Important Interventional Trials From EuroPCR 2020
EuroPCR 2020, the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, was virtual but provided an extensive variety of interventional and structural scientific updates. Below are summaries of some of the interesting presentations. Please note the "Quick Takes" included for each trial to serve as a reference to the important points. As always, thanks to our contributors.
Renal Denervation: 3-Year Follow-Up
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
- The Global SYMPLICITY Registry assessed the acute and longitudinal effects of renal denervation for uncontrolled hypertension or other conditions associated with increased sympathetic activity in over 2,500 patients followed up to 3 years.
- Significant, durable, and clinically meaningful reductions in office and 24-hour blood pressure (BP) measurements persisted out to 3 years regardless of extent of baseline medications.
- A safety analysis demonstrated a 0.3% risk of developing >70% renal artery stenosis with other safety endpoints, consistent with a hypertensive population.
Renal artery denervation has experienced a resurgence of interest based on trial design modifications, evolving catheter and energy source technology, and encouraging results from longer-term studies demonstrating persistent benefit. The Global SYMPLICITY Registry is a real-world registry of >2,860 patients with uncontrolled hypertensive or other conditions associated with increased sympathetic activity. Three-year follow-up was assessed in 2,530 patients. The baseline cohort included 2,747 patients followed to 6 months with 2,231 patients treated with Symplicity Flex (Medtronic; Minneapolis, MN) and 516 treated with the Symplicity Spyral (Medtronic; Minneapolis, MN). The population mean age was 61 ± 12 (standard deviation), and 57.9% were male. Pretreatment mean office systolic BP was 166 ± 25 with mean 24-hour systolic BP 155 ± 18. Patients were on a mean 4.6 ± 1.4 of antihypertension medication classes prior to denervation. Follow-up systolic office and 24-hour measurements were significantly lower compared to baseline with no deterioration in efficacy in 3-year follow-up. Furthermore, effectiveness was not dependent on numbers of initial drug therapy, and no increase in overall antihypertensive use occurred over follow-up.
Regarding complications, only 0.3% of patients developed renal artery stenosis >70%. Other cardiovascular complications were consistent with those expected for an older, hypertensive population.
Although it is a registry, this trial is useful in documenting real-world results in a significantly hypertensive population despite on average 4 or more antihypertensive medications with a low risk of complications and, importantly, continued clinical efficacy out to 3 years. Additional studies are needed to define the ideal and effective populations for this therapy, but a technology that reduces average office systolic BP with a mean of 164 by an average of 16% over 3 years (~25 mmHg) appears to have potential to improve BP control. Furthermore, given the multitude of limits to medical BP treatment, including drug side effects and frequent non-compliance leading to a high proportion of incompletely treated hypertensive patients, the potential opportunity for renal denervation therapy is extensive.
TRILUMINATE Trial of Percutaneous Tricuspid Valve Repair for Regurgitation
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
- Tricuspid regurgitation (TR) is a clinically important disease with increasing mortality as the disease progresses.
- The TRILUMINATE (Evaluation of Treatment With Abbott Transcatheter Clip Repair System in Patients With Moderate or Greater Tricuspid Regurgitation) trial enrolled 85 patients for TriClip system (Abbott Structural Heart; Santa Clara, CA) repair, which demonstrated a low procedure risk with improved clinical outcomes; 87% of patients had a persistent reduction in at least 1 TR grade at 1 year.
- Other clinical benefits included a 40% reduction in hospitalizations compared to the year before treatment.
TR is a frequent clinical problem that is often secondary to other cardiac conditions and associated with a progressive risk of recurrent hospitalization and mortality as severity increases. The TRILUMINATE trial assessed the efficacy of the percutaneous TriClip system for treatment of significant and symptomatic TR. The study was single arm, assessing the 1-year results for 85 treated patients from 21 sites in the United States and Europe with moderate to severe TR. At 1 year, 71% of patients had a continued 2 grade reduction, 16%, had a 1 grade reduction in TR, and only 13% had no grade change at 1 year. Overall, 87.1% of patients had at least a 1-grade, sustained reduction in TR.
Overall 1-year adverse events were low, with only 6 (7%) major adverse events. In addition to improved clinical symptoms, the recurrent hospitalization rate was significantly reduced by 40% (p = 0.0030) compared to the year before treatment. Other complications included frequent bleeding (10 patients) but no device embolization.
Physiological changes in cardiac structure occurred and persisted for the year of follow-up, including a significant reduction in right ventricular end diastolic diameter as well as a significant reduction in right atrial volume. Right ventricular function also improved based on progressive increases in tricuspid annular plane systolic excursion (considered the most sensitive measure of right ventricular function) over 1-year follow-up.
These data are intriguing and hopeful. The tricuspid has often been referred to as the "forgotten" valve, but indeed outcomes are related to the integrity of the valve and likely right ventricular function. Although this study is small in number and experience, it is encouraging that therapies including this one that address severe TR can be useful adjuncts for improving clinical outcomes in patients with severe TR.
DEFINITION II Trial: Stenting Techniques for Complex Bifurcation Lesions
By Tanveer Rab, MD, FACC
Emory University School of Medicine
- A prospective definition of complex bifurcation lesions including left main (LM) and non-LM lesions was validated as a useful criterion.
- Two-stent versus provisional stent procedures provided significantly better outcomes driven by a lower risk of late myocardial infarction (MI) for the predominantly double-kissing (DK) crush group, reaffirming a consistent finding from prior studies.
The DEFINITION II (Two-Stent vs. Provisional Stenting Techniques for Patients With Complex Coronary Bifurcation Lesions) trial was presented at EuroPCR 2020 and published in the European Heart Journal in June 2020.1 The study validated that lesion complexity of bifurcation lesions as described in the DEFINITION criteria2 (Figure 1) was best treated with two stents and strengthened the evidence for the DK crush technique.
The trial was an international multicenter study of 653 patients with complex coronary bifurcation lesions (both LM and non-LM) treated with a provisional versus a two-stent strategy, with 77.8% of these lesions treated with the DK crush technique.
The primary outcome, target-lesion failure (which included cardiac death, target vessel MI, and clinically driven target lesion revascularization) occurred in 11.4% of the provisional group and 6.1% in the two-stent group at 1 year (hazard ratio [HR] 0.52; 95% confidence interval [CI], 0.3-0.9). At 1 year, there were no differences in cardiac death (provisional = 2.5%; two-stent = 2.1%; HR 0.86; 95% CI, 0.31-2.37), all-cause death (provisional = 3.4%; two-stent = 2.7%; p = 0.629), or deﬁnite stent thrombosis (0.9% in both groups; p = 0.982). A higher incidence of MI occurred in the provisional group (7.1 % vs. 3.0%; p = 0.025), which requires further evaluation.
The results from this trial would suggest that for complex bifurcation lesions, systemic two-stent techniques provide better outcomes, and the DK crush technique continues its validation through multiple trials as the superior approach for these lesions. Furthermore, a universal definition of bifurcation lesion complexity was validated by this study.
CABG and PCI in Patients With CTO and Multivessel Disease
By Rahman Shah, MD, FACC
Alabama College of Osteopathic Medicine
Panama City, FL
- In patients with multivessel coronary artery disease (CAD) and chronic total occlusion (CTO), coronary artery bypass grafting (CABG) is associated with lower risk of the composite outcome (death, MI, stroke) and mortality at 5 years compared to percutaneous coronary intervention (PCI).
- However, if complete revascularization can be obtained via PCI and result in a residual SYNTAX score <8, then PCI and CABG might be associated with comparable outcomes at 5 years.
Traditionally, CABG has been the preferred revascularization strategy in patients with multivessel CAD and CTO. However, with improvements in technology for PCI for CTO recanalization, complication rates have decreased, and up to 90% success rates have been achieved at centers experienced with this procedure. Therefore, PCI has recently emerged as an alternative method of revascularization for these patients. Unfortunately, a high-quality randomized controlled trial comparing PCI with CABG for safety and efficacy has not been performed for those with CTO and multivessel CAD.
At EuroPCR 2020, Dr. Xu reported the 5-year outcomes of PCI versus CABG in a large cohort of patients with CTO and multivessel CAD enrolled at Fuwai hospital in China between 2010 and 2013. Of the 4,324 patients, 2,060 underwent PCI; the remainder underwent CABG. The primary outcome was major adverse cardiac event (MACE) rate (the composite rates for death, MI, and stroke) at 5 years. Results showed that across the entire cohort, PCI was associated with an increased risk of MACE and mortality at 5 years compared to CABG. Additionally, the PCI group was separated into subgroups based on residual SYNTAX score. Using those with residual SYNTAX score <8, PCI was comparable to CABG in the rates for MACE (adjusted HR 0.94; 95% CI, 0.71-1.17), all-cause mortality (adjusted HR 0.94; 95% CI, 0.64-1.38), and cardiac mortality (adjusted HR 0.58; 95% CI, 0.29-1.15) but showed a lower risk of stroke (adjusted HR 0.42; 95% CI, 0.22-0.78) and a greater risk of nonfatal MI (adjusted HR 3.29; 95% CI, 1.94-5.59). Using those with residual SYNTAX score >8, PCI was associated with a greater risk of MACE (adjusted HR 1.58; 95% CI, 1.31-1.92), all-cause mortality (adjusted HR 1.36; 95% CI, 1.04-1.78), cardiac mortality (adjusted HR 2.41; 95% CI, 1.71-3.41), and MI (adjusted HR 9.53; 95% CI, 6.38-14.23) but a lower risk of stroke (adjusted HR 0.34; 95% CI, 0.20-0.58).
The major strengths of this study were its large sample size and data from a real-world population. However, because of its observational nature, its study patients were not randomized to specific revascularization strategies; the treating physicians assigned the specific revascularization strategy for each patient, possibly introducing significant selection bias. An inverse probability of treatment weighting method could be used to adjust for this and other potential confounders (as done by the authors). But no matter how aggressive the model, it will never eliminate all potentially unmeasured confounders and other biases.
In conclusion, these registry data from 4,324 patients seem to suggest that for those with multivessel CAD including CTO, CABG is the preferred revascularization strategy given its association with improved mortality and composite outcomes at 5 years compared to PCI. However, if complete revascularization is obtained with PCI (residual SYNTAX score <8), the two might offer comparable outcomes at 5 years. Thus, based on these data, an experienced operator could consider PCI a potential alterative to CABG in patients with multivessel disease and CTO when there is a high likelihood of complete revascularization and a lower residual SYNTAX score. Because of the observational nature of these data, these findings should be interpreted with caution, and this study should be considered as hypothesis-testing rather than confirmatory. The definite answer to this important clinical issue can be answered only by performing well-conducted randomized trials.
ON-TIME 3 Trial Assessing Opioids in STEMI
By David Cox, MD, FACC
Brookwood Baptist Health
- Platelet inhibitory effects of oral P2Y12-receptor antagonists are delayed in patients with ST-segment elevation MI (STEMI) undergoing PCI due to delayed gastrointestinal absorption and potentially compounded by opioids, which slow gastrointestinal absorption.
- The ON-TIME 3 (The Effect of Opioids on P2Y12 Receptor Inhibition in Patients With ST-Elevation Myocardial Infarction Who Are Pre-treated With Crushed Ticagrelor) trial assessed platelet inhibition in acute STEMI comparing intravenous (IV) fentanyl versus IV acetaminophen in patients pretreated with crushed ticagrelor, aspirin, and heparin.
- The results demonstrated similar pain relief and significantly higher levels of ticagrelor with an insignificant trend toward lowered platelet reactivity unit levels.
The ON-TIME 3 trial was presented at EuroPCR 2020 and explored whether IV acetaminophen versus IV fentanyl can optimize platelet inhibition in STEMI. A total of 194 patients with STEMI was pretreated with crushed ticagrelor, aspirin, and heparin and then randomized to IV acetaminophen or fentanyl. An insignificant trend was seen in platelet reactivity units in favor of acetaminophen, significantly higher levels of ticagrelor were noted in the acetaminophen arm, and similar pain reduction was noted between the two drugs.
The trial was done well, and the results are intriguing. Most of us recall the now-famous pictures of clopidogrel tablets resting quietly in the stomach during primary PCI. We have all dealt with IV opioids causing patients to have nausea and vomiting, often losing their oral intake of pills and making the operator wonder if adequate platelet inhibition exists after emesis. So in terms of measuring ticagrelor levels at 1-3 hours, IV acetaminophen wins. But by about 7 hours, the differences melt away, and we never see any statistical difference in platelet reactivity units.
Other concerns exist. The cost of IV acetaminophen is substantial and needs to be weighed against the cost of opioids at your institution. Secondly, the correlation between ticagrelor levels and clinical outcomes remains unproven. These data would explain stent thrombosis in the first 7 hours but not so much after that.
The ON-TIME 3 trial does give us some important data for thought, and it is reassuring that pain control is equivalent. Of course, the amazing reality is that acute stent thrombosis in primary PCI is a rare event even when most operators simply use dual antiplatelet therapy and an anticoagulanttechnique matters! I doubt we will ever see a large randomized controlled trial comparing IV acetaminophen to opioids in STEMI, but these data suggest it may be a reasonable option for clinicians to consider.
CLASP Study of Transcatheter Repair on Patients With MR
By Jad Omran, MD
Sharp Health Care
San Diego, CA
- The CLASP study (The CLASP Study Edwards PASCAL TrAnScatheter Mitral Valve RePair System Study) is a single arm, multicenter trial of 109 patients with clinically and functionally severe mitral regurgitation (MR) (2/3 functional; 1/3 degenerative) treated with PASCAL (Edwards Lifesciences; Irvine, CA), a transseptal, edge-to-edge mitral repair device.
- One-year results show 92% survival with 88% freedom from heart failure hospitalization. MR was ≤1+ in 82% of patients and ≤2+ in 100% of patients; 88% of patients were New York Heart Association (NYHA) Class I/II.
The recent advances of the structural heart field prompted the introduction of various new technologies for percutaneous therapies of MR. The PASCAL mitral valve repair system is one of the new emerging devices in this field. It uses an edge-to-edge repair technique with transseptal approach. This device received its CE mark in February 2019. The 1-year outcomes of the CLASP study were presented at EuroPCR 2020.
The CLASP study was a single-arm multicenter study that included 62 patients who were 18 years and older with symptomatic 3+ or 4+ MR as confirmed by echocardiography and NYHA functional class more than II who were symptomatic despite optimal medical therapy. Patients were excluded if their mitral valve area was <4.0 cm2, their left ventricular ejection fraction was <20%, they had right-sided heart failure or evidence of right ventricular dysfunction, or they had life expectancy <12 months. At 30 days, The PASCAL repair system showed feasibility and acceptable safety in the treatment of severe MR. This was accompanied by clinically and statistically significant improvements in functional status, exercise capacity, and quality of life.3 The 6-month outcomes of the CLASP study were presented the Heart Failure Society of America Scientific Meeting. The PASCAL repair system was associated with high rates of freedom from mortality (94%) and heart failure hospitalization (89%) as well as significant reduction in MR severity.4
Primary endpoints included procedural success, clinical success, and major adverse event rate at 1 year. A total of 109 patients was treated (67% had functional MR; 33% had degenerative MR), mean age was 75.5 years, and 57% were NYHA Class III/IV. At 1 year, Kaplan-Meier survival was 92% with 88% freedom from heart failure hospitalization. MR was ≤1+ in 82% of patients, and MR was ≤2+ in 100% of patients; 88% of patients were NYHA Class I/II, and Kansas City Cardiomyopathy Questionnaire score improved 14 points (p < 0.001).5
The current results at 1 year line up with outcomes we saw at 1 and 6 months that indicate the high survival and low complication rates, low rates of heart failure hospitalization, sustainability in MR reduction over time, and the improvement of the functional status and quality of life. However, this study was limited by the small sample size, lack of some quantitative echocardiographic measurements for MR, and the lack of detailed medical therapy. Despite this, the current study represents a huge milestone in percutaneous mitral valve therapies and adds to the tools available for MR treatment. The CLASP IID/IIF (Edwards PASCAL CLASP IID/IIF Pivotal Clinical Trial) trial is an ongoing prospective multicenter randomized controlled trial that aims to establish the safety and effectiveness of the PASCAL mitral repair system compared to MitraClip (Abbott Vascular; Abbott Park, IL) in patients with MR who have been determined to be at prohibitive risk for mitral valve surgery.6
Routine Revascularization Versus Medical Therapy for SIHD: A Systematic Review and Meta-Analysis of Randomized Trials
By Alina M. Robert, MD, MPH, FACC
St. Luke's Idaho Cardiology Associates
- Results of a meta-analysis of 14 trials (including contemporary stent trials) comparing revascularization versus initial medical therapy are generally consistent with results from ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches).
- Specific results of the meta-analysis demonstrate that over a mean 4.5 years of follow-up, routine revascularization compared to medical therapy provides similar survival, reduced unstable angina, increased freedom from angina, and reduced non-procedural MI but increased procedural MI.
Bangalore and colleagues aimed to address remaining concerns following the recently published ISCHEMIA trial, which demonstrated no significant differences in survival and key cardiovascular outcomes between PCI and standard medical therapy in patients with moderate-severe stable ischemic heart disease (SIHD) without severe left ventricular systolic dysfunction (left ventricular ejection fraction ≥35%). In this meta-analysis, results were compiled and analyzed from 14 randomized studies evaluating outcomes in patients with SIHD undergoing revascularization versus medical therapy. An influence analysis was performed to ensure no single study significantly affected the summary effects. This meta-analysis confirms that routine revascularization versus initial medical therapy in patients with SIHD does not result in reduction of risk of death (risk ratio [RR] 0.99; 95% CI, 0.90-1.09), cardiovascular death (RR 0.92; 95% CI, 0.80-1.06), or overall MI (RR 0.93; 95% CI, 0.83-1.03). However, revascularization was favored with reduction in non-procedural MI (RR 0.76; 95% CI, 0.67-0.85) and unstable angina (RR 0.64; 95% CI, 0.45-0.92) driven by contemporary stent trials but at the cost of increased risk of periprocedural MI (RR 2.48; 95% CI, 1.86-3.31). No difference was demonstrated in the risk of stroke and heart failure, with improvement in freedom from angina. Notably, 31.9% of patients in the medical therapy group underwent revascularization during the mean 4.5 years of follow-up, which may reduce the differences between the 2 groups. The results of this meta-analysis are important to clinical practice because the study includes contemporary-era trials including 14,877 patients with a total of 64,678 patient-years of follow-up, providing robust statistical power to assess mortality risk. These results inform bedside decision-making discussions regarding treatment options as well as future guideline updates for management of SIHD.
- Zhang JJ, Ye F, Xu K, et al. Multicentre, randomized comparison of two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: the DEFINITION II trial. Eur Heart J 2020;41:2523-36.
- Chen SL, Sheiban I, Xu B, et al. Impact of the complexity of bifurcation lesions treated with drug-eluting stents: the DEFINITION study (Definitions and impact of complEx biFurcation lesIons on clinical outcomes after percutaNeous coronary IntervenTIOn using drug-eluting steNts). JACC Cardiovasc Interv 2014;7:1266-76.
- Lim DS, Kar S, Spargias K, et al. Transcatheter Valve Repair for Patients With Mitral Regurgitation: 30-Day Results of the CLASP Study. JACC Cardiovasc Interv 2019;12:1369-78.
- Mazimba S, et al. Abstract 014. Presented at: Heart Failure Society of America Annual Scientific Meeting; Sept. 13-16, 2019; Philadelphia, PA.
- Webb J. Six-month and one-year outcomes for transcatheter repair in patients with mitral regurgitation from the CLASP study (PCRonline.com website). Available at: https://www.pcronline.com/Cases-resources-images/Resources/Course-videos-slides/2020/Hot-lines-on-Mitral-interventions-part-1. Accessed July 15, 2020.
- Edwards PASCAL CLASP IID/IIF Pivotal Clinical Trial (CLASP IID/IIF) (ClinicalTrials.gov website). June 5, 2020. Available at https://clinicaltrials.gov/ct2/show/NCT03706833. Accessed July 15, 2020.
Keywords: Coronary Angiography, Antihypertensive Agents, Blood Pressure, Ventricular Function, Right, Tricuspid Valve Insufficiency, Renal Artery Obstruction, Renal Artery, Incidence, Prospective Studies, Confidence Intervals, Follow-Up Studies, Myocardial Infarction, Hypertension, Tricuspid Valve, Treatment Outcome, Percutaneous Coronary Intervention, Purinergic P2Y Receptor Antagonists, Platelet Aggregation Inhibitors, Coronary Artery Disease, ST Elevation Myocardial Infarction, Aspirin, Analgesics, Opioid, Systole, Acetaminophen, Fentanyl, Heparin, Anticoagulants, Mitral Valve, Sample Size, Mitral Valve Insufficiency, Ventricular Dysfunction, Right, Odds Ratio, Stroke Volume, Life Expectancy, Quality of Life, Feasibility Studies, Exercise Tolerance
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