ACC.21 Interventional Trial Take-Aways
The American College of Cardiology's 70th Annual Scientific Session & Expo (ACC.21) Virtual had remarkable content and really reflected how quickly and successfully virtual technology has progressed. The presentations and commentary were well delivered and remain available for those who registered, which is a nice benefit. Some of us still miss the live interactions with people, but there were sessions to exchange. Overall, it was an excellent conference for education and dissemination of new science.
Interventional science was well represented with a variety of new trials and extended information on some revolving trials such as ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches). A special thanks to members of the Interventional Member Section Leadership Council for their help by providing these succinct summaries, focusing on the important messages from each and supplemented by their opinions regarding the implications for practice and potential need for additional studies or analyses.
I trust you will find these summaries useful in support of your education and practice. As always, comments or suggestions are welcome.
RADIANCE-HTN TRIO (Endovascular Ultrasound Renal Denervation to Treat Hypertension Resistant to a Fixed Dose Triple Medication Pill)
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Renal artery denervation using ultrasound energy reduces blood pressure (BP) in patients with mild to moderate hypertension but has not been shown to be effective in treating resistant hypertension in such patients. To assess renal artery denervation effectiveness compared to a single pill of 3 drugs (angiotensin receptor blocker, calcium channel blocker, and a diuretic) in hypertension incompletely controlled by medications alone, 136 patients with resistant hypertension were randomized to renal artery denervation versus sham treatment.
The renal artery denervation group had on average an 8 mmHg drop in ambulatory daytime systolic BP, a 4.5 mmHg greater reduction than the sham group. Furthermore, BP lowering with renal artery denervation was greater than sham treatment for 24h, nighttime, and office systolic BP at 2 months.
These results are encouraging but require further evaluation including longer follow-up to demonstrate late benefit, alternative drug combinations (e.g., spironolactone for resistant BP), and better predictors of which patients respond to renal artery denervation.
These results are encouraging but will require definitive benefits over medical management, which in these patients was optimized for compliance with a single-pill strategy. Hypertension is a major risk factor that has increased in prevalence in recent years and remains poorly treated due to multiple factors including limits to medical therapy due to side effects and the realities of compliance even in the absence of broader insurance coverage. Given the challenges of achieving successful medical treatment in many patients and the relative increased risk of even modest, chronic elevations of BP, an effective non-medical treatment for selected patients has significant potential benefits for this population. Thus, longer term follow-up of renal artery denervation versus optimal medical treatment strategies is critical.
ATLANTIS (Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis)
By Mirvat A. Alasnag, MD
King Fahd Armed Forces Hospital
Jeddah, Saudi Arabia
This is a randomized, open-label, phase III trial designed to demonstrate the superiority of apixaban 5 mg BID over a standard-of-care comparator after successful transcatheter aortic valve implantation. The comparator was antiplatelets in those without an indication for oral anticoagulation (OAC) and vitamin K antagonists (VKA) in those with an indication for OAC. A four-dimensional cardiac computed tomography scan was the protocol mandated to identify subclinical valve thrombosis or reduced leaflet mobility. The trial noted that apixaban was not superior to standard of care in terms of net clinical benefit and in each stratum. The safety endpoint of bleeding was similar globally and in each stratum. Subclinical valve thrombosis was lower in the apixaban arm driven by the stratum of patients without an indication for OAC; however, it did not reach statistical significance. There was also a trend toward higher non-cardiovascular mortality observed in those without an indication for OAC.
At 1 year, this study found no significant difference in the composite of all-cause death, stroke, myocardial infarction (MI), valve thrombosis, pulmonary or systemic embolism, deep vein thrombosis, or major bleeding, which occurred in 18.4% of those assigned to apixaban and 20.1% assigned to standard of care. As such, it cannot be recommended for routine use particularly in those without an indication for OAC where a signal toward higher mortality was reported. This higher mortality was also reported in GALILEO (Global Study Comparing a Rivaroxaban-Based Antithrombotic Strategy to an Antiplatelet-Based Strategy After TAVR to Optimize Clinical Outcomes) in which rivaroxaban was investigated. There were higher ischemic and bleeding events in GALILEO overall that warranted its early termination (findings not observed in the ATLANTIS trial). Apixaban may be an option as an alternative to VKA in those who have a contraindication because the safety endpoint of bleeding was similar in the ATLANTIS trial. In addition, the rate of reduced leaflet mobility and leaflet thrombosis was 80% lower in the apixaban arm with fewer ischemic events. These results cannot be interpreted in isolation. At this time, the totality of evidence cannot correlate ischemic symptoms, valve gradient, and valve durability with the degree of reduced leaflet mobility. Finally, the ATLANTIS trial cannot be expanded to patients with a high ischemic risk such as valve-in-valve, recent stroke or transient ischemic attack, mechanical valves, concomitant coronary artery disease (CAD) with recent revascularization, and advanced kidney disease because these were excluded from the study.
VOYAGER PAD (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease)
By Pinak Bipin Shah, MD, FACC
Brigham and Women's Hospital, Heart and Vascular Center
Among 6,546 patients with symptomatic lower extremity peripheral artery disease (PAD) who were planned for peripheral revascularization, either by a surgical or endovascular approach, patients randomized to receive rivaroxaban 2.5 mg BID were less likely to experience the composite of acute limb ischemia, major amputation of a vascular cause, myocardial infraction, ischemic stroke, or cardiovascular death compared to patients randomized to placebo. Patients were already treated with aspirin and statin, and clopidogrel use was at investigator discretion. The number needed to treat for benefit was 39. In a pre-specified analysis, time to first adverse limb or cardiovascular event and total number of events were analyzed in the 2 groups. Of the 6,546 patients randomized, there were 4,714 first and subsequent vascular events. In addition to reducing the total primary endpoint events (hazard ratio 0.86; 95% confidence interval, 0.75-0.98; p = 0.02), rivaroxaban also reduced total vascular events (hazard ratio 0.86; 95% confidence interval, 0.70-0.95; p = 0.003). There was a non-statistical increase in major bleeding in patients treated with rivaroxaban.
Patients with peripheral vascular disease are at high risk for acute cardiac and vascular events. Rivaroxaban 2.5 mg BID has been shown to be beneficial in reducing adverse cardiovascular events when added to standard therapy for vascular disease. Patients who undergo lower extremity revascularization procedures are at particularly high risk for multiple cardiovascular events after their procedures. In this particularly vulnerable group, rivaroxaban reduced the overall burden of recurrence of all cardiac and vascular events over a follow-up of 3 years. The net clinical benefit suggests that rivaroxaban at 2.5 mg BID should be considered in higher risk patients with peripheral vascular disease.
TALOS-AMI (Ticagrelor Versus Clopidogrel in Stabilized Patients With Acute Myocardial Infarction)
By Matthew William Sherwood, MD, MHS, FACC
INOVA Heart and Vascular Institute
Falls Church, VA
The TALOS-AMI trial was a randomized, open-label, multi-center clinical trial that enrolled over 2,600 patients stabilized 1 month after MI initially treated with percutaneous coronary intervention (PCI). Patients were initially treated with dual antiplatelet therapy (DAPT) for the first 30 days post-PCI. If stable without complications, patients were then given aspirin 100 mg daily and randomized in a 1:1 fashion to either clopidogrel 75 mg daily or ticagrelor 90 mg BID. The primary outcomes measured in the trial included a composite of cardiovascular mortality, MI, stroke, or BARC bleeding up to 1 year post-PCI. The rationale of the study was to evaluate the safety and efficacy of de-escalating from more potent antiplatelet therapy (ticagrelor) to clopidogrel at 1 month post-MI treated with PCI. The composite endpoint occurred in 8.2% of patients on ticagrelor versus 4.6% of patients on clopidogrel, primarily driven by BARC bleeding, which occurred in 5.6% of patients on ticagrelor versus 3.0% of patients on clopidogrel.
In patients with acute MI treated with PCI who tolerated DAPT with aspirin and ticagrelor without complications in the first 30 days, a strategy of de-escalation to clopidogrel and aspirin was superior to continued ticagrelor and aspirin in the first year post-PCI. This was primarily driven by a reduction in bleeding for patients on clopidogrel versus ticagrelor. Rates of cardiovascular mortality, MI, and stroke were similar between these groups. The data are a reasonably strong signal that de-escalation of therapy at 1 month post-PCI from ticagrelor to clopidogrel is safe and associated with less bleeding and no increase in ischemic events.
However, the data are not fully generalizable to a broad population. All patients were enrolled in South Korea; therefore, the population was not ethnically or internationally diverse. Also, the use of radial access for PCI was only ~50% in this study, which may not reflect local practices. This study does add to the growing body of evidence that de-escalation of antiplatelet therapy at 30-90 days post-PCI may be well tolerated as seen in the TICO (Ticagrelor With or Without Aspirin in Acute Coronary Syndrome After PCI), TWILIGHT-ACS (Ticagrelor Alone vs. Ticagrelor Plus Aspirin Following Percutaneous Coronary Intervention in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes), and HOST-REDUCE-POLYTECH-ACS (Harmonizing Optimal Strategy for Treatment of Coronary Artery Diseases-Comparison of Reduction of Prasugrel Dose or Polymer Technology in ACS Patients) trials.
SAFE-PAD (Safety Assessment of Femoropopliteal Endovascular Treatment With Paclitaxel-Coated Devices)
By Shea Elizabeth Hogan, MD, FACC
Denver Health Medical Center
- Clinical impact of the data. Around the time I graduated from fellowship in 2013, there was an earnest debate in the vascular community about the best way to revascularize PAD in the femoropopliteal segment. Although endovascular intervention was faster and more convenient for patients, many required repeat interventions (sometimes yearly!) for recurrent in-stent restenosis. Paclitaxel drug-coated device development was truly revolutionary because these devices dramatically decrease the risk of in-stent restenosis. Due to proven effectiveness, drug-coated device use skyrocketed globally and was designated first-line therapy for femoropopliteal disease until 2018, when a meta-analysis of randomized clinical trials found increased 2- and 5-year mortality rates in patients treated with these devices compared to patients treated with non-drug-covered devices. This study had immense and immediate consequences, including US Food and Drug Administration (FDA) warnings about device use and reduction of drug-coated device use by 50% in the United States in 2019. These trends were followed by all my local colleagues (and myself, for that matter), who dramatically decreased drug-coated device utilization. And although device use has slowly increased with mounting data questioning the truth of the 2018 meta-analysis, the SAFE-PAD trial is likely the strongest yet to confirm that I can use the best available (drug-coated) therapy for my patients' femoropopliteal disease with less apprehension about increasing their risk of death and with less concern about future malpractice claims.
- Shift in device regulatory decision-making. The FDA is moving to place greater emphasis on observational data in the process of regulatory decision-making. This trial may become a model for future regulatory studies because it used real-world data and was designed with FDA input. Thus, understanding the SAFE-PAD study design may give us a glimpse into the future of FDA device regulation.
Combined ISCHEMIA Trials on Completeness of Revascularization
By Ajay J. Kirtane, MD, FACC
Columbia University Irving Medical Center
New York, NY
The landmark study ISCHEMIA compared with a conservative strategy for the treatment of patients with stable ischemic heart disease in whom left main disease was excluded by coronary computed tomography angiography. Although the trial demonstrated no overall difference in outcomes between the two study arms, a reduction in late events (particularly MI) was observed with the invasive approach, which was offset by periprocedural events. An untested hypothesis was whether a more complete revascularization could be associated with a further reduction in events compared with either incomplete revascularization or conservative therapy alone.
Although less than half of invasively managed patients achieved complete revascularization, overall event rates were lowest among the subset of invasively managed patients who received complete revascularization as adjudicated by the angiographic core laboratory. In an observational (non-randomized) comparison with patients in the conservative arm of the trial, the magnitude of difference in event rates between the invasive arm and the conservative arm was greatest among patients who received complete revascularization. Similarly, quality-of-life improvements were magnified among patients who received complete revascularization in comparison to both patients receiving incomplete revascularization and those treated with a conservative strategy.
Although observational in nature, these data suggest that if revascularization can be performed safely, the greatest benefits may be associated with a more complete revascularization. What is not answered by this analysis is whether there is a minimal degree of revascularization (or threshold) necessary to demonstrate incremental and clinically meaningful differences over a conservative approach alone.
TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention)
By Wayne B. Batchelor, MD, FACC
Virginia Heart/Inova Heart and Vascular Institute
Falls Church, VA
This study reported the extended follow-up of the original TAILOR-PCI trial, which randomized 1,849 patients with CYP2C19 loss of function alleles (*2 or *3) undergoing PCI for stable or unstable CAD to receive genotype-guided P2Y12 oral antiplatelet strategy versus conventional oral antiplatelet therapy. In the first year following PCI, the majority of patients in the genotype-guided strategy (75%) received ticagrelor while the vast majority (97%) of the conventional therapy arm received clopidogrel (each in addition to aspirin). Similar to the original 12-month results, extended follow-up reveled that, after a median follow-up of 39 months, there remained no difference (adjusted hazard ratio of 0.95; p = 0.74) in the occurrence of the primary composite endpoint (cardiovascular death, MI, stroke, stent thrombosis, or severe ischemia) between the 2 groups. Pre-specified subgroup analyses were unremarkable, and there was also no difference seen in major bleeding between the 2 groups. The conclusion from this extended follow-up study is that genotype-guided oral P2Y12 inhibition provides no clinical benefit compared to standard therapy in the setting of PCI for stable or unstable CAD.
This study largely puts to rest concerns about whether to test for CYP2C19 loss of function alleles and whether using this information to tailor antiplatelet therapy post-PCI provides benefit. Not only do the negative study results suggest that testing in this setting is unnecessary, but they also confirm that loss of function alleles do not appear to compromise the efficacy of standard DAPT using aspirin and clopidogrel, at least compared with more potent agents such as ticagrelor. Given the higher cost of genetic testing and ticagrelor and the fact that current guidelines do not support a testing-guided strategy for P2Y12 inhibition, this study is unlikely to impact current practice. Whether a particular subgroup that benefits from genotype-guided therapy will ever be identified remains to be seen.
Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Stable Ischemic Heart Disease, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, EP Basic Science, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and SIHD, Cardiac Surgery and VHD, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Angiography, Nuclear Imaging, Hypertension, Chronic Angina
Keywords: ACC21, ACC Annual Scientific Session, Transcatheter Aortic Valve Replacement, Fibrinolytic Agents, Spironolactone, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Calcium Channel Blockers, Ischemic Attack, Transient, Peripheral Arterial Disease, Aspirin, Blood Pressure, Coronary Artery Disease, Renal Artery, Aortic Valve, Diuretics, Angiotensins, Prevalence, Confidence Intervals, Standard of Care, Calcium Channels, Follow-Up Studies, Brain Ischemia, Stroke, Thrombosis, Myocardial Infarction, Hypertension, Ischemia, Embolism, Lower Extremity, Aortic Valve Stenosis, Aortic Valve Stenosis, Risk Factors, Kidney Diseases, Angiography, Drug Combinations, Hospitals, Insurance Coverage, Anticoagulants, Angiotensin Receptor Antagonists, Venous Thrombosis, Denervation, Tomography, Reference Standards, Vitamin K, Pharmaceutical Preparations, Platelet Aggregation Inhibitors, Acute Coronary Syndrome, Acute Coronary Syndrome, Percutaneous Coronary Intervention, Paclitaxel, United States Food and Drug Administration, Coronary Restenosis, Cardiac Catheterization, Genetic Testing, Genotype, Decision Making, Stents
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