Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout.

BACKGROUND: Cardiovascular risk is increased in patients with gout. We compared cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with those associated with allopurinol, a purine base analogue xanthine oxidase inhibitor, in patients with gout and cardiovascular disease. METHODS: We conducted a multicenter, double-blind, noninferiority trial involving patients with gout and cardiovascular disease; patients were randomly assigned to receive febuxostat or allopurinol and were stratified according to kidney function. The trial had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization). RESULTS: In total, 6190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up. In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P=0.002 for noninferiority). All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all-cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention-to-treat analysis. CONCLUSIONS: In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials.gov number, NCT01101035 .).

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis.

BACKGROUND: The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. METHODS: Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated. RESULTS: A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). CONCLUSIONS: At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .).

Clinical Trial Principles and Endpoint Definitions for Paravalvular Leaks in Surgical Prosthesis.

The VARC (Valve Academic Research Consortium) for transcatheter aortic valve replacement set the standard for selecting appropriate clinical endpoints reflecting safety and effectiveness of transcatheter devices, and defining single and composite clinical endpoints for clinical trials. No such standardization exists for circumferentially sutured surgical valve paravalvular leak (PVL) closure. This document seeks to provide core principles, appropriate clinical endpoints, and endpoint definitions to be used in clinical trials of PVL closure devices. The PVL Academic Research Consortium met to review evidence and make recommendations for assessment of disease severity, data collection, and updated endpoint definitions. A 5-class grading scheme to evaluate PVL was developed in concordance with VARC recommendations. Unresolved issues in the field are outlined. The current PVL Academic Research Consortium provides recommendations for assessment of disease severity, data collection, and endpoint definitions. Future research in the field is warranted.

Impact of Beta-Blockade on Cardiac Events in Patients with Chronic Severe Nonischemic Mitral Regurgitation.

OBJECTIVES: The aim of this study was to examine the impact of beta-blockade on cardiac events among patients with initially asymptomatic chronic severe nonischemic mitral valve regurgitation (MR). METHODS: Data from 52 consecutive patients in our prospective natural history study of isolated chronic severe nonischemic MR were assessed post hoc over 19 years to examine the relation of chronic beta-blockade use to subsequent cardiac events (death or indications for mitral valve surgery, MVS). At entry, all patients were free of surgical indications; 9 received beta-blockers. Cardiac event rate differences were analyzed by Kaplan-Meier log rank comparison. RESULTS: During follow-up, cardiac events included sudden death (1), heart failure (8), atrial fibrillation (6), left ventricular dimensions at systole ≥4.5 cm (11), left ventricular ejection fraction <60% (6), right ventricular ejection fraction <35% (2), and a combination of cardiac events (7). The cardiac event risk was 4-fold higher among patients receiving beta-blockers (average annual risk = 60.6%) versus those not receiving beta-blockers (average annual risk = 15.2%; p = 0.001). These effects remained statistically significant (p = 0.005) when analysis was adjusted for other baseline covariates. CONCLUSIONS: Beta-blockade appears to confer an increased risk of sudden cardiac death or indications for MVS among patients with chronic severe nonischemic MR. Randomized trials are needed to confirm these findings.

Survival after Aortic Valve Replacement for Aortic Regurgitation: Prediction from Preoperative Contractility Measurement.

BACKGROUND: Noninvasive measurement of myocardial contractility (end-systolic wall stress-adjusted change in left ventricular ejection fraction from rest to exercise [ΔLVEF - ΔESS]) predicts heart failure, subnormal LVEFrest, and sudden death in asymptomatic patients with chronic severe aortic regurgitation (AR). Here we assess the relation of preoperative ΔLVEF - ΔESS to survival after aortic valve replacement (AVR). METHODS: Patients who underwent AVR for chronic, isolated, pure severe AR (n = 66) were followed for 13.0 ± 6.4 event-free years. Preoperative ΔLVEF - ΔESS (from combined echocardiographic and radionuclide cineangiographic data) enabled cohort stratification into 3 terciles (-1 to -11% [normal or mild] contractility deficit, -12 to -16% [moderate], and ≤-17% [severe], identical with segregation in our earlier study) to relate preoperative contractility to postoperative survival and to age- and gender-matched US census data. RESULTS: Since AVR, 22 patients died (average annual risk [AAR] for all-cause mortality for the entire co hort = 3.15%). Preoperative ΔLVEF - ΔESS predicted postoperative survival (p = 0.009, log rank test). By contractility terciles, all-cause AARs were 1.44, 2.58, and 6.40%. Survival was lower than among US census comparators (p < 0.02), but the "mild" tercile was indistinguishable from census data (p = ns). By multivariable Cox regression, survival prediction by pre-AVR ΔLVEF - ΔESS was independent of, and superior to, prediction by age at surgery, gender, preoperative functional class, LVEFrest, LVEFexercise, change in LVEFrest to exercise, and LV diastolic or systolic dimensions (p ≤ 0.01, pre-AVR ΔLVEF - ΔESS vs. other covariates). CONCLUSION: In severe AR, preoperative contractility predicts post-AVR survival and may be prognostically superior to clinical, geometric and performance descriptors, potentially impacting on patient selection for surgery.

Prognostic implications of left ventricular global longitudinal strain in heart failure patients with narrow QRS complex treated with cardiac resynchronization therapy: a subanalysis of the randomized EchoCRT trial.

AIM: Left ventricular (LV) global longitudinal strain (GLS) reflects LV systolic function and correlates inversely with the extent of LV myocardial scar and fibrosis. The present subanalysis of the Echocardiography Guided CRT trial investigated the prognostic value of LV GLS in patients with narrow QRS complex. METHODS AND RESULTS: Left ventricular (LV) global longitudinal strain (GLS) was measured on the apical 2-, 4- and 3-chamber views using speckle tracking analysis. Measurement of baseline LV GLS was feasible in 755 patients (374 with cardiac resynchronization therapy (CRT)-ON and 381 with CRT-OFF). The median value of LV GLS in the overall population was 7.9%, interquartile range 6.2-10.1%. After a mean follow-up period of 19.4 months, 95 patients in the CRT-OFF group and 111 in the CRT-ON group reached the combined primary endpoint of all-cause mortality and heart failure hospitalization. Each 1% absolute unit decrease in LV GLS was independently associated with 11% increase in the risk to reach the primary endpoint (Hazard ratio 1.11; 95% confidence interval 95% 1.04-1.17, P < 0.001), after adjusting for ischaemic cardiomyopathy and randomization treatment among other clinically relevant variables. When categorizing patients according to quartiles of LV GLS, the primary endpoint occurred more frequently in patients in the lowest quartile (<6.2%) treated with CRT-ON vs. CRT-OFF (45.6% vs. 28.7%, P = 0.009) whereas, no differences were observed in patients with LV GLS ≥6.2% treated with CRT-OFF vs. CRT-ON (23.7% vs. 24.5%, respectively; P = 0.62). CONCLUSION: Low LV GLS is associated with poor outcome in heart failure patients with QRS width <130 ms, independent of randomization to CRT or not. Importantly, in the group of patients with the lowest LV GLS quartile, CRT may have a detrimental effect on clinical outcomes.

Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: the PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) Trial.

AIMS: Non-steroidal anti-inflammatory drugs (NSAIDs), both non-selective and selective cyclooxygenase-2 (COX-2) inhibitors, are among the most widely prescribed drugs worldwide, but associate with increased blood pressure (BP) and adverse cardiovascular (CV) events. PRECISION-ABPM, a substudy of PRECISION was conducted at 60 sites, to determine BP effects of the selective COX-2 inhibitor celecoxib vs. the non-selective NSAIDs naproxen and ibuprofen. METHODS AND RESULTS: In this double-blind, randomized, multicentre non-inferiority CV-safety trial, 444 patients (mean age 62 ± 10 years, 54% female) with osteoarthritis (92%) or rheumatoid arthritis (8%) and evidence of or at increased risk for coronary artery disease received celecoxib (100-200 mg bid), ibuprofen (600-800 mg tid), or naproxen (375-500 mg bid) with matching placebos in a 1: 1: 1 allocation, to assess the effect on 24-h ambulatory BP after 4 months. The change in mean 24-h systolic BP (SBP) in celecoxib, ibuprofen and naproxen-treated patients was -0.3 mmHg [95% confidence interval (CI), -2.25, 1.74], 3.7 (95% CI, 1.72, 5.58) and 1.6 mmHg (95% CI, -0.40, 3.57), respectively. These changes resulted in a difference of - 3.9 mmHg (P = 0.0009) between celecoxib and ibuprofen, of - 1.8 mmHg (P = 0.12) between celecoxib and naproxen, and of - 2.1 mmHg (P = 0.08) between naproxen and ibuprofen. The percentage of patients with normal baseline BP who developed hypertension (mean 24-h SBP ≥ 130 and/or diastolic BP ≥ 80 mmHg) was 23.2% for ibuprofen, 19.0% for naproxen, and 10.3% for celecoxib (odds ratio 0.39, P = 0.004 and odds ratio 0.49, P = 0.03 vs. ibuprofen and naproxen, respectively). CONCLUSIONS: In PRECISION-ABPM, allocation to the non-selective NSAID ibuprofen, compared with the COX-2 selective inhibitor celecoxib was associated with a significant increase of SBP, and a higher incidence of new-onset hypertension. CLINICALTRIALS: gov number NCT00346216.

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.

Surgical Treatment of Ischemic Mitral Regurgitation: Valve Repair Versus Replacement.

PURPOSE OF REVIEW: Ischemic mitral regurgitation (MR), which occurs in about 20-30% patients with a prior myocardial infarction, is associated with worsening heart failure and an increase in cardiovascular mortality. It should be treated surgically if certain hemodynamic severity criteria are met and in patients who continue to experience symptoms of heart failure despite optimal medical therapy. However, current guidelines do not suggest which of the available approaches to mitral valve surgery-mitral valve (MV) repair or replacement (MVR) is superior for this indication. While MV repair is reported to confer improved survival, MVR may provide higher rates of freedom from recurrent MR. This article attempts to provide the reader with a comprehensive review and comparison of current techniques of mitral valve surgery in patients with severe ischemic MR. RECENT FINDINGS: The first randomized trial to compare MV repair versus MVR in patients with severe ischemic MR, the Cardiothoracic Surgical Trials Network (CTSN) trial, was recently concluded and reported no significant difference in the primary outcome of left ventricular end systolic volume index between the two approaches at either 1- or 2-year follow-ups. Data comparing approaches of MV repair and MVR for ischemic MR is largely limited to small, non-randomized retrospective trials. The only randomized trial data to examine this issue suggested no difference in mortality with either MVR or MV repair; however, MVR was shown to be consistently associated with higher rates of MR recurrence. Certain echocardiographic features have been reported to predict poor outcomes with MVR and may help refine the selection of the surgical approach in the individual patient.

Association of persistent or worsened echocardiographic dyssynchrony with unfavourable clinical outcomes in heart failure patients with narrow QRS width: a subgroup analysis of the EchoCRT trial.

AIMS: EchoCRT was a randomized trial of cardiac resynchronization therapy (CRT) in severely symptomatic heart failure (HF) patients with narrow QRS width <130 ms, ejection fraction ≤35%, and echocardiographic dyssynchrony. All received CRT implants which were then randomized to CRT-On or CRT-Off. While the trial showed no benefit of CRT to these patients, the aim of this subgroup analysis was to test the hypothesis that persistent or worsening dyssynchrony is associated with unfavourable clinical outcomes. METHODS AND RESULTS: We studied 614 EchoCRT patients with baseline and 6-month echocardiograms. Baseline dyssynchrony required for study inclusion was either tissue Doppler imaging longitudinal velocity delay ≥80 ms or speckle-tracking radial strain delay ≥130 ms. Persistent dyssynchrony at 6 months was observed similarly in both groups (77% in CRT-On; 76% in CRT-Off). Persistent dyssynchrony was associated with a significantly higher primary end point of death or HF hospitalization (HR = 1.54, 95% CI 1.03-2.30, P = 0.03), and in particular secondary endpoint of HF hospitalization (HR = 1.66, 95% CI 1.07-2.57, P = 0.02). HF hospitalizations were also associated with worsening longitudinal dyssynchrony (HR = 1.45, 95% CI 1.02-2.05, P = 0.037), and worsening radial dyssynchrony (HR = 1.81, 95% CI 1.16-2.81, P = 0.008). Associations of persistent or worsening dyssynchrony with outcomes were similar in CRT-Off and CRT-On groups. CONCLUSIONS: Persistent or worsening echocardiographic dyssynchrony in HF patients with narrow QRS width was a marker for unfavourable clinical outcomes unaffected by CRT. In particular, echocardiographic dyssynchrony on follow-up was strongly associated with HF hospitalizations and appears to be a prognostic marker of disease severity.

Cardiac-resynchronization therapy in heart failure with a narrow QRS complex.

BACKGROUND: Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in chronic systolic heart failure with a wide QRS complex. Mechanical dyssynchrony also occurs in patients with a narrow QRS complex, which suggests the potential usefulness of CRT in such patients. METHODS: We conducted a randomized trial involving 115 centers to evaluate the effect of CRT in patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35% or less, a QRS duration of less than 130 msec, and echocardiographic evidence of left ventricular dyssynchrony. All patients underwent device implantation and were randomly assigned to have CRT capability turned on or off. The primary efficacy outcome was the composite of death from any cause or first hospitalization for worsening heart failure. RESULTS: On March 13, 2013, the study was stopped for futility on the recommendation of the data and safety monitoring board. At study closure, the 809 patients who had undergone randomization had been followed for a mean of 19.4 months. The primary outcome occurred in 116 of 404 patients in the CRT group, as compared with 102 of 405 in the control group (28.7% vs. 25.2%; hazard ratio, 1.20; 95% confidence interval [CI], 0.92 to 1.57; P=0.15). There were 45 deaths in the CRT group and 26 in the control group (11.1% vs. 6.4%; hazard ratio, 1.81; 95% CI, 1.11 to 2.93; P=0.02). CONCLUSIONS: In patients with systolic heart failure and a QRS duration of less than 130 msec, CRT does not reduce the rate of death or hospitalization for heart failure and may increase mortality. (Funded by Biotronik and GE Healthcare; EchoCRT ClinicalTrials.gov number, NCT00683696.).

The effect of QRS duration on cardiac resynchronization therapy in patients with a narrow QRS complex: a subgroup analysis of the EchoCRT trial.

AIMS: In EchoCRT, a randomized trial evaluating the effect of cardiac resynchronization therapy (CRT) in patients with a QRS duration of <130 ms and echocardiographic evidence of left ventricular dyssynchrony, the primary outcome occurred more frequently in the CRT when compared with the control group. According to current heart failure guidelines, CRT is recommended in patients with a QRS duration of ≥120 ms. However, there is some ambiguity from clinical trial data regarding the benefit of patients with a QRS duration of 120-130 ms. METHODS AND RESULTS: The main EchoCRT trial was prematurely terminated due to futility. For the current subgroup analysis we compared data for CRT-ON vs. -OFF in patients with QRS < 120 (n = 661) and QRS 120-130 ms (n = 139). On uni- and multivariable analyses, no significant interaction was observed between the two groups and randomized treatment for the primary or any of the secondary endpoints. On multivariable analysis, a higher risk for the primary endpoint was observed in patients with a QRS duration of 120-130 ms randomized to CRT-ON vs. CRT-OFF (hazard ratio 2.18, 95% CI 1.02-4.65; P = 0.044). However, no statistically significant interaction, compared with patients with QRS < 120 ms randomized to CRT-ON vs. CRT-OFF, was noted (P-interaction = 0.160). CONCLUSIONS: In this pre-specified subgroup analysis of EchoCRT, no benefit of CRT was evident in patients with a QRS duration of 120-130 ms. These data further question the usefulness of CRT in this patient population.

Clinical trial design principles and endpoint definitions for transcatheter mitral valve repair and replacement: part 1: clinical trial design principles: A consensus document from the mitral valve academic research consortium.

Mitral regurgitation (MR) is one of the most prevalent valve disorders and has numerous aetiologies, including primary (organic) MR, due to underlying degenerative/structural mitral valve (MV) pathology, and secondary (functional) MR, which is principally caused by global or regional left ventricular remodelling and/or severe left atrial dilation. Diagnosis and optimal management of MR requires integration of valve disease and heart failure specialists, MV cardiac surgeons, interventional cardiologists with expertise in structural heart disease, and imaging experts. The introduction of transcatheter MV therapies has highlighted the need for a consensus approach to pragmatic clinical trial design and uniform endpoint definitions to evaluate outcomes in patients with MR. The Mitral Valve Academic Research Consortium is a collaboration between leading academic research organizations and physician-scientists specializing in MV disease from the United States and Europe. Three in-person meetings were held in Virginia and New York during which 44 heart failure, valve, and imaging experts, MV surgeons and interventional cardiologists, clinical trial specialists and statisticians, and representatives from the U.S. Food and Drug Administration considered all aspects of MV pathophysiology, prognosis, and therapies, culminating in a 2-part document describing consensus recommendations for clinical trial design (Part 1) and endpoint definitions (Part 2) to guide evaluation of transcatheter and surgical therapies for MR. The adoption of these recommendations will afford robustness and consistency in the comparative effectiveness evaluation of new devices and approaches to treat MR. These principles may be useful for regulatory assessment of new transcatheter MV devices, as well as for monitoring local and regional outcomes to guide quality improvement initiatives.

Heart Rate, Life Expectancy and the Cardiovascular System: Therapeutic Considerations.

It has long been known that life span is inversely related to resting heart rate in most organisms. This association between heart rate and survival has been attributed to the metabolic rate, which is greater in smaller animals and is directly associated with heart rate. Studies have shown that heart rate is related to survival in apparently healthy individuals and in patients with different underlying cardiovascular diseases. A decrease in heart rate due to therapeutic interventions may result in an increase in survival. However, there are many factors regulating heart rate, and it is quite plausible that these may independently affect life expectancy. Nonetheless, a fast heart rate itself affects the cardiovascular system in multiple ways (it increases ventricular work, myocardial oxygen consumption, endothelial stress, aortic/arterial stiffness, decreases myocardial oxygen supply, other) which, in turn, may affect survival. In this brief review, the effects of heart rate on the heart, arterial system and survival will be discussed.

Effect of Combining Ivabradine and ß-Blockers: Focus on the Use of Carvedilol in the SHIFT Population.

OBJECTIVES: We explored the prescription of ß-blockers with ivabradine in patients with systolic heart failure, focusing on the most frequently coprescribed ß-blocker, carvedilol. METHODS: We analyzed outcomes in SHIFT patients with systolic heart failure who were prescribed ß-blockers (carvedilol, bisoprolol, metoprolol, or nebivolol) with ivabradine or placebo. Analysis was by intention to treat in patients prescribed a ß-blocker at the time of the event. RESULTS: Data were available for 2,596 patients receiving carvedilol, 1,483 bisoprolol, 1,424 metoprolol, and 197 nebivolol. Mean treatment duration was 19 months. There was no difference in the effect of ivabradine on the primary composite endpoint of cardiovascular death or heart failure hospitalization between the various ß-blockers [hazard ratios (HR) for risk reduction, 0.75-0.89; p for interaction=0.86]. Patients prescribed carvedilol with ivabradine had lower rates of primary composite endpoint (HR 0.80, 95% CI: 0.68-0.94), heart failure hospitalization (HR 0.73, 95% CI: 0.61-0.88), and cardiovascular hospitalization (HR 0.80, 95% CI: 0.69-0.92) versus carvedilol with placebo. The dosage of carvedilol had no detectable effect and there were no unexpected safety issues. CONCLUSIONS: Whatever ß-blocker was coprescribed with ivabradine, there were improvements in cardiovascular outcomes in patients with systolic heart failure, especially with the most prescribed ß-blocker--carvedilol.

Relation of indirect vasodilator use to prognosis in patients with chronic severe mitral regurgitation.

OBJECTIVES: The relation of indirect vasodilator use to cardiac events (CE) is undefined for chronic severe nonischemic mitral regurgitation (MR). The aim of this study was to resolve this knowledge deficiency. METHODS: Data from 52 consecutive patients in our prospective natural history study with isolated chronic severe nonischemic MR were assessed post hoc over 19 years to examine the relation of indirect vasodilator use to subsequent CE (death or indications for valve surgery). At entry, no patient had surgical indications, 14% had hypertension (HTN) and 7 chronically received vasodilators (5 angiotensin-converting enzyme inhibitor, 1 receptor blocker and 1 α-adrenergic blocker). CE differences were assessed by log-rank comparison of Kaplan-Meier curves. RESULTS: During follow-up, CE included sudden death (1 patient), heart failure (7 patients), atrial fibrillation (6 patients), left ventricular (LV) systolic dimension >4.5 cm (12 patients), LV ejection fraction (EF) <60% (7 patients), right ventricular EF <35% (2 patients) and combination CE (7 patients). Overall, vasodilator use did not predict CE (not significant). However, patients without HTN had higher CE rates with vasodilators than without (p = 0.007), while those with HTN and vasodilators had lower CE rates than those without vasodilators (p = 0.04). CONCLUSION: Vasodilator use appears to confer no survival benefit in patients with chronic severe MR. The small number of patients with HTN precludes conclusions about modulation of vasodilator effect by HTN. Randomized trials are needed to conclusively evaluate this association.