Cardiology

Dangas, G. D., J. G. P. Tijssen, J. Wohrle, L. Sondergaard, M. Gilard, H. Mollmann, R. R. Makkar, H. C. Herrmann, G. Giustino, S. Baldus, O. De Backer, A. H. C. Guimaraes, L. Gullestad, A. Kini, D. von Lewinski, M. Mack, R. Moreno, U. Schafer, J. Seeger, D. Tchetche, K. Thomitzek, M. Valgimigli, P. Vranckx, R. C. Welsh, P. Wildgoose, A. A. Volkl, A. Zazula, R. G. M. van Amsterdam, R. Mehran and S. Windecker (2019). “A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement.” New England Journal of Medicine Nov 16. [Epub ahead of print].

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BACKGROUND: Whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear. METHODS: We randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns. RESULTS: After a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53). CONCLUSIONS: In patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.).

Al-Bawardy, R., S. Vemulapalli, V. H. Thourani, M. Mack, D. Dai, A. Stebbins, I. Palacios, I. Inglessis, R. Sakhuja, E. Ben-Assa, J. J. Passeri, J. P. Dal-Bianco, E. Yucel, S. Melnitchouk, G. J. Vlahakes, A. S. Jassar and S. Elmariah (2019). “Association of Pulmonary Hypertension With Clinical Outcomes of Transcatheter Mitral Valve Repair.” JAMA Cardiol Nov 20. [Epub ahead of print].

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Importance: Pulmonary hypertension (pHTN) is associated with increased risk of mortality after mitral valve surgery for mitral regurgitation. However, its association with clinical outcomes in patients undergoing transcatheter mitral valve repair (TMVr) with a commercially available system (MitraClip) is unknown. Objective: To assess the association of pHTN with readmissions for heart failure and 1-year all-cause mortality after TMVr. Design, Setting, and Participants: This retrospective cohort study analyzed 4071 patients who underwent TMVr with the MitraClip system from November 4, 2013, through March 31, 2017, across 232 US sites in the Society of Thoracic Surgery/American College of Cardiology Transcatheter Valve Therapy registry. Patients were stratified into the following 4 groups based on invasive mean pulmonary arterial pressure (mPAP): 1103 with no pHTN (mPAP, <25 mm Hg [group 1]); 1399 with mild pHTN (mPAP, 25-34 mm Hg [group 2]); 1011 with moderate pHTN (mPAP, 35-44 mm Hg [group 3]); and 558 with severe pHTN (mPAP, >/=45 mm Hg [group 4]). Data were analyzed from November 4, 2013, through March 31, 2017. Interventions: Patients were stratified into groups before TMVr, and clinical outcomes were assessed at 1 year after intervention. Main Outcomes and Measures: Primary end point was a composite of 1-year mortality and readmissions for heart failure. Secondary end points were 30-day and 1-year mortality and readmissions for heart failure. Linkage to Centers for Medicare & Medicaid Services administrative claims was performed to assess 1-year outcomes in 2381 patients. Results: Among the 4071 patients included in the analysis, the median age was 81 years (interquartile range, 73-86 years); 1885 (46.3%) were women and 2186 (53.7%) were men. The composite rate of 1-year mortality and readmissions for heart failure was 33.6% (95% CI, 31.6%-35.7%), which was higher in those with pHTN (27.8% [95% CI, 24.2%-31.5%] in group 1, 32.4% [95% CI, 29.0%-35.8%] in group 2, 36.0% [95% CI, 31.8%-40.2%] in group 3, and 45.2% [95% CI, 39.1%-51.0%] in group 4; P < .001). Similarly, 1-year mortality (16.3% [95% CI, 13.4%-19.5%] in group 1, 19.8% [95% CI, 17.0%-22.8%] in group 2, 22.4% [95% CI, 18.8%-26.1%] in group 3, and 27.8% [95% CI, 22.6%-33.3%] in group 4; P < .001) increased across pHTN groups. The association of pHTN with mortality persisted despite multivariable adjustment (hazard ratio per 5-mm Hg mPAP increase, 1.05; 95% CI, 1.01-1.09; P = .02). Conclusions and Relevance: These findings suggest that pHTN is associated with increased mortality and readmission for heart failure in patients undergoing TMVr using the MitraClip system for severe mitral regurgitation. Further efforts are needed to determine whether earlier intervention before pHTN develops will improve clinical outcomes.

Vaduganathan, M., B. L. Claggett, A. S. Desai, S. D. Anker, S. V. Perrone, S. Janssens, D. Milicic, J. L. Arango, M. Packer, V. C. Shi, M. P. Lefkowitz, J. J. V. McMurray and S. D. Solomon (2019). “Prior Heart Failure Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan Compared with Valsartan in HFpEF.” J Am Coll Cardiol Nov 6. [Epub ahead of print].

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BACKGROUND: The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death. OBJECTIVES: To determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to HF hospitalization among patients with HF and preserved ejection fraction (HFpEF). METHODS: In this post hoc analysis of PARAGON-HF, we assessed risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (>/=45%). Primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed using a semiparametric proportional rates method, stratified by geographic region. RESULTS: Of 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31-90 days, 435 (9%) within 91-180 days, 694 (14%) after 180 days, and 2,490 (52%) were never previously hospitalized. Over median 35 months follow-up, risk of total HF hospitalizations and cardiovascular death was inversely and non-linearly associated with timing from prior HF hospitalization (P<0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio 0.73; 95% confidence interval 0.53-0.99) to patients never hospitalized (rate ratio 1.00; 95% confidence interval 0.80-1.24); trend in relative risk reduction Pinteraction=0.15. With valsartan alone, rate of total primary events was 26.7 (180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (180 days or who were never hospitalized; trend in absolute risk reduction Pinteraction=0.050. CONCLUSIONS: Recent hospitalization for HFpEF identifies patients at high-risk for near-term clinical progression. In the PARAGON-HF trial, relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrants prospective validation.

Squiers, J., H. Baumgarten, G. Filardo, D. Sass, B. Pollock, J. Edgerton, R. Marcel, J. M. DiMaio and R. L. Smith (2019). “Prospective Evaluation of a Blood Transfusion Protocol for Patients Undergoing Cardiac Surgery.” Ann Thorac Surg Nov 23. [Epub ahead of print].

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BACKGROUND: The Society of Thoracic Surgeons clinical practice guidelines recommend the creation of an interdisciplinary blood management team to implement protocols for improved blood transfusion practices. We report our center’s prospective evaluation of a blood transfusion protocol. METHODS: An interdisciplinary blood management team developed protocols for transfusion of packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate. The protocols were prospectively evaluated by tracking transfusions administered to consecutive patients undergoing cardiac surgery, and the primary outcome of interest was the mean number of adjusted units of blood product transfused per patient. Protocol implementation phases were separated by washout phases to control for a potential Hawthorne effect associated with protocol implementation. Protocol compliance was also assessed. RESULTS: A total of 1441 patients underwent cardiac surgery during the 16-month study period. Although there was no statistically significant reduction in transfusions with an unadjusted analysis, there was a significant trend towards reduction of mean adjusted total units transfused per patient over the course of the study period (p<0.001). The mean adjusted total units transfused per patient were significantly less during the second washout phase (2.8 units, 95%CI 2.3-3.3) and second protocol phase (2.8 units, 95%CI 2.32-3.27) as compared to the initial baseline survey phase (3.6 units, 95%CI 3.1-4.1; p<0.05 for both comparisons). Only 55.2% of all units were transfused in compliance to the implemented protocols: platelets (46.8%), cryoprecipitate (32.1%), packed red blood cells (60.7%), and fresh frozen plasma (53.6%). CONCLUSIONS: During a prospective evaluation of blood transfusion protocols, a risk-adjusted analysis demonstrated a reduction in transfusions despite poor protocol compliance.

Solomon, S. D., M. Vaduganathan, B. L. Claggett, M. Packer, M. Zile, K. Swedberg, J. Rouleau, M. A. Pfeffer, A. Desai, L. H. Lund, L. Koeber, I. Anand, N. K. Sweitzer, G. Linssen, B. Merkely, J. L. Arango, D. Vinereanu, C. H. Chen, M. Senni, A. Sibulo, S. Boytsov, V. Shi, A. Rizkala, M. Lefkowitz and J. J. V. McMurray (2019). “Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure.” Circulation Nov 17. [Epub ahead of print].

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Background: While disease modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin- system (RAS) inhibitor alone in two similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. Methods: We combined data from PARADIGM-HF (LVEF eligibility/=45%; n=4,796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories:22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality and non-cardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. Results: Among 13,195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of non-cardiovascular death, among patients in the highest vs. lowest groups. Overall sacubitril/valsartan was superior to RAS inhibition for first cardiovascular death or heart failure hospitalization (HR 0.84, 95% CI 0.78, 0.90), cardiovascular death (HR 0.84, 95% CI 0.76, 0.92), heart failure hospitalization (HR 0.84, 95% CI 0.77, 0.91), and all-cause mortality (HR 0.88, 95% CI 0.81, 0.96). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction p=0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. Conclusions:The therapeutic effects of sacubitril/valsartan, compared with a RAS inhibitor alone, vary by LVEF, with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. Clinical Trial Registration: NCT01920711. PARADIGM-HF Unique Identifier: NCT01035255.