Dabigatran versus warfarin in patients with mechanical heart valves.

BACKGROUND: Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves. METHODS: In this phase 2 dose-validation study, we studied two populations of patients: those who had undergone aortic- or mitral-valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier. Patients were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin. The selection of the initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter. The warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk. The primary end point was the trough plasma level of dabigatran. RESULTS: The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding. CONCLUSIONS: The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.).

Perindopril and ß-blocker for the prevention of cardiac events and mortality in stable coronary artery disease patients: A EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) subanalysis.

BACKGROUND: ß-Blockers relieve angina/ischemia in stable coronary artery disease (CAD), and angiotensin-converting enzyme inhibitors prevent CAD outcomes. In EUROPA, the angiotensin-converting enzyme inhibitor perindopril reduced cardiovascular outcomes in low-risk stable CAD patients over 4.2 years. This post hoc analysis examined whether the addition of perindopril to ß-blocker in EUROPA had additional benefits on outcomes compared with standard therapy including ß-blocker. METHODS: EUROPA was a multicenter, double-blind, placebo-controlled, randomized trial in patients with documented stable CAD. Randomized EUROPA patients who received ß-blocker at baseline were identified, and the effect on cardiovascular outcomes of adding perindopril or placebo was analyzed. Endpoints were the same as those in EUROPA. RESULTS: At baseline, 62% (n = 7534 [3789 on perindopril and 3745 on placebo]) received ß-blocker. Treatment with perindopril/ß-blocker reduced the relative risk of the primary end point (cardiovascular death, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 24% compared with placebo/ß-blocker (HR, 0.76; 95% CI, 0.64-0.91; P = .002). Addition of perindopril also reduced fatal or nonfatal myocardial infarction by 28% (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and hospitalization for heart failure by 45% (HR, 0.55; 95% CI, 0.33-0.93; P = .025). Serious adverse drug reactions were rare in both groups, and cardiovascular death and hospitalizations occurred less often with perindopril/ß-blocker. CONCLUSIONS: The addition of perindopril to ß-blocker in stable CAD patients was safe and resulted in reductions in cardiovascular outcomes and mortality compared with standard therapy including ß-blocker.

Risk stratification for sudden cardiac death: current status and challenges for the future.

Sudden cardiac death (SCD) remains a daunting problem. It is a major public health issue for several reasons: from its prevalence (20% of total mortality in the industrialized world) to the devastating psycho-social impact on society and on the families of victims often still in their prime, and it represents a challenge for medicine, and especially for cardiology. This text summarizes the discussions and opinions of a group of investigators with a long-standing interest in this field. We addressed the occurrence of SCD in individuals apparently healthy, in patients with heart disease and mild or severe cardiac dysfunction, and in those with genetically based arrhythmic diseases. Recognizing the need for more accurate registries of the global and regional distribution of SCD in these different categories, we focused on the assessment of risk for SCD in these four groups, looking at the significance of alterations in cardiac function, of signs of electrical instability identified by ECG abnormalities or by autonomic tests, and of the progressive impact of genetic screening. Special attention was given to the identification of areas of research more or less likely to provide useful information, and thereby more or less suitable for the investment of time and of research funds.

Genetic variation and gender determine bradykinin type 1 receptor responses in human tissue: implications for the ACE-inhibitor-induced effects in patients with coronary artery disease.

The efficacy of the ACE (angiotensin-converting enzyme) inhibitor perindopril in coronary artery disease [EUROPA (European trial on reduction of cardiac events with perindopril in stable coronary artery disease) study] is associated with the rs12050217 A/G single nucleotide polymorphism in the B1 receptor (bradykinin type 1 receptor) gene. To investigate the underlying mechanism, we examined the effect of this polymorphism on B1-receptor-mediated coronary artery dilation and peripheral blood mononuclear cell activation. Vasorelaxant responses of human coronary microarteries from subjects without coronary disease to des-Arg(9)-bradykinin and to bradykinin were studied in organ bath experiments. Des-Arg9-bradykinin responses were endothelium-dependent and exclusively mediated by B1 receptors, whereas responses to bradykinin were induced through B2 receptors (bradykinin type 2 receptors). The presence of the G allele reduced the response to 3 × 10(-8) mol/l des-Arg(9)-bradykinin by 29% [AA (n=13) compared with AG/GG (n=8); P<0.03], and tended to lower concentration-related responses (P=0.065) to this agonist, whereas the responses to bradykinin were unaffected by the rs12050217 genotype. In freshly obtained human mononuclear cells 1 µmol/l des-Arg(9)-bradykinin increased expression of the pro-inflammatory factors CXCL5 (CXC chemokine ligand 5) and IL6 (interleukin-6). These responses were not affected by genotype and exclusively occurred in blood cells from women, correlating (in the case of CXCL5) with their plasma 17ß-oestradiol levels (r(2)=0.32, P=0.02; n=17). IL-1ß (interleukin-1ß) increased CXCL5 and IL6 expression in both genders, and this response was not associated with 17ß-oestradiol levels. The gender difference in responses to B1 receptor stimulation in blood mononuclear cells implies possible gender differences in the response to ACE inhibitor therapy, which needs to be studied more comprehensively. The observed decrease in coronary vasodilator response might contribute to the impaired treatment response to perindopril of G allele carriers found in the EUROPA study.

A systematic review on pharmacogenetics in cardiovascular disease: is it ready for clinical application?

Pharmacogenetics is the search for heritable genetic polymorphisms that influence responses to drug therapy. The most important application of pharmacogenetics is to guide choosing agents with the greatest potential of efficacy and smallest risk of adverse drug reactions. Many studies focusing on drug-gene interactions have been published in recent years, some of which led to adaptation of FDA recommendations, indicating that we are on the verge of the clinical application of genetic information in drug therapy. This systematic review provides a comprehensive overview of the current knowledge on pharmacogenetics of all major drug classes currently used in the treatment of cardiovascular diseases.

The prevalence of early repolarization in patients with noncompaction cardiomyopathy presenting with malignant ventricular arrhythmias.

UNLABELLED: Early Repolarization in Noncompaction Cardiomyopathy. BACKGROUND: Early repolarization (ER) is associated with malignant ventricular arrhythmias, including ventricular fibrillation (VF) and sudden cardiac death (SCD). One possible mechanism is increased trabeculation with deep intramyocardial invagination, carrying the Purkinje system deeper into the myocardium resulting in delayed depolarization and inhomogenous repolarization. Noncompaction cardiomyopathy (NCCM) is a recently classified, primary cardiomyopathy with excessive trabeculations. In these patients ventricular arrhythmias, including sustained VT and VF, occur frequently. The aim of this study was to determine the prevalence of ER in NCCM patients, especially in those primarily presenting with malignant ventricular arrhythmias or SCD. METHODS: We analyzed prospective data from our NCCM registry including 84 patients, median age: 40 (3-79) years. RESULTS: Fourteen patients (17%) initially presented with sustained VT (n = 5) or VF (n = 9) and 70 (83%) with heart failure or else. After the exclusion of 20 patients with the left bundle branch block, 25 (39%) NCCM patients had ER; 3 (6%) located in inferior leads, 14 (27%) in lateral leads, and 8 (15%) in both. None had ER in leads V1 to V3. In those presenting with VT/VF, 9/12 (75%) had ER (2 in inferior leads, 3 in lateral leads and 4 in both), versus 16/52 (31%) in the other patients (P = 0.02). If the NCCM population was dichotomized according to the presence or absence of ER, the long-term outcome for VT/VF appeared worse in the ER positive patients (P = 0.05). CONCLUSION: There is a high prevalence of ER in NCCM patients, especially in those who present with malignant ventricular arrhythmias. (J Cardiovasc Electrophysiol, Vol. 23, pp. 938-944, September 2012).

No relationship between left ventricular radial wall motion and longitudinal velocity and the extent and severity of noncompaction cardiomyopathy.

BACKGROUND: Noncompaction cardiomyopathy (NCCM) is characterized by a prominent trabecular meshwork and deep intertrabecular recesses. Although systolic dysfunction is common, limited information is available on differences in wall motion of the normal compacted and noncompacted segments. The purpose of this study was to assess radial wall motion and longitudinal wall velocity in patients with NCCM, according to the extent and severity of noncompaction. METHODS: The study comprised 29 patients in sinus rhythm (age 41 ± 15 years, 15 men), who fulfilled stringent diagnostic criteria for NCCM and compared to 29 age and gender matched healthy controls. Segmental radial wall motion of all compacted and noncompacted segments was assessed with the standard visual wall motion score index and longitudinal systolic (Sm) wall velocity with tissue Doppler imaging of the mitral annulus. For each LV wall a normalized Sm value was calculated. The extent and severity of NC in each LV segment was assessed both in a qualitative and quantitative manner. RESULTS: Heart failure was the primary clinical presentation in half of the patients. NCCM patients had a wall motion score index of 1.68 ± 0.43 and a normalized Sm of 82 ± 20%. The total and maximal noncompaction scores were not related to the wall motion score index and the normalized Sm. NCCM patients with and without heart failure had similar total and maximal noncompaction scores. CONCLUSIONS: In NCCM patient's radial wall motion and longitudinal LV wall velocity is impaired but not related to the extent or severity of noncompaction.

Indications and outcome of implantable cardioverter-defibrillators for primary and secondary prophylaxis in patients with noncompaction cardiomyopathy.

BACKGROUND: Noncompaction cardiomyopathy (NCCM) is a rare, primary cardiomyopathy, with initial presentation of heart failure, emboli, or arrhythmias, including sudden cardiac death. Implantable cardioverter-defibrillators (ICDs) are frequently used for primary and secondary prevention in different cardiomyopathy patients, but data about ICD in NCCM are scarce. The aim of this study was, therefore, to investigate ICD indications and outcomes in NCCM patients. METHODS AND RESULTS: We collected prospective data from our NCCM cohort (n = 77 pts, mean age: 40 ± 14 years). ICD was implanted in 44 (57%) patients with NCCM according to the current ICD guidelines for nonischemic cardiomyopathies: in 12 for secondary prevention (7 × ventricular fibrillation, 5 × sustained ventricular tachycardia [VT]) and in 32 patients for primary prevention (heart failure/severe LV dysfunction). During a mean follow-up of 33 ± 24 months, 8 patients presented with appropriate ICD shocks due to sustained VT after median 6.1 [1-16] months. This included 4 of 32 (13%) patients in the primary prevention group and 4 of 12 (33%) in the secondary prevention group (P = 0.04). 9 patients presented with inappropriate ICD therapy: 6 (19%) in the primary and 3 (25%) in the secondary prevention group, at a median follow-up of 4 (2-23) months. CONCLUSIONS: In our cohort of NCCM patients, an ICD was frequently implanted for primary or secondary prevention of sudden cardiac death. At follow-up, frequent appropriate ICD therapy was observed in both groups, supporting the application of current ICD guidelines for primary and secondary prevention of sudden cardiac death in NCCM.

Controversies in cardiovascular medicine: Chronic stable coronary artery disease: drugs vs. revascularization.

Coronary artery disease remains the leading cause of mortality in most industrialized countries, although age-standardized mortality related to coronary artery disease (CAD) has decreased by more than 40% during the last two decades. Coronary atherosclerosis may cause angina pectoris, myocardial infarction, heart failure, arrhythmia, and sudden death. Medical management of atherosclerosis and its manifestation aims at retardation of progression of plaque formation, prevention of plaque rupture, and subsequent events and treatment of symptoms, when these occur as well as treatment of the sequelae of the disease. Revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) is performed as treatment of flow-limiting coronary stenosis to reduce myocardial ischaemia. In high-risk patients with acute coronary syndromes (ACS), a routine invasive strategy with revascularization in most patients provides the best outcome with a significant reduction in death and myocardial infarction compared with an initial conservative strategy. Conversely, the benefit of revascularization among patients with chronic stable CAD has been called into question. This review will provide information that revascularization exerts favourable effects on symptoms, quality of life, exercise capacity, and survival, particularly in those with extensive CAD and documented moderate-to-severe ischaemia. Accordingly, CABG and PCI should be considered a valuable adjunct rather than an alternative to medical therapy.

Impaired microcirculation predicts poor outcome of patients with acute myocardial infarction complicated by cardiogenic shock.

AIMS: we investigated the relationship between sublingual perfused capillary density (PCD) as a measure of tissue perfusion and outcome (i.e. occurrence of organ failure and mortality) in patients with cardiogenic shock from acute myocardial infarction. METHODS AND RESULTS: we performed a prospective study in 68 patients. Using Sidestream Dark Field imaging, PCD was measured after hospital admission (T0, baseline) and 24 h later (T1). We compared patients with baseline PCD ≤ median to patients with baseline PCD > median. Sequential organ failure assessment (SOFA) scores were calculated at both time points. The Kaplan-Meier 30-day survival analyses were performed and predictors of 30-day mortality were identified. The baseline PCD was a predictor of the change in the SOFA score between T0 and T1 (ΔSOFA; ρ = -0.25, P = 0.04). Organ failure recovered more frequently in patients with PCD > median (>10.3 mm mm(-2); n = 33) than in patients with PCD ≤ median (n = 35; 52 vs. 29%, P < 0.05). Twenty-two patients (32%) died: 17 patients (49%) with PCD ≤ median vs. 5 patients (15%) with PCD > median (P = 0.004). After adjustment, the cardiac power index [odds ratio (OR): 0.48, 95% CI: 0.24-0.94) and PCD (OR: 0.65, 95% CI: 0.45-0.92) remained significant predictors of 30-day outcome. Patients with baseline sublingual PCD ≤ median that improved at T1 had a considerable better prognosis relative to patients who had a persistently low PCD. CONCLUSION: diminished sublingual PCD, at baseline or following treatment, is associated with development of multi-organ failure and is a predictor of poor outcome in patients with acute myocardial infarction complicated by cardiogenic shock.

Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease.

AIMS: The efficacy of angiotensin-converting enzyme (ACE)-inhibitors in stable coronary artery disease (CAD) may be increased by targeting the therapy to those patients most likely to benefit. However, these patients cannot be identified by clinical characteristics. We developed a genetic profile to predict the treatment benefit of ACE-inhibitors exist and to optimize therapy with ACE-inhibitors. METHODS AND RESULTS: In 8907 stable CAD patients participating in the randomized placebo-controlled EUROPA-trial, we analysed 12 candidate genes within the pharmacodynamic pathway of ACE-inhibitors, using 52 haplotype-tagging-single nucleotide polymorphisms (SNPs). The primary outcome was the reduction in cardiovascular mortality, non-fatal myocardial infarction, and resuscitated cardiac arrest during 4.2 years of follow-up. Multivariate Cox regression was performed with multiple testing corrections using permutation analysis. Three polymorphisms, located in the angiotensin-II type I receptor and bradykinin type I receptor genes, were significantly associated with the treatment benefit of perindopril after multivariate adjustment for confounders and correction for multiple testing. A pharmacogenetic score, combining these three SNPs, demonstrated a stepwise reduction of risk in the placebo group and a stepwise decrease in treatment benefit of perindopril with an increasing scores (interaction P < 0.0001). A pronounced treatment benefit was observed in a subgroup of 73.5% of the patients [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.56-0.79], whereas no benefit was apparent in the remaining 26.5% (HR 1.26; 95% CI 0.97-1.67) with a trend towards a harmful effect. In 1051 patients with cerebrovascular disease from the PROGRESS-trial, treated with perindopril or placebo, an interaction effect of similar direction and magnitude, although not statistically significant, was observed. CONCLUSION: The current study is the first to identify genetic determinants of treatment benefit of ACE-inhibitor therapy. We developed a genetic profile which predicts the treatment benefit of ACE-inhibitors and which could be used to optimize therapy.

ST2 and mortality in non-ST-segment elevation acute coronary syndrome.

BACKGROUND: ST2 is a member of the interleukin-1 receptor family that is up-regulated in conditions associated with increased myocardial strain. ST2 has been shown to be independently predictive of adverse outcome in heart failure and ST-segment elevation myocardial infarction, but its prognostic value in non-ST-elevation acute coronary syndrome (NSTE-ACS) has not been established. METHODS: We measured ST2 at randomization and after 24, 48, and 72 hours in 403 NSTE-ACS patients from the GUSTO IV study, and studied its kinetics and its associations to clinical baseline factors and 1-year mortality. RESULTS: Median ST2 levels decreased from 28.4 U/mL at randomization to 21.8 U/mL at 72 hours (P < .001). Peak levels were noted 6 to 17 hours after symptom onset. Randomization ST2 levels were independently associated to N-terminal pro-B-type natriuretic peptide but otherwise exhibited only weak relations to cardiovascular risk factors and comorbidities, and biomarkers of myocardial necrosis or inflammation. ST2 was related to 1-year mortality independently of clinical risk indicators (odds ratio 2.3 [95% CI 1.1-4.6], P = .03) but lost its predictive value after additional adjustment for prognostic biomarkers, in particular N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: ST2 levels are elevated early in NSTE-ACS and predict 1-year mortality. Our data indicate that ST2 represents an interesting novel pathophysiologic pathway in the setting of ischemia-related myocardial dysfunction. However, future prospective evaluations in larger populations are needed before the clinical utility of ST2 can be determined.

Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary artery disease. Post hoc analysis of the EUROPA study.

BACKGROUND: The purposes of the study were to determine the effects of addition of perindopril to long-term continuous treatment with calcium-channel blocker (CCB) on cardiac outcomes in the stable coronary artery disease (CAD) population of EUROPA and to explore the presence of synergy between perindopril and CCB in secondary prevention. METHODS: We identified participants receiving CCB at every visit during the 4.2-year follow-up and analyzed the effect of addition of perindopril (n = 1,022 perindopril/CCB vs n = 1,100 placebo/CCB). RESULTS: Addition of perindopril to CCB significantly reduced total mortality by 46% (P < .01 vs placebo) and primary end point (a composite of cardiovascular mortality, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 35% (P < .05 vs placebo). There were 41%, 54%, and 28% reductions in cardiovascular mortality, hospitalization for heart failure, and myocardial infarction, respectively. Comparison of hazard ratios suggests the presence of a clinical synergy between perindopril and CCB, with a greater effect than addition of individual effects. CONCLUSION: Addition of perindopril to CCB in stable CAD patients had a significant supplementary impact on cardiac outcomes and mortality.

Prediction of 30-day mortality in older patients with a first acute myocardial infarction.

OBJECTIVES: This study sought predictors of mortality in patients aged >or=75 years with a first ST-segment elevation myocardial infarction (STEMI) and evaluated the validity of the GUSTO-I and TIMI risk models. METHODS: Clinical variables, treatment and mortality data from 433 consecutive patients were collected. Univariable and multivariable logistic regression analyses were applied to identify baseline factors associated with 30-day mortality. Subsequently a model predicting 30-day mortality was created and compared with the performance of the GUSTO-I and TIMI models. RESULTS: After adjustment, a higher Killip class was the most important predictor (OR 16.1; 95% CI 5.7-45.6). Elevated heart rate, longer time delay to admission, hyperglycemia and older age were also associated with increased risk. Patients with hypercholesterolemia had a significantly lower risk (OR 0.46; 95% CI 0.24-0.86). Discrimination (c-statistic 0.79, 95% CI 0.75-0.84) and calibration (Hosmer-Lemeshow 6, p = 0.5) of our model were good. The GUSTO-I and TIMI risk scores produced adequate discrimination within our dataset (c-statistic 0.76, 95% CI 0.71-0.81, and c-statistic 0.77, 95% CI 0.72-0.82, respectively), but calibration was not satisfactory (HL 21.8, p = 0.005 for GUSTO-I, and HL 20.6, p = 0.008 for TIMI). CONCLUSIONS: Short-term mortality in elderly patients with a first STEMI depends most importantly on initial clinical and hemodynamic status. The GUSTO-I and TIMI models are insufficiently adequate for providing an exact estimate of 30-day mortality risk.

Recovery of long-axis left ventricular function after aortic valve replacement in patients with severe aortic stenosis.

BACKGROUND: Patients with aortic stenosis (AS) should undergo aortic valve replacement (AVR) before irreversible LV dysfunction has developed. Assessment of long-axis left ventricular (LV) function may assist in proper timing of AVR. OBJECTIVES: To assess serial changes in long-axis LV function before and after AVR in patients with severe AS and preserved LV ejection fraction. METHODS: The study comprised 27 consecutive patients (mean age 64.9 ± 11.7 years, 15 males) with symptomatic severe AS, scheduled for AVR. Seventeen subjects without known cardiac disease, matched for age, gender, LV ejection fraction and cardiovascular risk factors, served as a control group. Long-axis LV function assessment was done with tissue Doppler imaging at 3 weeks, 6 months, and 12 months after AVR. RESULTS: Mean aortic valve area in the AS group was 0.70 ± 0.24 cm². Pre-AVR peak systolic mitral annular velocities were significantly lower compared to controls (6.7 ± 1.5 vs. 8.9 ± 2.0 cm/s, P < 0.05). Post-AVR peak systolic mitral annular velocities improved to 9.1 ± 2.9 at 3 weeks, 8.6 ± 2.7 at 6 months, and 8.1 ± 1.7 cm/s at 12 months (P < 0.05). Improvements were seen over the whole range of pre-AVR peak systolic mitral annular velocities. Patients with improved Sm after AVR (defined as ≥ 10% compared to baseline values) did not differ in baseline characteristics as compared to those who did not improve. CONCLUSIONS: In patients with severe AS and preserved LV ejection fraction, abnormal systolic mitral annular velocities improve after AVR, independent of the pre-AVR value.