ESC 2017: Trials on Valvular Heart Disease

1. Effect of Sildenafil on Clinical Outcomes in Patients with Corrected Valvular Heart Disease and Residual Pulmonary Hypertension: The Sildenafil for Improving Outcomes after Valvular Correction (SIOVAC) Trial

Presented by Javier Bermejo, MD

Key Question

Does chronic treatment with sildenafil improve clinical outcomes in patients with residual pulmonary hypertension after successfully corrected valvular heart disease?

Characteristics

  • Academically funded, multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial conducted in 18 tertiary public hospitals in Spain.
  • Enrollment criteria: Patients who underwent successful valve replacement or repair procedure (aortic, mitral, or tricuspid) at least 1 year prior to inclusion + within 1 month had invasively measured mean pulmonary artery pressure ≥30 mm Hg.
  • Patients were randomized 1:1 to oral sildenafil (40 mg 3 times daily) or to placebo for 6 months.
  • Clinical assessment, echocardiography, cardiac magnetic resonance imaging (CMRI), B-type natriuretic peptide (BNP), and 6-minute walking test were done pre-randomization and at 3 and 6 months post-randomization.
  • Primary outcome: composite clinical score of all-cause mortality, heart failure (HF) admission, change in World Health Organization functional class, and patient global self-assessment. This composite classified patients' outcome into improved, worsened, or unchanged.
  • Secondary outcomes: the clinical composite score adjusted for baseline covariables, the time to major cardiac events (cardiac death or HF hospitalization), and number of HF admissions.
  • Intention to treat analysis.

Key Findings

  • A total of 200 patients was randomized (median age 72 years, 77% women): 104 in the sildenafil arm and 96 in the placebo arm.
  • In each arm, 85 patients completed the study.
  • Respectively, 91%, 39%, 45%, 61%, and 31% of patients had undergone mitral valve surgery, tricuspid valve surgery, aortic valve surgery, combined valvular surgery, and reintervention.
  • Baseline hemodynamics: median pulmonary capillary pressure = 22 mm Hg, mean pulmonary artery pressure = 38 mm Hg, and pulmonary vascular resistance = 3.3 Wood units.
  • Outcomes:
    • At 6 months, 33% of Sildenafil group versus 15% of placebo group had worsened composite clinical score (odds ratio for improvement 0.39, 95% confidence interval [CI] 0.22, 0.67). Findings persisted in the per-protocol analysis and after multivariate adjustment.
    • Two patients in the Sildenafil group versus 1 in the placebo group died due to HF (p = 0.63).
    • There were earlier and more major adverse cardiac events in the Sildenafil group (hazard ratio [HR] 2.0, 95% CI 1.0, 4.0) driven by HF events in the Sildenafil group.
    • No significant differences between groups in the change from baseline in functional capacity, 6-minute walk distance, or BNP levels.
    • Echocardiography-derived systolic pulmonary artery pressure was 64 ± 13 mm Hg in the Sildenafil group at baseline and 64 ± 15 mm Hg at 6 months post-randomization. In the placebo group, systolic pulmonary artery pressure was 64 ± 18 mm Hg at baseline and 65 ± 18 at 6 months post-randomization.
    • Extensive sub-group analyses did not reveal any clinical or hemodynamic sub-groups that benefitted from Sildenafil.

Implications

  • Treatment with sildenafil with 40 mg 3 times daily in the described cohort led to unfavorable outcomes compared with placebo.
  • Further studies are needed to investigate whether these findings are generalizable to patients with valve disease prior to surgical correction and whether other pulmonary vasodilators would yield similar findings.

2. Leaflet Thrombosis Following Transcatheter Aortic Valve Replacement: Insights from the MAUDE Database

Presented by Ankur Karla, MD

Key Question

Does clinical leaflet thrombosis in transcatheter aortic valve replacement (TAVR) have significance beyond peri-TAVR stroke or transient ischemic attack (TIA)?

Characteristics

  • Data obtained from the 2012-2015 MAUDE (Manufacturer and User Facility Device Experience) database submitted to the Food and Drug Administration.
  • MAUDE database searched for all entries with an identifier indicating a TAVR-related adverse event.
  • Selected entries were then searched for "leaflet," "central aortic regurgitation," and "aortic stenosis."
  • Exclusion criteria: absence of "leaflet" term, procedure-related complications, and unknown/other entries.
  • Definition of a leaflet thrombosis event:
    • Presence of acute- or subacute-onset HF or stroke/TIA symptoms with one of the following:
      • Direct visualization of leaflet thrombosis on echocardiogram, or increase in mean gradient >10 mm Hg with no thrombus visible, or regression of elevated mean gradient after oral anticoagulation therapy
      • Presence of reduced leaflet motion or hypoattenuated leaflet thickening on computed tomography angiogram
      • Evidence of device thrombosis at autopsy or via examination of tissue during reoperation
    • Timing: acute (0-3 days), subacute (3 days to 3 months), late (3 months to 1 year), and very late (>1 year).
    • Outcomes: stroke or TIA, cardiogenic shock (vasopressor or mechanical circulatory support), and death from any cause.

Key Findings

  • The database had 5,691 TAVR-related adverse events.
  • There were 156 adverse events that met study methods, which were classified into leaflet restriction (n = 129) and leaflet malcoaptation (n = 27).
    • Leaflet thrombosis occurred in 30 cases (29 in leaflet restriction, 1 in leaflet malcoaptation). Of those 30 events, 20 events occurred in Edwards SAPIEN valves (Edwards Lifesciences; Irvine, CA) and 10 events occurred in Medtronic CoreValve (Medtronic, Inc.; Minneapolis, MN) valves.
    • Out of 30, 18 (60%) occurred within 1 year.
    • Presentation: aortic stenosis (53.3%), aortic regurgitation (23.3%), both (13.3%), and stroke/TIA (10%).
    • Outcomes: stroke/TIA (10%), cardiogenic shock (6.7%), and death (30%).
    • Interventions to address leaflet thrombosis: Antiplatelet/anticoagulant (26.7%), valve-in-valve TAVR (10%), and surgery (46.7%).

Implications

  • Although not common, clinical leaflet thrombosis is a serious event with significant implications that often require re-intervention. The majority of events occurred within 1 year of TAVR implantation.
  • This study does not examine the incidence of subclinical leaflet thrombosis and its association with valve degeneration that takes longer to manifest clinically.
  • A randomized clinical trial is needed to assess whether post-TAVR anticoagulation is superior to standard of care with antiplatelet therapy.
  • Whether newer generation valves have fewer incidences of clinical and subclinical leaflet thrombosis is yet to be defined.

3. Myocardial Scar Predicts Mortality in Severe Aortic Stenosis: Data from the BSCMR Valve Consortium

Presented by Thomas Treibel, MBBS

Key Question

Are parameters of left ventricular (LV) adaptation (hypertrophy, dilatation, impairment, and scar) incremental predictors of mortality after valve intervention in aortic stenosis?

Characteristics

  • Longitudinal observational outcome study between 2003 and 2015 at 6 surgical centers in the United Kingdom. Patients with severe AS who underwent surgical aortic valve replacement (SAVR) or TAVR had echocardiography and CMRI.
  • Exclusion criteria: pregnancy, breastfeeding, estimated glomerular filtration rate <30 mL/min/1·73 m2, CMRI non-conditional devices.
  • Scar was defined by the presence of late gadolinium enhancement (LGE).
  • LGE was adjudicated by two blinded reviewers and quantified by the full-width half-maximum method.
  • Primary outcome: all-cause mortality. Secondary outcome: cardiovascular mortality.

Key Findings

  • A total of 703 patients was enrolled, mean age 73 ± 11 years, 63% male, mean aortic valve gradient 49 ± 16 mm Hg.
  • Scar was present in 51% (17% infarct pattern, 34% non-infarct pattern).
  • Management: 400 underwent SAVR, 275 underwent TAVR, and 28 underwent medical.
  • All-cause mortality: 166 (24%) at a median of 3.6 years (52 post-SAVR, 93 post-TAVR, 21 medical).
  • Presence of LV scar increased all-cause mortality (28.7% vs. 14.5%, p < 0.001) and cardiovascular mortality (16.6% vs. 6.4%, p < 0.001) irrespective of infarct pattern or management.
  • Quantitatively, for every 1% increase in scar burden, there was 10% increase in all-cause mortality and 9% increase in cardiovascular mortality.
  • Predictors of all-cause mortality: age (HR 1.07, p < 0.001), scar presence (HR 2.13, p = 0.003), and female sex (HR 1.69, p = 0.018).

Implications

  • Presence of LV scar portends worse prognosis irrespective of pattern or etiology. However, unknown and unmeasured confounders might have affected the results. Thus, a randomized trial is needed to test whether early intervention to pre-empt scar development and/or progression is beneficial.
  • Further investigation is required to determine whether LV scar should be part of pre-intervention risk assessment for patients undergoing aortic valve replacement.

4. Delayed Pacemaker Requirement After TAVR With Sapien 3: How Long Should We Monitor?

Presented by F. De Torres Alba, MD

Key Questions

How long do patients remain at risk to develop conduction abnormalities requiring permanent pacemaker (PPM) implantation after TAVR? How long should patients be monitored post-TAVR for conduction abnormalities?

Characteristics

  • Inclusion: All patients undergoing TAVR with an Edwards SAPIEN 3 valve (Edwards Lifesciences; Irvine, CA) excluding patients with prior PPM and valve-in-valve procedures. All patients had 7 days of continuous electrocardiogram telemetry monitoring.
  • Decision to implant PPM was left to the discretion of the treating team.

Key Findings

  • Of the 606 patients who met the inclusion criteria, 76 (12.4%) underwent in-hospital PPM implantation.
  • There were no statistical differences in baseline clinical or procedural characteristics between those who received versus those who did not receive a PPM.
  • Of all patients, 36% had baseline pre-TAVR conduction abnormalities, none with an indication for a PPM pre-TAVR. The two most common conduction abnormalities at baseline were first degree atrioventricular block and left bundle branch block.
  • Of all patients, 36% developed new conduction abnormalities (most common left bundle branch block and third degree atrioventricular block), but only 76 patients (12.4%) had high-grade conduction abnormalities and received PPM.
  • Of the 76 patients who underwent PPM implantation, 88% of them had a Class I indication.
  • Timing of conduction abnormalities leading to PPM implantation: intraprocedural (n = 35), day 1 (n = 17), day 2 (n = 7), days 3-7 (n = 17 or 21% of PPM implantations).
  • Of the 17 patients with late onset (days 3-7) conduction abnormalities, 7 patients had no baseline conduction abnormalities, and 4 patients had no baseline or new (within 48 hours) conduction abnormalities.

Implications

  • The authors suggest that these findings support continuous electrocardiogram telemetry monitoring for 7 days post-valve implantation for native severe aortic valve stenosis.
  • The safety and effectiveness of ambulatory continuous rhythm monitoring for all patients post-TAVR should be tested in clinical trials.

Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Pulmonary Hypertension and Venous Thromboembolism, Valvular Heart Disease, Aortic Surgery, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Pulmonary Hypertension, Interventions and Structural Heart Disease

Keywords: ESC Congress, ESC2017, Hypertension, Pulmonary, Heart Valve Diseases, Transcatheter Aortic Valve Replacement, Thrombosis, Heart Valve Prosthesis, Cicatrix, Aortic Valve Stenosis, Myocardium, Heart Valve Prosthesis Implantation


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