José Silva-Cardoso

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

Background— Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results— We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74–0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52–0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro–B-type natriuretic peptide and troponin) versus enalapril. Conclusions— Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Direct Comparison of Cardiac Magnetic Resonance and Multidetector Computed Tomography Stress-Rest Perfusion Imaging for Detection of Coronary Artery Disease

OBJECTIVES This study sought to compare the diagnostic performance of a multidetector computed tomography (MDCT) integrated protocol (IP) including coronary angiography (CTA) and stress-rest perfusion (CTP) with cardiac magnetic resonance myocardial perfusion imaging (CMR-Perf) for detection of functionally significant coronary artery disease (CAD). BACKGROUND MDCT stress-rest perfusion methods were recently described as adjunctive tools to improve CTA accuracy for detection of functionally significant CAD. However, only a few studies compared these MDCT-IP with other clinically validated perfusion techniques like CMR-Perf. Furthermore, CTP has never been validated against the invasive reference standard, fractional flow reserve (FFR), in patients with suspected CAD. METHODS 101 symptomatic patients with suspected CAD (62 ± 8.0 years, 67% males) and intermediate/high pre-test probability underwent MDCT, CMR and invasive coronary angiography. Functionally significant CAD was defined by the presence of occlusive/subocclusive stenoses or FFR measurements ≤ 0.80 in vessels >2mm. RESULTS On a patient-based model, the MDCT-IP had a sensitivity, specificity, positive and negative predictive values of 89%, 83%, 80% and 90%, respectively (global accuracy 85%). These results were closely related with those achieved by CMR-Perf: 89%, 88%, 85% and 91%, respectively (global accuracy 88%). When comparing test accuracies using noninferiority analysis, differences greater than 11% in favour of CMR-Perf can be confidently excluded. CONCLUSIONS MDCT protocols integrating CTA and stress-rest perfusion detect functionally significant CAD with similar accuracy as CMR-Perf. Both approaches yield a very good accuracy. Integration of CTP and CTA improves MDCT performance for the detection of relevant CAD in intermediate to high pre-test probability populations.

Distribution and Risk Profile of Paroxysmal, Persistent, and Permanent Atrial Fibrillation in Routine Clinical Practice: Insight from the RealiseAF International Registry

Background— There is a paucity of international data on the various types of atrial fibrillation (AF) outside the highly selected populations from randomized trials. This study aimed to describe patient characteristics, risk factors, comorbidities, symptoms, management strategy, and control of different types of AF in real-life practice. Methods and Results— Real-life global survey evaluating patients with atrial fibrillation (RealiseAF) was a contemporary, large-scale, cross-sectional international survey of patients with AF who had ≥1 episode in the past 12 months. Investigators were randomly selected to avoid bias. Among 9816 eligible patients from 831 sites in 26 countries, 2606 (26.5%) had paroxysmal, 2341 (23.8%) had persistent, and 4869 (49.6%) had permanent AF. As AF progressed from paroxysmal to persistent and permanent forms, the prevalence of comorbidities, such as heart failure (32.9%, 44.3%, and 55.6%), coronary artery disease (30.0%, 32.9%, and 34.3%), cerebrovascular disease (11.7%, 10.8%, and 17.6%), and valvular disease (16.7%, 21.2%, and 35.8%), increased, and the prevalence of lone AF decreased. Similarly, there was an increase in mean CHADS2 [cardiac failure, hypertension, age, diabetes, stroke (doubled)] score (1.7, 1.8, and 2.2), and more than half of patients (51.0%, 56.7%, and 67.3%) qualified for oral anticoagulants. Almost 90% of patients received ≥1 antiarrhythmic drug, but >60% had European Heart Rhythm Association symptom scores from II to IV. Furthermore, 40.7% of persistent and 49.8% of permanent AF patients were still in AF with a heart rate >80 beats per minute. Conclusions— This survey disclosed high cardiovascular risks and an unmet need in daily practice for patients with any type of AF, especially those with the permanent form.

Clinical picture and risk prediction of short-term mortality in cardiogenic shock

The aim of this study was to investigate the clinical picture and outcome of cardiogenic shock and to develop a risk prediction score for short‐term mortality.

A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure

Aims Although active-controlled trials with renin–angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos. Methods and results We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15–39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27–48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16–45%; P < 0.0001) for cardiovascular death, 46% (33–56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11–39%; P < 0.0001) for all-cause mortality. Conclusion These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.

Cardiac magnetic resonance myocardial perfusion imaging for detection of functionally significant obstructive coronary artery disease: A prospective study

BACKGROUND Cardiac magnetic resonance myocardial perfusion imaging (CMR-MPI) is considered a state of the art non-invasive modality for the detection of reversible ischemia. Recent studies have shown its utility in the diagnosis of coronary artery disease (CAD) and superiority over other established techniques. However, only a few studies compared CMR-MPI against the invasive standard including fractional flow reserve (FFR) and clinical validation in non-specialized centers is scarce. The aim of this study was to validate CMR-MPI in a real-world clinical environment and to test its diagnostic accuracy in symptomatic patients with suspected CAD versus FFR as the reference standard of functionally significant disease. METHODS AND RESULTS 103 symptomatic consecutive patients (62 ± 8.0 years, 66% males) with suspected CAD and intermediate or high probability of disease underwent sequential CMR and invasive coronary angiography (XA). The CMR protocol included stress-rest adenosine perfusion, SSFP cine imaging and late-enhancement imaging. Functionally significant CAD was defined as occlusive/sub-occlusive stenoses on XA or non-occlusive stenoses with a FFR measurement of <0.80 in vessels >2mm. On a patient-based model, CMR-MPI had sensitivity, specificity, positive and negative predictive values of 89%, 88%, 85%, and 91%, respectively, with a global accuracy of 88%. On a vessel-based analysis, these values were 80%, 93%, 79% and 94%, respectively, with a global accuracy of 90%. CONCLUSIONS CMR-MPI had a very high accuracy for detection of functionally significant CAD as assessed by FFR in patients with intermediate to high pretest probability.

Additive Value of Magnetic Resonance Coronary Angiography in a Comprehensive Cardiac Magnetic Resonance Stress-Rest Protocol for Detection of Functionally Significant Coronary Artery Disease A Pilot Study

Background— Cardiovascular magnetic resonance (CMR) myocardial perfusion imaging (MPI) is a state-of-the-art noninvasive modality for detection of myocardial ischemia and coronary artery disease. Magnetic resonance coronary angiography (MRCA) allows visualization of the coronary tree, but its incremental value as part of a CMR protocol including MPI and late gadolinium enhancement (LGE) is not well established. We aimed to evaluate the additive diagnostic value of a 3-dimensional whole-heart MRCA integration into a 1.5T CMR-MPI/LGE protocol for the detection of functionally significant coronary artery disease. Methods and Results— Forty-three symptomatic patients (61±8.3 years; 65% men) with suspected coronary artery disease and intermediate/high-pretest probability underwent CMR (including CMR-MPI, MRCA, and LGE) and x-ray invasive coronary angiography (XA) with fractional flow reserve evaluation. Diagnostic performances of MRCA, CMR-MPI/LGE, and MRCA+CMR-MPI/LGE integration were determined having XA+fractional flow reserve as standard for coronary artery disease (≥90% stenosis/occlusion or fractional flow reserve⩽0.80 in vessels>2 mm). MRCA inclusion into the CMR protocol was associated with a mean increase of 7.9±4.69 (0–17.7) minutes in total examination duration (14%). On patient-based analysis, MRCA had 96% sensitivity, 68% specificity, positive predictive value of 79%, and negative predictive value of 93%. CMR-MPI/LGE had 79% sensitivity, 95% specificity, positive predictive value of 95%, and negative predictive value of 78%. Integration of MRCA with CMR-MPI/LGE further improved CMR performance to 96% sensitivity, 89% specificity, positive predictive value of 92%, and negative predictive value of 94%, with a global accuracy of 93%. Conclusions— In this intermediate/high-pretest population, integration of noncontrast-enhanced whole-heart MRCA nonsignificantly improved per-patient diagnostic accuracy of a comprehensive 1.5-T stress-rest CMR-MPI/LGE protocol at a cost of longer scanning times.

Incremental value of adenosine stress cardiac magnetic resonance in coronary artery disease detection

INTRODUCTION Cardiac magnetic resonance myocardial perfusion imaging (CMR-MPI) is considered a state-of-the-art non-invasive modality for ischemia detection but its additive value in a multiple-test strategy in patients with suspected coronary artery disease (CAD) is not fully validated. We aimed to evaluate CMR-MPI integration with exercise treadmill test (ETT) for the diagnostic workup of patients with suspected CAD, having invasive fractional flow reserve (FFR) as reference standard. METHODS In this prospective single-center study, patients with suspected CAD underwent sequential ETT, CMR-MPI and X-ray invasive coronary angiography (XA). Significant CAD was defined by the presence of stenosis >40% with FFR ≤ 0.8 in vessels >2 mm or ≥90% stenosis/occlusion. RESULTS 80 symptomatic patients (68% male, 61 ± 8 years) were enrolled. Compared to ETT, CMR-MPI showed similar sensitivity (81%) and higher specificity (93 vs. 58%, p < 0.001) for CAD detection (prevalence = 46%) translating into better diagnostic performance (AUC 0.87 vs. 0.70; p = 0.002). CMR-MPI improved accuracy independently of ETT in all patients with high pre-test probability and in intermediate-probability patients but those with a clearly positive-ETT (symptoms + ST-shift), in whom ETT correctly identified CAD. In the low-probability group CMR-MPI was useful as a gatekeeper for XA after a positive-ETT. The best integrating protocol achieved a global accuracy of 89% (AUC 0.88) and was clearly superior to an approach based solely in ETT (AUC 0.70, p < 0.001), yet similar to isolated CMR-MPI (AUC 0.87, p = ns). CONCLUSIONS CMR-MPI has high sensitivity and specificity for CAD detection and may be combined with ETT in a diagnostic workflow aiming to increase accuracy and reduce the number of unnecessary catheterizations.

Telemonitoring in heart failure: A state-of-the-art review

Heart failure is associated with high costs which are mainly the result of recurrent hospital admissions. New strategies to detect early decompensation and prevent heart failure-related hospitalizations and reduce total health care costs are needed. Telemonitoring is a novel tool based on the use of recent communication technologies to monitor simple clinical variables, in order to enable early detection of heart failure decompensation, providing an opportunity to prevent hospitalization. From conventional telemonitoring to more recent strategies using implantable cardiac devices or implantable hemodynamic monitors, the subject is under active investigation. Despite the beneficial effects reported by meta-analyses of small non-controlled studies, major randomized controlled trials have failed to demonstrate a positive impact of this strategy. Additionally, evidence regarding the value of newer monitoring devices is somewhat contradictory, as some studies show benefits in prognosis which are not confirmed by others. This paper provides an overview of the existing evidence on telemonitoring in heart failure and a comprehensive state-of-the-art discussion on this topic.

Predictors of Myocardial Dysfunction in Human Immunodeficiency Virus-Infected Patients

BACKGROUND Some of the most frequent manifestations of heart involvement in human immunodeficiency virus (HIV) infection include right and left ventricular dysfunction. The pathogenesis remains obscure. METHODS AND RESULTS This prospective clinical and echocardiographic study involved 181 patients at all stages of HIV infection. We tested a set of clinical variables using a backward logistic regression model to assess their ability to independently predict the presence of ventricular dysfunction. The presence of pulmonary infections (all etiologies mixed) was the only variable independently associated with isolated right ventricular dysfunction (odds ratio = 4.08; P = .02). Signs suggestive of pulmonary arterial hypertension were present in 71% of the patients with right ventricular dilation. History of previous opportunistic infections (all etiologies mixed) (odds ratio = 10.9; P = .0026) and time since the diagnosis of acquired immunodeficiency syndrome more than 12 months (odds ratio = 6.6; P = .03) were the only two independent predictors of left ventricular dysfunction. CONCLUSIONS Isolated right ventricular dysfunction may be secondary to pulmonary hypertension caused by repetitive pulmonary infections and not to primary myocardial disease. The aggressive treatment of opportunistic infections may become an important element of heart failure prophylaxis in HIV infection because they may be associated with left ventricular dysfunction.