Cardiology

Kristensen, S. L., F. Martinez, P. S. Jhund, J. L. Arango, J. Belohlavek, S. Boytsov, W. Cabrera, E. Gomez, A. A. Hagege, J. Huang, S. Kiatchoosakun, K. S. Kim, I. Mendoza, M. Senni, I. B. Squire, D. Vinereanu, R. C. Wong, J. Gong, M. P. Lefkowitz, A. R. Rizkala, J. L. Rouleau, V. C. Shi, S. D. Solomon, K. Swedberg, M. R. Zile, M. Packer and J. J. McMurray (2016). “Geographic variations in the paradigm-hf heart failure trial.” Eur Heart J: 2016 June [Epub ahead of print].

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AIMS: The globalization of clinical trials has highlighted geographic variations in patient characteristics, event rates, and treatment effects. We investigated these further in PARADIGM-HF, the largest and most globally representative trial in heart failure (HF) to date. METHODS AND RESULTS: We looked at five regions: North America (NA) 622 (8%), Western Europe (WE) 1680 (20%), Central/Eastern Europe/Russia (CEER) 2762 (33%), Latin America (LA) 1413 (17%), and Asia-Pacific (AP) 1487 (18%). Notable differences included: WE patients (mean age 68 years) and NA (65 years) were older than AP (58 years) and LA (63 years) and had more coronary disease; NA and CEER patients had the worst signs, symptoms, and functional status. North American patients were the most likely to have a defibrillating-device (53 vs. 2% AP) and least likely prescribed a mineralocorticoid receptor antagonist (36 vs. 61% LA). Other evidence-based therapies were used most frequently in NA and WE. Rates of the primary composite outcome of cardiovascular (CV) death or HF hospitalization (per 100 patient-years) varied among regions: NA 13.5 (95% CI 11.7-15.6), WE 9.6 (8.6-10.6), CEER 12.3 (11.4-13.2), LA 11.2 (10.0-12.5), and AP 12.5 (11.3-13.8). After adjustment for prognostic variables, relative to NA, the risk of CV death was higher in LA and AP and the risk of HF hospitalization lower in WE. The benefit of sacubitril/valsartan was consistent across regions. CONCLUSION: There were many regional differences in PARADIGM-HF, including in age, symptoms, comorbidity, background therapy, and event-rates, although these did not modify the benefit of sacubitril/valsartan.

Okumura, N., P. S. Jhund, J. Gong, M. P. Lefkowitz, A. R. Rizkala, J. L. Rouleau, V. C. Shi, K. Swedberg, M. R. Zile, S. D. Solomon, M. Packer and J. J. McMurray (2016). “Importance of clinical worsening of heart failure treated in the outpatient setting: Evidence from the prospective comparison of arni with acei to determine impact on global mortality and morbidity in heart failure trial (paradigm-hf).” Circulation 133(23): 2254-2262.

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BACKGROUND: Many episodes of worsening of heart failure (HF) are treated by increasing oral therapy or temporary intravenous treatment in the community or emergency department (ED), without hospital admission. We studied the frequency and prognostic importance of these episodes of worsening in the Prospective Comparison of ARNI (angiotensin-receptor-neprilysin inhibitor) with ACEI (angiotensin-converting enzyme inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF). METHODS AND RESULTS: Outpatient intensification of HF therapy was added to an expanded composite outcome with ED visits, HF hospitalizations, and cardiovascular deaths. In an examination of first nonfatal events, 361 of 8399 patients (4.3%) had outpatient intensification of HF therapy without a subsequent event (ie, ED visit/HF hospitalizations) within 30 days; 78 of 8399 (1.0%) had an ED visit without previous outpatient intensification of HF therapy or a subsequent event within 30 days; and 1107 of 8399 (13.2%) had HF hospitalizations without a preceding event. The risk of death (in comparison with no-event patients) was similar after each manifestation of worsening: outpatient intensification of HF therapy (hazard ratio, 4.8; 95% confidence interval, 3.9-5.9); ED visit (hazard ratio, 4.5; 95% confidence interval, 3.0-6.7); HF hospitalizations (hazard ratio, 5.9; 95% confidence interval, 5.2-6.6). The expanded composite added 14% more events and shortened time to accrual of a fixed number of events. The benefit of sacubitril/valsartan over enalapril was similar to the primary outcome for the expanded composite (hazard ratio, 0.79; 95% confidence interval, 0.73-0.86) and was consistent across the components of the latter. CONCLUSIONS: Focusing only on HF hospitalizations underestimates the frequency of worsening and the serious implications of all manifestations of worsening. For clinical trials conducted in an era of heightened efforts to avoid HF hospitalizations, inclusion of episodes of outpatient treatment intensification (and ED visits) in a composite outcome adds an important number of events and shortens the time taken to accrue a target number of end points in an event-driven trial.

Sherwood, M. and P. A. McCullough (2016). “Chronic kidney disease from screening, detection, and awareness, to prevention.” Lancet Glob Health 4(5): e288-289.

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A critical link exists between awareness of risk, the presence of disease, and steps taken by the patient and clinician to change the natural history of disease. Chronic illnesses such as diabetes mellitus, dyslipidaemia, anaemia and a multitude of endocrinological and rheumatological diseases are relatively silent and rely on the clinical laboratory for diagnosis, particularly in their early stages. Probably no such illness permits such a large loss of organ function before symptoms become present as chronic kidney disease (CKD). 1 Thus, the considerable dependence on the laboratory to establish the diagnosis of CKD is an issue for low-income and middle-income countries (LMIC), where access to in-vitro diagnostics on a screening basis might not be universally available. Even in high-income countries where routine laboratory tests are performed, CKD seems to lag considerably behind diabetes mellitus, hypertension, and cardiovascular disease in terms of patient and clinician awareness. 2 This difference is partly due to the two-dimensional nature of CKD defined as a reduction in estimated glomerular filtration rate (eGFR) and the presence of markers of chronic kidney damage (albuminuria or imaging evidence) over 3 months time. Thus, to have the eGFR and albumin:creatinine ratio at the same time and clearly inform the patient of the potential presence of CKD is complex.

Leon, M. B., C. R. Smith, M. J. Mack, R. R. Makkar, L. G. Svensson, S. K. Kodali, V. H. Thourani, E. M. Tuzcu, D. C. Miller, H. C. Herrmann, D. Doshi, D. J. Cohen, A. D. Pichard, S. Kapadia, T. Dewey, V. Babaliaros, W. Y. Szeto, M. R. Williams, D. Kereiakes, A. Zajarias, K. L. Greason, B. K. Whisenant, R. W. Hodson, J. W. Moses, A. Trento, D. L. Brown, W. F. Fearon, P. Pibarot, R. T. Hahn, W. A. Jaber, W. N. Anderson, M. C. Alu and J. G. Webb (2016). “Transcatheter or surgical aortic-valve replacement in intermediate-risk patients.” N Engl J Med 374(17): 1609-1620.

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BACKGROUND: Previous trials have shown that among high-risk patients with aortic stenosis, survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. We evaluated the two procedures in a randomized trial involving intermediate-risk patients. METHODS: We randomly assigned 2032 intermediate-risk patients with severe aortic stenosis, at 57 centers, to undergo either TAVR or surgical replacement. The primary end point was death from any cause or disabling stroke at 2 years. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, patients were entered into one of two cohorts on the basis of clinical and imaging findings; 76.3% of the patients were included in the transfemoral-access cohort and 23.7% in the transthoracic-access cohort. RESULTS: The rate of death from any cause or disabling stroke was similar in the TAVR group and the surgery group (P=0.001 for noninferiority). At 2 years, the Kaplan-Meier event rates were 19.3% in the TAVR group and 21.1% in the surgery group (hazard ratio in the TAVR group, 0.89; 95% confidence interval [CI], 0.73 to 1.09; P=0.25). In the transfemoral-access cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P=0.05), whereas in the transthoracic-access cohort, outcomes were similar in the two groups. TAVR resulted in larger aortic-valve areas than did surgery and also resulted in lower rates of acute kidney injury, severe bleeding, and new-onset atrial fibrillation; surgery resulted in fewer major vascular complications and less paravalvular aortic regurgitation. CONCLUSIONS: In intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke.

Roberts, W. C., M. Moore, J. M. Ko and B. L. Hamman (2016). “Mitral valve replacement after failed mitral ring insertion with or without leaflet/chordal repair for pure mitral regurgitation.” Am J Cardiol 117(11): 1790-1807.

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Mitral repair operations for correction of pure mitral regurgitation (MR) are generally quite successful. Occasionally, however, the reparative procedure incompletely corrects the MR or the MR recurs. From March 1993 to January 2016, twenty nine patients had mitral valve replacement after the initial mitral repair operation, and observations in them were analyzed. All 29 patients at the repair operation had an annular ring inserted and later (<1 year in 6 and >1 year in 21) mitral valve replacement. The cause of the MR before the repair operation appears to have been prolapse in 16 patients (55%), secondary (functional) in 12 (41%) (ischemic in 5), and infective endocarditis which healed in 1 (3%). At the replacement operation the excised anterior mitral leaflet was thickened in all 29 patients. Some degree of stenosis appeared to have been present in 16 of the 29 patients before the replacement operation, although only 10 had an echocardiographic or hemodynamic recording of a transvalvular gradient; at least 11 patients had restricted motion of the posterior mitral leaflet; 10, ring dehiscence; 2, severe hemolysis; and 2, left ventricular outflow obstruction. In conclusion, there are multiple reasons for valve replacement after earlier mitral repair. Uniformly, at the time of the replacement, the mitral leaflets were thickened by fibrous tissue. Measurement of the area enclosed by the 360 degrees rings and study of the excised leaflet suggest that the ring itself may have contributed to the leaflet scarring and development of some transmitral stenosis.