Important Trial Results for Interventional Cardiology From SCAI and EuroPCR 2018

Introduction
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

The following is a selection of relevant studies presented at this spring's interventional meetings, Congress of the European Association of Percutaneous Coronary Intervention (EuroPCR) 2018 and Society for Cardiovascular Angiography and Interventions (SCAI) 2018 Scientific Sessions, and expert commentary on the results and implications for practice by an outstanding group of contributors. I remain grateful for the excellent insight provided by these experts. Your comments are always appreciated.

Strategies to Reduce Acute Kidney Injury and Improve Clinical Outcomes After Percutaneous Coronary Intervention: A Subgroup analysis of the Prevention of Serious Adverse Events Following Angiography (PRESERVE) Trial
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

The PRESERVE (Prevention of Serious Adverse Events Following Angiography) trial, a multicenter/multinational (including 35 Veterans Administration sites), was presented at the American Heart Association Scientific Sessions 2017. As reported, the primary trial randomized over 4,000 patients in a 2 x 2 factorial-designed trial comparing intravenous (IV) sodium bicarbonate or oral n-acetylcysteine to IV sodium chloride for prevention of contrast-induced nephropathy in patients with chronic kidney disease undergoing diagnostic or interventional contrast procedures. The primary composite endpoint was death, need for dialysis, or persistent renal failure at 90 days. The results showed no significant benefit for the either treatment strategy compared with IV sodium chloride.

However, given the potentially higher renal risk for patients undergoing percutaneous coronary intervention (PCI) because of greater average contrast and often more severe vascular disease and general risk factors such as diabetes, a sub-analysis was performed of the PCI-only subset. These results were presented at the SCAI 2018 Scientific Sessions in May.

In the PCI sub-study, 1,161 patients undergoing PCI were randomly included in 4 patient groups. The percent primary composite endpoint by patient group occurred as follows:

  1. IV sodium bicarbonate = 2.6%
  2. IV sodium chloride = 4.0%
  3. N-acetylcholine = 3.8%
  4. Placebo = 2.8%

These differences were not statistically significant. Thus, despite conflicting results from studies over the years, it seems the benefit of either sodium bicarbonate to alkalize the urine or n-acetylcysteine to reduce free radicals to prevent contrast-associated kidney events in patients with renal risk is non-existent. For now, strategies to prevent contrast-induced nephropathy should continue to emphasize saline hydration and contrast sparing. Sodium bicarbonate and n-acetylcysteine are now relegated to the list of initially hopeful therapies that ultimately failed to show benefit in preventing contrast-related kidney damage. May they rest in peace.

Immunomodulatory Therapy Reduces Atherosclerotic Plaque Burden by Coronary Computed Tomography Angiography in Psoriasis at One-Year
By Antonio Abbate, MD
Virginia Commonwealth University
Richmond, VA

Atherosclerosis is an inflammatory disease,1 and, as such, pro-inflammatory stimuli are expected to promote atherosclerosis and its complication. Until recently, the only proof that inflammation caused atherosclerosis to progress was the indirect evidence that patients with a greater inflammatory burden (systemically or within the plaques) had a worse outcome. Almost exactly 1 year ago, the results of the first large phase III clinical trial, CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), addressing the effects of a targeted anti-inflammatory therapy with canakinumab, an antibody blocking interleukin-1-beta, were presented, showing a significant reduction in recurrent ischemic events with treatment versus placebo.2 The study presented by Youssef Elnabawi at the SCAI 2018 Scientific Sessions confirms the role of anti-inflammatory drugs in the prevention of atherosclerosis progression and expands the finding to a subgroup of patients at increased risk, those affected by systemic inflammation due to psoriasis. Although the study is limited by its retrospective nature and lack of random treatment assignment, the finding of reduced progression of the disease in patients treated with a cytokine blocking therapy (biologic), which was for the most part composed by blockers of the tumor necrosis factor-alpha, is certainly reassuring and promising. These data confirm that systemic inflammation is a modifiable risk factor and suggest that there may be more than one viable strategy to inhibit inflammation. The clinical implications of these findings may be that in the context of a systemic inflammatory disease, like psoriasis, the treatment may be aimed not only at improving symptoms but also at reducing the inflammatory burden. A secondary analysis of the CANTOS trial showed that the so-called responders (those achieving a C reactive protein level <2 mg/l) experienced a large benefit in terms of cardiovascular risk reduction. It is reasonable, therefore, to expect that in other systemic inflammatory conditions also, achieving a laboratory 'remission' may be linked to the most favorable outcomes. This hypothesis, however, requires testing in prospective randomized clinical trials.

The Grey-Zone FFR (GzFFR) Trial (A Randomised Controlled Trial in Stable Intermediate Coronary Lesions and Grey-zone FFR Values With Evaluation of the Diagnostic Utility of Invasive Coronary Physiological Indices and Quantitative Perfusion MRI)
By Gregory J. Dehmer, MD, MACC
The Carilion Clinic & Virginia Tech Carilion School of Medicine
Roanoke, VA

GzFFR (A Trial in Stable Intermediate Coronary Lesions and Grey-zone FFR Values) was a small study (n = 108) performed in patients with single-vessel coronary artery disease who have an intermediate stenosis severity (30-80% diameter narrowing) and a fractional flow reserve (FFR) value between 0.75 and 0.82. Once identified and before treatment, patients underwent stress perfusion magnetic resonance imaging (MRI) to define the presence and extent of myocardial ischemia. Patients were then randomized to optimal medical therapy (OMT) versus PCI with OMT. The primary outcome measure was angina status assessed by the Seattle Angina Questionnaire at 3 months. Secondary outcome measures were major adverse cardiovascular events (death, myocardial infarction [MI], urgent revascularization, and stroke) and total number of antianginal medications at 3 and 12 months after randomization. Compared with OMT alone, PCI plus OMT improved angina frequency and health-related quality of life and reduced myocardial ischemia as assessed by MRI. Results for the secondary outcome measures are unknown at this point, but given the small number of patients studied and the overall low incidence of these events, it seems unlikely that significant differences would be found between groups. In addition to the small number of subjects studied, patients and physicians were not blinded to their treatment, which, admittedly, is difficult to accomplish and lacking from many PCI trials. Although completed in October 2016, the study has not yet been published in a peer-reviewed journal.

The findings of an intermediate stenosis severity coupled with an FFR in the "grey-zone" are not uncommon in a busy invasive practice, so guidance about the best option for treatment in such patients is important. Several non-randomized studies derived from databases of FFR measurements have been published but unfortunately provide mixed recommendations for patients with grey-zone FFR values.3-7 Some studies suggest that PCI can be safely deferred in such patients, whereas others demonstrate improvement in some outcome variables by performing PCI. Until a well-controlled definitive study is performed, clinicians will need to combine their best judgment with patient preference to make treatment decisions in individual patients. Factors such as the severity of symptoms, results of stress testing or stress imaging if available, lesion location and characteristics, myocardium at risk, and comorbid conditions all should be considered when making therapeutic decisions in the grey zone.

The Nationwide Italian SICI-GISE Cross-Sectional ERIS Study
By Lloyd W. Klein, MD, FACC
Gottlieb Memorial Hospital, Loyola University Health System
Melrose Park, IL

Translesional physiologic measurements supplement coronary angiographic appraisal of severity, enhancing the accuracy of diagnosis and optimizing the selection of patients for revascularization and other treatment options.8 Physiological assessment becomes decisive when there is conflicting information among symptoms, ischemic testing, and angiographic anatomy. When applied in intermediate coronary lesions at the time of diagnostic angiography, these tests can help better select optimal coronary revascularization strategy in a high percentage of patients. Yet despite the proven accuracy and utility, clinical studies show that the use of these modalities is limited. National registries suggest its use is 10% or less of cases.

The ERIS (Evolving Routine Standards in Intracoronary Physiology) study describes the current use of invasive coronary physiology assessment and attempts to discern the reasons for its limited use in daily practice. The study was presented as a late-breaking clinical trial at the recent EuroPCR 2018 Congress in Paris and was published in JACC: Cardiovascular Interventions.9

The ERIS study is a prospective study involving 76 Italian catheterization laboratories. Each center had a 60-day window to include consecutive cases that fulfilled criteria of 2 pre-specified subgroups:

  1. The physiology assessment group comprises patients who had operators apply FFR or instantaneous wave-free ratio assessment
  2. The visual estimation group comprises patients who had operators decide not to perform invasive assessment, although the patients met the inclusion and exclusion criteria

The study included 1,858 cases (n = 1,177 in the physiology assessment group; n = 681 in the visual estimation group). Physiology-based guidance was used in 7 and 13% of the total volume of angiographic coronary interventions and PCI, respectively. This low figure, in line with US usage, was found even though use of coronary physiology assessment met the current guideline indications in approximately 50% of cases. The main reason for not using physiology guidance was the operator's confidence that clinical and angiographic data alone were sufficient.

These provocative results are not surprising, but they are concerning because there is no suggestion of a trend to more frequent use of these modalities. That is disturbing in an environment of concern for under- and over-utilization of stenting and the threats of the insurance industry to withhold payment for procedures that they determine are inappropriately performed based on ambiguous criteria. Moreover, functional revascularization holds great promise for improving case selection for bypass surgery and coronary interventions.

To improve quality of care, we must acknowledge the findings of studies that show frequent misclassification of stenosis severity based solely on visual angiographic estimation. In FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation),10 of intermediate severity lesions of 50-70% diameter narrowing, only 35% were hemodynamically significant; in lesions with 71-90% diameter stenosis, for which many operators would perform PCI, 20% were not hemodynamically significant and did not require PCI.

Studies like ERIS allow us to understand how clinical outcomes can be improved and where to employ further educational efforts. FFR improves our ability to judge coronary stenosis severity; optimal contemporary practice is contingent on using this technique correctly to improve outcomes for our patients.

The Abbott Post-Approval Study 1 MitraClip Registry: 1-year Results of the First 2,000 Patients in the Transcatheter Valve Therapy Registry
By Jad Omran, MD
Sulpizio Cardiovascular Center, UC San Diego Health Care System
La Jolla, CA

Several studies have evaluated the safety and efficacy of the MitraClip procedure (Abbott Vascular; Santa Clara, CA) for treatment of symptomatic patients with +3 and +4 mitral regurgitation (MR) and prohibitive surgical risk. EVEREST (Endovascular Valve Edge-to-Edge Repair Study) was a prospective multicenter cohort study that showed an acceptable efficacy in reducing MR severity.11 EVEREST II (Endovascular Valve Edge-to-Edge Repair Study II) was a multicenter randomized trial that compared MitraClip with conventional surgical repair or MV replacement. The MitraClip was less effective than surgical repair due to the increased prevalence of residual MR compared with surgery. However, MitraClip reduced the severity of MR, improved symptoms, and led to reverse left ventricular (LV) remodeling.12 The improvement in New York Heart Association (NYHA) functional class at 1 year was sustained at 4 years. The EVEREST II High Risk Registry and EVERST II REALISM registry had an impressive 30-day mortality of less than 5%, with significant improvement in symptomatic status, reduced rate of hospitalization, and improved LV remodeling at 1 year.13,14

Presented at the SCAI 2018 Scientific Sessions, the post-approval study was a prospective, single-arm, multicenter, observational study evaluating the safety and efficacy of MitraClip in real-world setting. Data were extracted from the first 2,000 MitraClip patients consecutively entered into the Transcatheter Valve Therapy Registry, which is housed jointly by the American College of Cardiology Foundation and the Society for Thoracic Surgeons. Study primary endpoints evaluated at 30 days and 1 year included all-cause mortality, stroke, MR severity with LV end-diastolic volume and LV internal diameter at end diastole, NYHA functional class, and heart failure (HF)-related hospitalizations (at 1 year only). Additional outcomes included 6-Minute Walk Test distance and Kansas City Cardiomyopathy Questionnaire quality of life.

The mean age was 79, and 43% of patients were female. Mean Society for Thoracic Surgeons MV replacement score was 10.9. At 1 year, 86.6% of patients had post-procedural MR of 2+, and there was 81.7% freedom from all-cause mortality. Measurements of the LV by echocardiogram showed improvement in LV end-diastolic volume and LV internal diameter at end diastole with 8.5 ml and 0.2 cm mean reduction, respectively. Clinical measures at 1 year show mean improvement of 37.9 m in the 6-Minute Walk Test, 30-point increase in the Kansas City Cardiomyopathy Questionnaire quality-of-life scale, and 83.4% improvement with NYHA I/II at 1 year. The HF-related hospitalization was 0.09 per patient per year. In a multivariable logistic regression analysis, predictors for 1-year composite death or HF included residual MR >+2, moderate to severe tricuspid regurgitation, and NYHA III/IV at baseline.

The current study has important clinical implications. It is reflective of real-world experience, with MitraClip procedure proving its safety and feasibility as an alternative therapy for severe MR in patients with prohibitive surgical risk. The reported improvement in LV remodeling at 1 year correlates with outcomes of prior studies, emphasizing the benefit of MR intervention. Improvement in symptoms and quality of life are important gains because symptomatic status served as a trigger for the intervention. Predictors of composite death or HF were important aspects of this study that echo prior data and help identifying patients with higher risk for readmission.

Nevertheless, the study does have limitations. As in any registry study, data are subjected to reporting bias. The lack of comparative group is something worthy of mention. Moreover, echocardiographic variables were site reported and not assessed by a core laboratory, particularly MR etiology and the severity grade. The mean procedure time was relatively long (186 min), which could be attributed to early experience with the procedure and the learning curve. Finally, outcomes based on MR etiology were not reported (degenerative versus functional MR), although the forthcoming COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial will address outcomes of MitraClip in functional MR adequately.

The MitraClip XTR System (Abbott Vascular; Santa Clara, CA) represents the new generation of MitraClip that recently gained US Food and Drug Administration approval. It features advanced navigation, steering, and position capabilities for operators to navigate through difficult anatomies. Would these capabilities translate into better clinical outcomes? That question has yet to be answered.

RADIANCE-HTN SOLO and SPYRAL HTN-ON MED: Hope or Hype for Renal Denervation for Hypertension
By Robert D. Safian, MD, FACC
Center for Innovation & Research in Cardiovascular Diseases, Beaumont Health
Royal Oak, MI

During the recent EuroPCR 2018 Congress meeting in Paris, two late-breaking presentations shed additional light on catheter-based renal denervation for hypertension; both were published in the June 19, 2018, issue of The Lancet.15,16 The SPYRAL HTN-ON MED (Investigation of Catheter-Based Renal Denervation in Patients With Uncontrolled Hypertension in the Presence of Antihypertensive Medications) trial was a single-blind sham-control study of the first 80 patients with refractory hypertension (defined as office systolic blood pressure [BP] 150-180 mmHg and diastolic BP ≥90 mmHg) despite stable doses of 1-3 antihypertensive medications who were randomly assigned to invasive renal denervation with a newly designed multielectrode radiofrequency ablation catheter (n = 38) or sham control with invasive renal angiography without denervation (n = 42).15 The primary endpoint was the change in ambulatory BP at 6 months, and drug surveillance was used to assess medication compliance.

The principal findings of this study were that compared with baseline measurements, there were statistically significant declines in all BP measurements at 6 months (systolic and diastolic, ambulatory and office) (absolute decline in ambulatory systolic BP was 9 mmHg, p < 0.0001) in the denervation group. There was no change in any BP measurements in control patients, and there were no major adverse events in any patients; 60% of patients were compliant with medication.

RADIANCE-HTN SOLO (A Study of the ReCor Medical Paradise System in Clinical Hypertension) was a single-blind sham-control study of 146 patients with persistent hypertension (defined as ambulatory BP 135/85-170/105 mmHg) after 4-week discontinuation of ≤2 antihypertensive medications who were randomly assigned to invasive renal denervation with a unique ultrasound ablation catheter (n = 74) or sham control with invasive renal angiography without denervation (n = 72).16 The primary endpoint was the change in daytime ambulatory systolic BP at 2 months (off medication, unless predefined endpoints were met). The principal findings of this study were that the reduction in daytime ambulatory systolic BP was greater after renal denervation (-8.5 mmHg) than after control procedure (-2.2 mmHg) (absolute difference in systolic BP was -6.3 mmHg, p = 0.0001) and that there were no major adverse events in any patients. Hypertension was "cured" (ambulatory BP <135/85 mmHg on no medication) in 20% and 3% of denervation and control patients, respectively (p = 0.001).

Together, these 2 trials confirm the safety and short-term hypertension benefits (using ambulatory BP measurements obtained 2-6 months after treatment) for renal denervation (using 2 different denervation techniques) in 2 different patient populations (refractory hypertension on medication and moderate hypertension off medication) using well-designed randomized clinical trials compared with sham controls. These studies also suggest that better understanding of the distribution of renal sympathetic nerves coupled with better devices to achieve denervation have led to improved results.

Accordingly, there is renewed hope that renal denervation may indeed have a therapeutic role in hypertension management. Nevertheless, this optimism should be cautious for many reasons. First, these two studies included a total of 226 patients followed for 2-6 months, so they should be considered within the context of "proof-of-principle"; definitive trials with larger sample sizes and long-term follow-up are essential. Second, although not specifically reported in these trials, there is widespread acknowledgment of the frequency of non-responders to renal denervation (perhaps 25-30% of patients). Third, it is very disconcerting that there is no reliable method for immediate assessment of renal sympathetic nerve activity, which adds uncertainty to appropriate patient selection and assessment of hypertension outcome, particularly when confounded by the high likelihood of non-responders and poor medication compliance. Fourth, the absolute reduction in ambulatory BP after denervation is relatively small. I am not minimizing the importance of even small declines in BP as a surrogate for major clinical outcomes, but we must study clinical outcomes (death, stroke, MI, HF, and renal failure), either as primary endpoints of larger clinical trials or as recorded outcomes in large clinical registries. Finally, there are other potential applications of renal denervation (chronic kidney disease, HF, atrial fibrillation, etc.) that will require study apart from hypertension. Personally, these trials have renewed my enthusiasm for renal denervation and provide further support for cardiologists as being among the most data-driven practitioners in medicine.

References

  1. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999;340:115-26.
  2. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017;377:1119-31.
  3. Kang DY, Ahn JM, Lee CH, et al. Deferred vs. performed revascularization for coronary stenosis with grey-zone fractional flow reserve values: data from the IRIS-FFR registry. Eur Heart J 2018;39:1610-9.
  4. Adjedj J, De Bruyne B, Floré V, et al. Significance of Intermediate Values of Fractional Flow Reserve in Patients With Coronary Artery Disease. Circulation 2016;133:502-8.
  5. Agarwal SK, Kasula S, Edupuganti MM, et al. Clinical Decision-Making for the Hemodynamic "Gray Zone" (FFR 0.75-0.80) and Long-Term Outcomes. J Invasive Cardiol 2017;29:371-6.
  6. Courtis J, Rodés-Cabau J, Larose E, et al. Comparison of medical treatment and coronary revascularization in patients with moderate coronary lesions and borderline fractional flow reserve measurements. Catheter Cardiovasc Interv 2008;71:541-8.
  7. Lindstaedt M, Halilcavusogullari Y, Yazar A, et al. Clinical outcome following conservative vs revascularization therapy in patients with stable coronary artery disease and borderline fractional flow reserve measurements. Clin Cardiol 2010;33:77-83.
  8. Lotfi A, Davies JE, Fearon WF, Grines CL, Kern MJ, Klein LW. Focused update of expert consensus statement: Use of invasive assessments of coronary physiology and structure: A position statement of the society of cardiac angiography and interventions. Catheter Cardiovasc Interv 2018;Jul 3:[Epub ahead of print].
  9. Tebaldi M, Biscaglia S, Fineschi M, et al. Evolving Routine Standards in Invasive Hemodynamic Assessment of Coronary Stenosis: The Nationwide Italian SICI-GISE Cross-Sectional ERIS Study. JACC Cardiovasc Interv 2018;11:1482-91.
  10. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360:213-24.
  11. Feldman T, Kar S, Rinaldi M, et al. Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort. J Am Coll Cardiol 2009;54:686-94.
  12. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395-406.
  13. Glower DD, Kar S, Trento A, et al. Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study. J Am Coll Cardiol 2014;64:172-81.
  14. Sharma RP, Makar M, Kar S. An Overview of the Mitraclip Procedure: Indications, Procedural Characteristics, and Clinical Outcomes. J Struct Heart Dis 2015;1:127-36.
  15. Kandzari DE, Böhm M, Mahfoud F, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet 2018;391:2346-55.
  16. Azizi M, Schmieder RE, Mahfoud F, et al. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet 2018;391:2335-45.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Structural Heart Disease, Angiography, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Nuclear Imaging, Hypertension, Mitral Regurgitation

Keywords: Acetylcholine, Acetylcysteine, Acute Kidney Injury, American Heart Association, Angina Pectoris, Angiography, Antibodies, Monoclonal, Antihypertensive Agents, Atherosclerosis, Atrial Fibrillation, Biological Products, Blood Pressure, Cardiovascular Diseases, Cardiomyopathies, Catheter Ablation, Catheterization, Coronary Angiography, Constriction, Pathologic, Coronary Artery Disease, Coronary Stenosis, C-Reactive Protein, Cross-Sectional Studies, Denervation, Diabetes Mellitus, Diastole, Echocardiography, Follow-Up Studies, Free Radicals, Heart Failure, Hypertension, Immunomodulation, Incidence, Inflammation, Interleukin-1beta, Kidney, Logistic Models, Magnetic Resonance Angiography, Medication Adherence, Mitral Valve Insufficiency, Myocardial Infarction, Myocardium, Outcome Assessment (Health Care), Patient Preference, Patient Readmission, Patient Selection, Percutaneous Coronary Intervention, Plaque, Atherosclerotic, Prevalence, Prospective Studies, Psoriasis, Quality of Life, Quercus, Random Allocation, Registries, Renal Dialysis, Renal Insufficiency, Renal Insufficiency, Chronic, Retrospective Studies, Risk Factors, Sample Size, Single-Blind Method, Sodium Bicarbonate, Sodium Chloride, Stroke, Surgeons, Thrombosis, Tricuspid Valve Insufficiency, Tumor Necrosis Factor-alpha, United States Department of Veterans Affairs, United States Food and Drug Administration


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