, Renal Artery, Acute Kidney Injury, Aortic Valve Stenosis, Atrial Fibrillation, Cardiac Surgical Procedures, Geriatrics, Heart Failure, Heart Valve Diseases, Heart Valve Prosthesis, Pacemaker, Artificial, Stroke, Transcatheter Aortic Valve Replacement, Vascular Diseases, Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Cardiac Surgical Procedures, Embolic Protection Devices, Geriatrics, Heart Failure, Heart Valve Diseases, Hemorrhage, Myocardial Infarction, Risk, Secondary Prevention, Stroke, Transcatheter Aortic Valve Replacement, Vitamin K, Mitral Valve, Heart Valve Prosthesis Implantation, Heart Valve Diseases, Heart Defects, Congenital, ACC Annual Scientific Session, acc20
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