Top ten risk factors for morbidity and mortality in patients with chronic systolic heart failure and elevated heart rate: the SHIFT risk model

Aims We identified easily obtained baseline characteristics associated with outcomes in patients with chronic heart failure (HF) and elevated heart rate (HR) receiving contemporary guideline-recommended therapy in the SHIFT trial, and used them to develop a prognostic model. Methods We selected the 10 best predictors for each of four outcomes (cardiovascular death or HF hospitalisation; all-cause mortality; cardiovascular mortality; and HF hospitalisation). All variables with p &#60; 0.05 for association were entered into a forward stepwise Cox regression model. Our initial analysis excluded baseline therapies, though randomisation to ivabradine or placebo was forced into the model for the composite endpoint and HF hospitalisation. Results Increased resting HR, low ejection fraction, raised creatinine, New York Heart Association class III/IV, longer duration of HF, history of left bundle branch block, low systolic blood pressure and, for three models, age were strong predictors of all outcomes. Additional predictors were low body mass index, male gender, ischaemic HF, low total cholesterol, no history of hyperlipidaemia or dyslipidaemia and presence of atrial fibrillation/flutter. The c-statistics for the four outcomes ranged from 67.6% to 69.5%. There was no evidence for lack of fit of the models with the exception of all-cause mortality (p = 0.017). Similar results were found including baseline therapies. Conclusion The SHIFT Risk Model includes simple, readily obtainable clinical characteristics to produce important prognostic information in patients with chronic HF, systolic dysfunction, and elevated HR. This may help better calibrate management to individual patient risk.</p

The effect of cardiac resynchronization on morbidity and mortality in heart failure

Background: Cardiac resynchronization reduces symptoms and improves left ventricular function in many patients with heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony. We evaluated its effects on morbidity and mortality. Methods: Patients with New York Heart Association class III or IV heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony who were receiving standard pharmacologic therapy were randomly assigned to receive medical therapy alone or with cardiac resynchronization. The primary end point was the time to death from any cause or an unplanned hospitalization for a major cardiovascular event. The principal secondary end point was death from any cause. Results: A total of 813 patients were enrolled and followed for a mean of 29.4 months. The primary end point was reached by 159 patients in the cardiac-resynchronization group, as compared with 224 patients in the medical-therapy group (39 percent vs. 55 percent; hazard ratio, 0.63; 95 percent confidence interval, 0.51 to 0.77; P&lt;0.001). There were 82 deaths in the cardiac-resynchronization group, as compared with 120 in the medical-therapy group (20 percent vs. 30 percent; hazard ratio 0.64; 95 percent confidence interval, 0.48 to 0.85; P&lt;0.002). As compared with medical therapy, cardiac resynchronization reduced the interventricular mechanical delay, the end-systolic volume index, and the area of the mitral regurgitant jet; increased the left ventricular ejection fraction; and improved symptoms and the quality of life (P&lt;0.01 for all comparisons). Conclusions: In patients with heart failure and cardiac dyssynchrony, cardiac resynchronization improves symptoms and the quality of life and reduces complications and the risk of death. These benefits are in addition to those afforded by standard pharmacologic therapy. The implantation of a cardiac-resynchronization device should routinely be considered in such patients

Effect of visit-to-visit variation of heart rate and systolic blood pressure on outcomes in chronic systolic heart failure: results from the Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial (SHIFT) trial

Background: Elevated resting heart rate (HR) and low systolic blood pressure (SBP) are related to poor outcomes in heart failure (HF). The association between visit-to-visit variation in SBP and HR and risk in HF is unknown. Methods and Results: In Systolic Heart Failure Treatment with the If inhibitor ivabradine Trial (SHIFT) patients, we evaluated relationships between mean HR, mean SBP, and visit-to-visit variations (coefficient of variation [CV]=SD/mean×100%) in SBP and HR (SBP-CV and HR-CV, respectively) and primary composite endpoint (cardiovascular mortality or HF hospitalization), its components, all-cause mortality, and all-cause hospitalization. High HR and low SBP were closely associated with risk for primary endpoint, all-cause mortality, and HF hospitalization. The highest number of primary endpoint events occurred in the highest HR tertile (38.8% vs 16.4% lowest tertile; P&lt;0.001). For HR-CV, patients at highest risk were those in the lowest tertile. Patients in the lowest thirds of mean SBP and SBP-CV had the highest risk. The combination of high HR and low HR-CV had an additive deleterious effect on risk, as did that of low SBP and low SBP-CV. Ivabradine reduced mean HR and increased HR-CV, and increased SBP and SBP-CV slightly. Conclusions: Beyond high HR and low SBP, low HR-CV and low SBP-CV are predictors of cardiovascular outcomes with additive effects on risk in HF, but with an unknown effect size. Beyond HR reduction, ivabradine increases HR-CV. Low visit-to-visit variation of HR and SBP might signal risk of cardiovascular outcomes in systolic HF. Clinical Trial Registration: URL: http://www.isrctn.com/. Unique identifier: ISRCTN70429960

Efficacy profile of ivabradine in patients with heart failure plus angina pectoris

Objectives: In the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), slowing of the heart rate with ivabradine reduced cardiovascular death or heart failure hospitalizations among patients with systolic chronic heart failure (CHF). Subsequently, in the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) slowing of the heart rate in patients without CHF provided no benefit for cardiovascular death or nonfatal myocardial infarction (primary composite end point), with secondary analyses suggesting possible harm in the angina subgroup. Therefore, we examined the impact of ivabradine in the patients with CHF plus angina in SHIFT. Methods: SHIFT enrolled adults with stable, symptomatic CHF, a left ventricular ejection fraction ≤35% and a sinus rhythm with a resting heart rate ≥70 bpm. Outcomes were the SHIFT and SIGNIFY primary composite end points and their components. Results: Of 6,505 patients in SHIFT, 2,220 (34%) reported angina at randomization. Ivabradine numerically, but not significantly, reduced the SIGNIFY primary composite end point by 8, 11 and 11% in the SHIFT angina subgroup, nonangina subgroup and overall population, respectively. Ivabradine also reduced the SHIFT primary composite end point in all 3 subgroups. Conclusions: In SHIFT, ivabradine showed consistent reduction of cardiovascular outcomes in patients with CHF; similar results were seen in the subgroup of SHIFT patients with angina

Long-term physical training and left ventricular remodelling after anterior myocardial infraction: Results of the excercise in anterior myocardial infraction (EAMI) trial

AbstractObjectives. The aim of this multicenter randomized study was to investigate whether long-term physical training would influence left ventricular remodeling after anterior myocardial infarction.Background. Exercise is currently recommended for patients after myocardial infarction; however, the effects of long-term physical training on ventricular size and remodeling still have to be defined.Methods. Patients with no contraindications to exercise were studied 4 to 8 weeks after anterior Q wave myocardial infarction and 6 months later by echocardiography at rest and bicycle ergometric testing. After the initial study, patients were randomly allocated to a 6-month exercise training program (n = 49) or a control group (n = 46). A computerized system was used to derive echocardiographic variables of ventricular size, function and topography.Results. After 6 mongths, a significant (p < 0.01) increase in work capacity (from 4,596 ± 1,246 to 5,508 ± 1,335 kp-m) was observed only in the training group, whereas global ventricular size, regional dilation and shape distortion did not change in either the control or the training group. However, compared with patients with an ejection fraction >40%, patients with an ejection fraction ≤ 40% had more significant (p < 0.001) ventricular enlargement at entry and demonstrated further (p < 0.01) global and regional dilation after 6 months, in both the control and the training, group (end-diastolic volume from 77 ± 14 to 85 ± 17 ml/m2in the control group and from 74 ± 11 to 77 ± 15 ml/m2in the training group; regional dilation from 46 ± 18% to 57 ± 21% in the control group and from 42 ± 18% to 44 ± 26% in the training group). Ventricular size and topography did not change in patients with an ejection fraction >40%.Conclusions. Patients with poor left ventricular function 1 to 2 months after anterior myocardial infarction are prone to further global and regional dilation. Exercise training does not appear to influence this spontaneous deterioration. Thus, postinfarction patients without clinical complications, even those with a large anterior infarction, may benefit from long-term physical training without any additional negative effect on ventricular size and topography

Budget impact of adding ivabradine to standard of care in patients with chronic systolic heart failure in the United States

BACKGROUND: Heart failure (HF) costs $21 billion annually in direct health care costs, 80 OBJECTIVE: To estimate the budget impact of ivabradine from a U.S. commercial payer perspective. METHODS: A budget impact model estimated the per-member-per month (PMPM) impact of introducing ivabradine to existing formularies by comparing a reference scenario (SoC) and a new drug scenario (ivabradine + SoC) in hypothetical 1 million-member commercial and Medicare Advantage plans. In both scenarios, U.S. claims data were used for the reference cumulative annual rates of hospitalizations (HF, non-HF cardiovascular [CV], and non-CV), and hospitalization rates were adjusted using SHIFT data. The model controlled for mortality risk using SHIFT and U.S. life table data, and hospitalization costs were obtained from U.S. claims data: HF-related =$37,507; non-HF CV = $28,951; and non-CV =$17,904. The annualized wholesale acquisition cost of ivabradine was $4,500, with baseline use for this new drug at 2 RESULTS: Based on the approved U.S. indication, approximately 2,000 commercially insured patients from a 1 million-member commercial plan were eligible to receive ivabradine. Ivabradine resulted in a PMPM cost savings of$0.01 and $0.04 in years 1 and 3 of the core model, respectively. After including the acquisition price for ivabradine, the model showed a decrease in total costs in the commercial ($991,256 and $474,499, respectively) and Medicare populations ($13,849,262 and $4,280,291, respectively) in year 1. This decrease was driven by ivabradine’s reduction in hospitalization rates. For the core model, the estimated pharmacy-only PMPM in year 1 was$0.01 for the commercial population and $0.24 for the Medicare Advantage population. CONCLUSIONS: Adding ivabradine to SoC led to lower average annual treatment costs. The negative PMPM budget impact indicates that ivabradine is an affordable option for U.S. payers

Incremental benefit of drug therapies for chronic heart failure with reduced ejection fraction: a network meta-analysis

Aims: A network meta‐analysis (NMA) of all recommended drug groups for the treatment of heart failure with reduced ejection fraction (HFrEF), including their combinations, was performed to assess the relative efficacy and incremental benefit. Methods and results: A search was made in biomedical databases for randomized controlled trials published between 1987 and 2017 on angiotensin‐converting enzyme inhibitors (ACEIs), beta‐blockers (BBs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), ivabradine (IVA), or angiotensin receptor–neprilysin inhibitors (ARNI). A total of 58 relevant trials were identified. The relative efficacy of each treatment group (or combination) in terms of all‐cause mortality, cardiovascular mortality, all‐cause hospitalizations and hospitalizations for heart failure, per patient‐year of follow‐up, were combined in a random‐effects Bayesian NMA. The pairwise comparison between each regimen and for each outcome was estimated. The NMA was dominated by 15 large‐scale trials with between 1984 and 18 898 patient‐years of follow‐up. Combinations of drug groups showed incremental benefits on outcomes over single groups. The most effective combinations were ARNI+BB + MRA and ACEI+BB + MRA + IVA, showing reductions in all‐cause mortality (vs. placebo) of 62% and 59%, respectively; hazard ratios were 0.38 [credible interval (CrI) 0.20–0.65] and 0.41 (CrI 0.21–0.70); and in all‐cause hospitalizations with reductions of 42% for both. These two combinations were also the most effective for the other outcomes studied. Conclusion: Our analysis shows that the incremental use of combinations of disease‐modifying therapies has resulted in the progressive improvement in mortality and hospitalization outcomes in HFrEF. Our findings support the current guideline recommendations

Predicting the Long-Term Effects of Cardiac Resynchronization Therapy on Mortality From Baseline Variables and the Early Response A Report From the CARE-HF (Cardiac Resynchronization in Heart Failure) Trial

ObjectivesThis study was designed to investigate whether selected baseline variables and early response markers predict the effects of cardiac resynchronization therapy (CRT) on long-term mortality.BackgroundCardiac resynchronization therapy reduces long-term morbidity and mortality in patients with moderate or severe heart failure and markers of cardiac dyssynchrony, but not all patients respond to a similar extent.MethodsIn the CARE-HF (Cardiac Resynchronization in Heart Failure) study, 813 patients with heart failure and markers of cardiac dyssynchrony were randomly assigned to receive or not receive CRT in addition to pharmacological treatment and were followed for a median of 37.6 months. A model including assigned treatment, 15 pre-specified baseline variables, and 8 markers of response at 3 months was constructed to predict all-cause mortality.ResultsOn multivariable analysis, plasma concentration of amino terminal pro–brain natriuretic peptide (univariate and multivariable model chi-square test: 105.0 and 48.4; both p < 0.0001) and severity of mitral regurgitation (chi-square test: 44.0 and 17.9; both p < 0.0001) at 3 months, regardless of assigned treatment, were the strongest predictors of mortality. Ischemic heart disease as the cause of ventricular dysfunction (chi-square test: 34.9 and 7.4; p < 0.0001 and p = 0.0066), being in New York Heart Association functional class IV (chi-square test: 18.8 and 9.6; p < 0.0001 and p = 0.0020), or having less interventricular mechanical delay (chi-square test: 29.8 and 8.8; p < 0.0001 and p = 0.0029) at baseline all predicted a worse outcome. However, the reduction in mortality in patients assigned to CRT was similar before (hazard ratio: 0.602; 95% confidence interval: 0.468 to 0.774) and after (hazard ratio: 0.679; 95% confidence interval: 0.494 to 0.914) adjustment for variables measured at baseline and at 3 months.ConclusionsPatients who have more severe mitral regurgitation or persistently elevated amino terminal pro–brain natriuretic peptide despite treatment for heart failure, including CRT, have a higher mortality. However, patients assigned to CRT had a lower mortality even after adjusting for variables measured before and 3 months after intervention. The effect of CRT on mortality cannot be usefully predicted using such information. (CARE-HF CArdiac Resynchronization in Heart Failure; NCT00170300