Central sleep apnea is associated with poor prognosis and death in patients with heart failure. Adaptive servo-ventilation is a therapy that uses a noninvasive ventilator to treat central sleep apnea ...by delivering servo-controlled inspiratory pressure support on top of expiratory positive airway pressure. We investigated the effects of adaptive servo-ventilation in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea.
We randomly assigned 1325 patients with a left ventricular ejection fraction of 45% or less, an apnea-hypopnea index (AHI) of 15 or more events (occurrences of apnea or hypopnea) per hour, and a predominance of central events to receive guideline-based medical treatment with adaptive servo-ventilation or guideline-based medical treatment alone (control). The primary end point in the time-to-event analysis was the first event of death from any cause, lifesaving cardiovascular intervention (cardiac transplantation, implantation of a ventricular assist device, resuscitation after sudden cardiac arrest, or appropriate lifesaving shock), or unplanned hospitalization for worsening heart failure.
In the adaptive servo-ventilation group, the mean AHI at 12 months was 6.6 events per hour. The incidence of the primary end point did not differ significantly between the adaptive servo-ventilation group and the control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval CI, 0.97 to 1.31; P=0.10). All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=0.01; and hazard ratio for cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=0.006).
Adaptive servo-ventilation had no significant effect on the primary end point in patients who had heart failure with reduced ejection fraction and predominantly central sleep apnea, but all-cause and cardiovascular mortality were both increased with this therapy. (Funded by ResMed and others; SERVE-HF ClinicalTrials.gov number, NCT00733343.).
Objectives This study investigated the effect of catheter-based renal sympathetic denervation (RD) on left ventricular hypertrophy (LVH) and systolic and diastolic function in patients with resistant ...hypertension. Background LVH and diastolic dysfunction are associated with elevated sympathetic activity and increased morbidity and mortality. The effect of RD on LVH and LV function is unclear. Methods Forty-six patients underwent bilateral RD, and 18 patients served as controls. Transthoracic echocardiography was performed at baseline, and after 1 month and 6 months. Results Besides reduction of systolic and diastolic blood pressure (−22.5/−7.2 mm Hg at 1 month and −27.8/−8.8 mm Hg at 6 months, p < 0.001 at each time point), RD significantly reduced mean interventricular septum thickness from 14.1 ± 1.9 mm to 13.4 ± 2.1 mm and 12.5 ± 1.4 mm (p = 0.007), and LV mass index from 53.9 ± 15.6 g/m2.7 (112.4 ± 33.9 g/m2 ) to 47.0 ± 14.2 g/m2.7 (103.6 ± 30.5 g/m2 ) and 44.7 ± 14.9 g/m2.7 (94.9 ± 29.8 g/m2 ) (p < 0.001) at 1 month and 6 months, respectively. The mitral valve lateral E/E′ decreased after RD from 9.9 ± 4.0 to 7.9 ± 2.2 at 1 month and 7.4 ± 2.7 at 6 months (p < 0.001), indicating reduction of LV filling pressures. Isovolumic relaxation time shortened (baseline 109.1 ± 21.7 ms vs. 85.6 ± 24.4 ms at 6 months, p = 0.006), whereas ejection fraction significantly increased after RD (baseline: 63.1 ± 8.1% vs. 70.1 ± 11.5% at 6 months, p < 0.001). No significant changes were obtained in control patients. Conclusions Besides the known effect on blood pressure, our study showed for the first time that RD significantly reduces LV mass and improves diastolic function, which might have important prognostic implications in patients with resistant hypertension at high cardiovascular risk.
Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator. This study evaluated the haemodynamic effect and safety of cinaciguat added to standard therapy in patients with acute ...decompensated heart failure (ADHF).
In this placebo-controlled, phase IIb study (NCT00559650), 139 patients admitted with ADHF, pulmonary capillary wedge pressure (PCWP) ≥18 mmHg, left ventricular ejection fraction <40%, and a pre-existing need for invasive haemodynamic monitoring were randomized 2:1 to cinaciguat:placebo (continuous i.v. infusion). The dose was titrated for 8 h and maintained for 16-40 h (starting dose: 100 μg/h). At 8 h, mean PCWP changed from 25.7 ± 5.0 mmHg by -7.7 mmHg with cinaciguat and from 25.0 ± 5.3 mmHg by -3.7 mmHg with placebo (P < 0.0001). The mean right atrial pressure changed from 12.4 ± 5.3 mmHg by -2.7 mmHg with cinaciguat and from 11.8 ± 4.9 mmHg by -0.6 mmHg with placebo (P= 0.0019). Cinaciguat also decreased the pulmonary and systemic vascular resistance and the mean arterial pressure, and increased the cardiac index (all P < 0.0001 vs. placebo). Systolic blood pressure changed by -21.6 ± 17.0 mmHg with cinaciguat and -5.0 ± 14.5 mmHg with placebo. Adverse events were experienced by 71 and 45% of patients receiving cinaciguat and placebo, respectively. No adverse effects on the 30-day mortality were seen; however, the trial was stopped prematurely due to an increased occurrence of hypotension at cinaciguat doses ≥200 µg/h.
Cinaciguat unloaded the heart in patients with ADHF. However, high doses were associated with hypotension.
The wearable cardioverter defibrillator (WCD) is increasingly used in patients at elevated risk for ventricular arrhythmias but not fulfilling the indications for an implantable cardioverter ...defibrillator (ICD). Currently, there is an insufficient risk prediction of fatal arrhythmias in patients at risk. In this study, we assessed the prognostic role of baseline electrocardiogram (ECG) in WCD patients.
WCD patients from diverse clinical institutions in Germany (n = 227) were retrospectively enrolled and investigated for the incidences of death or ventricular arrhythmias during WCD wearing. In addition, the widely accepted ECG predictors of adverse outcome were analyzed in patients with arrhythmic events.
Life-threatening arrhythmias occurred in 22 (9.7 %) patients, mostly in subjects with ischemic heart disease (15 of 22). There was no difference in baseline left ventricular ejection fraction (LVEF) in subjects with and without arrhythmic events (31.3 ± 7.9 % vs. 32.6 ± 8.3 %; p = 0,24). Patients with arrhythmia exhibited significantly longer QRS duration (109.5 ± 23.1 ms vs. 100.6 ± 22.3 ms, p = 0,04), Tpeak-Tend (Tp-e) (103.1 ± 15.6 ms vs. 93.2 ± 19.2 ms, p = 0,01) and QTc (475.0 ± 60.0 ms vs. 429.6 ± 59.4 ms, p < 0,001) intervals. In contrast, no significant differences were found for incidences of fragmented QRS (27.3 % vs. 24 %, p = 0.79) and inverted/biphasic T-waves (16.6 % vs. 22.7 %, p = 0,55). In multivariate regression analysis both Tp-e (HR 1.03; 95 % CI 1.001–1.057; p = 0.02) and QTc (HR 1.02; 95 % CI 1.006–1.026; p < 0.001) were identified as independent predictors of ventricular arrhythmias.
After WCD use, the prophylactic ICD was indicated in 76 patients (33 %) with uneventful clinical course but persistent LVEF ≤35 %. The ECG analysis in these subjects did not reveal any relevant changes in arrhythmogenesis markers.
ECG repolarization markers Tp-e and QTc are associated with malignant arrhythmias in WCD patients and may be used - in addition to other established risk markers - to identify appropriate patients for ICD implantation.
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•The wearable cardioverter defibrillator is safe and effective in patients with elevated risk for fatal arrhythmias.•Tp-e and QTc are independent electrocardiographic (ECG) predictors of adverse events in these patients.•ECG can serve as an additional risk stratification tool in this high-risk subgroup.
Aims
The SERVE‐HF trial investigated the impact of treating central sleep apnoea (CSA) with adaptive servo‐ventilation (ASV) in patients with systolic heart failure. A preplanned substudy was ...conducted to provide insight into mechanistic changes underlying the observed effects of ASV, including assessment of changes in left ventricular function, ventricular remodelling, and cardiac, renal and inflammatory biomarkers.
Methods and results
In a subset of the 1325 randomised patients, echocardiography, cardiac magnetic resonance imaging (cMRI) and biomarker analysis were performed at baseline, and 3 and 12 months. In secondary analyses, data for patients with baseline and 12‐month values were evaluated; 312 patients participated in the substudy. The primary endpoint, change in echocardiographically determined left ventricular ejection fraction from baseline to 12 months, did not differ significantly between the ASV and the control groups. There were also no significant between‐group differences for changes in left ventricular dimensions, wall thickness, diastolic function or right ventricular dimensions and ejection fraction (echocardiography), and on cMRI (in small patient numbers). Plasma N‐terminal pro B‐type natriuretic peptide concentration decreased in both groups, and values were similar at 12 months. There were no significant between‐group differences in changes in cardiac, renal and systemic inflammation biomarkers.
Conclusion
In patients with systolic heart failure and CSA, addition of ASV to guideline‐based medical management had no statistically significant effect on cardiac structure and function, or on cardiac biomarkers, renal function and systemic inflammation over 12 months. The increased cardiovascular mortality reported in SERVE‐HF may not be related to adverse remodelling or worsening heart failure.
A large randomised treatment trial (SERVE-HF) showed that treatment of central sleep apnoea with adaptive servoventilation in patients with heart failure and reduced ejection fraction (HFREF) ...increased mortality, although the analysis of the composite primary endpoint (time to first event of death from any cause, life-saving cardiovascular intervention, or unplanned hospital admission for worsening heart failure) was neutral. This secondary multistate modelling analysis of SERVE-HF data investigated associations between adaptive servoventilation and individual components of the primary endpoint to try to better understand the mechanisms underlying the observed increased mortality.
In SERVE-HF, participants were randomly assigned to receive either optimum medical treatment for heart failure alone (control group), or in combination with adaptive servoventilation. We analysed individual components of the primary SERVE-HF endpoint separately in a multistate model, with and without three covariates suggested for effect modification (implantable cardioverter defibrillator at baseline, left ventricular ejection fraction LVEF, and proportion of Cheyne-Stokes Respiration CSR). The SERVE-HF study is registered with ClinicalTrials.gov, number NCT00733343.
Univariate analysis showed an increased risk of both cardiovascular death without previous hospital admission (hazard ratio HR 2·59, 95% CI 1·54-4·37, p<0·001) and cardiovascular death after a life-saving event (1·57, 1·01-2·44, p=0·045) in the group receiving adaptive servoventilation versus the control group. Adjusted analysis showed that the increased risk attributed to adaptive servoventilation of cardiovascular death without previous hospital admission for worsening heart failure varied with LVEF and that the risk attributed to adaptive servoventilation of hospital admission for worsening heart failure varied with LVEF and CSR. In patients with LVEF less than or equal to 30%, use of adaptive servoventilation markedly increased the risk of cardiovascular death without previous hospital admission (HR 5·21, 95% CI 2·11-12·89, p=0·026).
Adaptive servoventilation is associated with an increased risk of cardiovascular death in patients with heart failure and reduced ejection fraction (LVEF ≤45%) treated for predominant central sleep apnoea. This multistate modelling analysis shows that this risk is increased for cardiovascular death in patients not previously admitted to hospital, presumably due to sudden death, and in patients with poor left ventricular function.
ResMed.
Background Composite end points of major adverse cardiovascular events (MACEs) are standard measures for comparing treatment in large cardiovascular outcome studies. This analysis from PROspective ...pioglitAzone Clinical Trial In macro Vascular Events (PROactive) evaluated the effects of pioglitazone on the prespecified MACE end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE1) and on 6 post hoc MACE composites (various combinations of all-cause, cardiovascular, or cardiac mortality; plus nonfatal myocardial infarction; plus nonfatal stroke; and/or acute coronary syndrome) in patients with type 2 diabetes. Methods PROactive was a cardiovascular outcome study that randomized patients with type 2 diabetes to pioglitazone (n = 2605) or placebo (n = 2633), in addition to existing glucose-lowering and cardiovascular medications. Pioglitazone was titrated from 15 to 45 mg/d based upon tolerability. Mean follow-up was 34.5 months. Results At final visit, 257 (9.9%) pioglitazone-treated and 313 (11.9%) placebo-treated patients had a first event that contributed to the MACE1 end point (hazard ratio 0.82, 95% CI 0.70-0.97, P = .0201). There were statistically significant differences in favor of pioglitazone in 5 of the other MACE end points ( P < .05) and a trend to benefit in the sixth ( P = .052), with hazard ratios of 0.79 to 0.83. Conclusions In patients with advanced type 2 diabetes at high risk for cardiovascular events, pioglitazone treatment resulted in significant risk reductions in MACE composite end points to 3 years.
Aims The impact on outcome of the implementation of European guidelines for the treatment of chronic heart failure (CHF) has not been evaluated. We investigated the consequences of adherence to care ...by cardiologists on the rate of CHF and cardiovascular (CV) hospitalizations and time to CV hospitalization. Methods and results We constructed class adherence indicators for angiotensin-converting enzyme (ACE)-inhibitors, beta-blockers, spironolactone, diuretics, and cardiac glycosides and GAIs (GAI3 adherence to first three classes of heart failure medication, GAI5 adherence to five classes). In the study, 1410 evaluable patients (mean age 69, 69% males, New York Heart Association (NYHA) II: 64%, III: 34%, IV: 2%) were enrolled and followed up for 6 months by 150 randomly selected cardiologists/cardiology departments from six European countries (France, Germany, Italy, The Netherlands, Spain, and UK). Overall, adherence to treatment guidelines was 60 (GAI3) and 63% (GAI5) and was better for ACE-I (88%) or diuretics (82%) than for cardiac glycosides (52%), beta-blockers (58%), and spironolactone (36%). In the three tertiles of the population defined by a decreasing mean adherence score value, CHF and CV hospitalization rates were, respectively, 6.7, 9.7, and 14.7% and 11.2, 15.9, and 20.6% (P<0.002 and P<0.001, respectively). Global adherence indicator GAI3 was an independent predictor of time to CV hospitalization in a multi-variable model together with NYHA Class, history of CHF hospitalization, ischaemic aetiology, diabetes mellitus, and hypertension. Conclusion We demonstrate that adherence of physicians to treatment guidelines is a strong predictor of fewer CV hospitalizations in actual practice. There is a need to develop further quality improvement programmes in this condition.
Patients with diabetes and chronic kidney disease (CKD) are at particularly high risk for cardiovascular disease (CVD). This post hoc analysis from the PROspective pioglitAzone Clinical Trial In ...macroVascular Events (PROactive) investigated the relationship between CKD and incident CVD in a population of patients with diabetes and documented macrovascular disease, as well as the effects of pioglitazone treatment on recurrent CVD. CKD, defined as an estimated GFR <60 ml/min per 1.73m(2), was present in 597 (11.6%) of 5154 patients. More patients with CKD reached the primary composite end point (all-cause mortality, myocardial infarction (MI), stroke, acute coronary syndrome, coronary/carotid arterial intervention, leg revascularization, or amputation above the ankle) than patients without CKD (27.5 versus 19.6%; P < 0.0001). Patients with CKD were also more likely to reach a secondary composite end point (all-cause mortality, MI, and stroke). Patients who had CKD and were treated with pioglitazone were less likely to reach the secondary end point (hazard ratio 0.66; 95% confidence interval 0.45 to 0.98), but this association was not observed among those with better renal function. In addition, there was a greater decline in estimated GFR with pioglitazone (between-group difference 0.8 ml/min per 1.73 m(2)/yr) than with placebo. In conclusion, CKD is an independent risk factor for cardiovascular events and death among patients with diabetes and preexisting macrovascular disease. Patients who had CKD and were treated with pioglitazone were less likely to reach a composite end point of all-cause death, MI, and stroke, independent of the severity of renal impairment.
Aims
Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing prevalence. Sleep‐disordered breathing (SDB) is an important co‐morbidity in HFpEF. The SchlaHF‐XT registry ...evaluated the sex‐specific prevalence and predictors of SDB, including obstructive (OSA) and central sleep apnoea, in patients with HFpEF compared with heart failure with mildly reduced (HFmrEF) or reduced (HFrEF) ejection fraction.
Methods and results
Consecutive adults with chronic heart failure treated according to current guidelines were enrolled. The presence of moderate‐to‐severe SDB (apnoea–hypopnoea index ≥15/h) was determined using Type 3 polygraphic devices. Of 3289 patients included, 2032 had HFpEF, 559 had HFmrEF, and 698 had HFrEF, of whom 34, 21, 23, and 42%, respectively, were female. Prevalence of SDB in HFpEF was high, but significantly lower than in HFmrEF or HFrEF (36% vs. 41 and 48%, respectively). Rates of SDB in males and females were 41 and 28% in HFpEF, 44 and 30% in HFmrEF, and 50 and 40% in HFrEF. The proportion of males and females with SDB who had OSA was significantly greater in those with HFpEF vs. HFrEF. Male sex, older age, higher body mass index, and New York Heart Association functional Class III/IV were significant predictors of moderate‐to‐severe SDB in HFpEF patients.
Conclusions
Prevalence of SDB in HFpEF was high, but lower than in patients with HFmrEF or HFrEF. Moderate‐to‐severe SDB occurred more frequently in males than in females across the whole spectrum of heart failure. In both sexes, the proportion of OSA in SDB patients with HFpEF was higher than in those with HFrEF.
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