Prognostic value of myocardial perfusion scintigraphy in asymptomatic patients with diabetes mellitus at high cardiovascular risk: 5-year follow-up of the prospective multicenter BARDOT trial.

BACKGROUND: The Basel Asymptomatic High-Risk Diabetics' Outcome Trial (BARDOT) demonstrated that asymptomatic diabetic patients with an abnormal myocardial perfusion scintigraphy (MPS) were at increased risk of major adverse cardiovascular events (MACEs) at 2-year follow-up. It remains unclear whether this finding holds true even for a longer follow-up. METHODS: Four hundred patients with type 2 diabetes, neither history nor symptoms of coronary artery disease (CAD), were evaluated clinically and with MPS. Patients were followed up for 5 years. Major adverse cardiovascular events (MACEs) were defined as all-cause death, myocardial infarction, or late coronary revascularization. RESULTS: At baseline, an abnormal MPS (SSS ≥ 4 or SDS ≥ 2) was found in 87 of 400 patients (22%). MACE within 5 years occurred in 14 patients with abnormal MPS (16.1%) and in 22 with normal scan (1.7%), p = 0.009; 15 deaths were recorded. Patients with completely normal MPS (SSS and SDS = 0) had lower rates of MACEs than patients with abnormal scans (2.5% vs. 7.0%, p = 0.032). Patients with abnormal MPS who had undergone revascularization had a lower mortality rate and a better event-free survival from MI and revascularization than patients with abnormal MPS who had either undergone medical therapy only or could not be revascularized (p = 0.002). CONCLUSIONS: MPS may have prognostic value in asymptomatic diabetic patients at high cardiovascular risk over a follow-up period of 5 years. Patients with completely normal MPS have a low event rate and may not need retesting within 5 years. Patients with an abnormal MPS have higher event rates and may benefit from a combined medical and revascularization approach.

Long-Term Results After Drug-Eluting Versus Bare-Metal Stent Implantation in Saphenous Vein Grafts: Randomized Controlled Trial.

Background Efficacy data on drug-eluting stents (DES) versus bare-metal stents (BMS) in saphenous vein grafts are controversial. We aimed to compare DES with BMS among patients undergoing saphenous vein grafts intervention regarding long-term outcome. Methods and Results In this multinational trial, patients were randomized to paclitaxel-eluting or BMS. The primary end point was major adverse cardiac events (cardiac death, nonfatal myocardial infarction, and target-vessel revascularization at 1 year. Secondary end points included major adverse cardiac events and its individual components at 5-year follow-up. One hundred seventy-three patients were included in the trial (89 DES versus 84 BMS). One-year major adverse cardiac event rates were lower in DES compared with BMS (2.2% versus 16.0%, hazard ratio, 0.14; 95% CI, 0.03-0.64, P=0.01), which was mainly driven by a reduction of subsequent myocardial infarctions and need for target-vessel revascularization. Five-year major adverse cardiac event rates remained lower in the DES compared with the BMS arm (35.5% versus 56.1%, hazard ratio, 0.40; 95% CI, 0.23-0.68, P<0.001). A landmark-analysis from 1 to 5 years revealed a persistent benefit of DES over BMS (hazard ratio, 0.33; 95% CI, 0.13-0.74, P=0.007) in terms of target-vessel revascularization. More patients in the BMS group underwent multiple target-vessel revascularization procedures throughout the study period compared with the DES group (DES 1.1% [n=1] versus BMS 9.5% [n=8], P=0.013). Enrollment was stopped before the target sample size of 240 patients was reached. Conclusions In this randomized controlled trial with prospective long-term follow-up of up to 5 years, DES showed a better efficacy than BMS with sustained benefits over time. DES may be the preferred strategy in this patient population. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00595647.

Limited role for fibroblast growth factor 23 in assessing prognosis in heart failure patients: data from the TIME-CHF trial.

AIM: Fibroblast growth factor 23 (FGF23) is an intensively studied biomarker at the crossroads of cardiovascular disease, heart failure (HF) and chronic kidney disease. Independent associations between increasing FGF23 levels and cardiovascular events were found in many, but not all studies. By analysing data from the TIME-CHF cohort, we sought to investigate the prognostic value of FGF23 in an elderly, multimorbid HF patient cohort. We determined differences between intact (iFGF23) and C-terminal FGF23 (cFGF23) regarding their prognostic value and their levels over time in different HF subgroups according to left ventricular ejection fraction (LVEF). METHODS AND RESULTS: In this multicentre trial of 622 patients with symptomatic HF aged ≥60 years, we determined iFGF23 and cFGF23 at baseline, 3, 6 and 12-month follow-up. In unadjusted analyses, cFGF23 significantly predicted all HF-related outcomes at all time points. The predictive value of iFGF23 was less and not statistically significant at baseline. After multivariable adjustments, the association between both cFGF23 and iFGF23 and outcome lost statistical significance apart from cFGF23 at month 3. Overall, patients with preserved and mid-range LVEF had higher levels of iFGF23 and cFGF23 than those with reduced LVEF. Levels decreased significantly during the first 3 months in mid-range and reduced LVEF patients, but did not significantly change over time in those with preserved LVEF. CONCLUSIONS: Fibroblast growth factor 23 is of limited value regarding risk prediction in this elderly HF population. Potentially heterogeneous roles of FGF23 in different LVEF groups deserve further investigation.

Do ultrathin strut bare-metal stents with passive coating improve efficacy in large coronary arteries? Insights from the randomized, multicenter BASKET-PROVE trials.

BACKGROUND: The new generation thinner-strut silicon carbide (SiC) coated cobalt chromium (CoCr) bare-metal stents (BMS) are designed to accelerate rapid endothelialisation and reduce thrombogenicity when implanted in coronary arteries. However, smaller studies suggest higher rates of symptomatic restenosis in patients receiving the newer generation BMS. We investigated the efficacy of a newer generation ultrathin strut silicon-carbide coated cobalt-chromium (CoCr) BMS (SCC-BMS) as compared to an older thin-strut uncoated CoCr BMS (UC-BMS) in patients presenting with coronary artery disease requiring stenting of large vessels (≥3.0 mm). METHODS: All patients randomized to SCC- (n = 761) or UC-BMS (n = 765) in the two BASKET-PROVE trials were included. Design, patients, interventions and follow-up were similar between trials except differing regimens of dual antiplatelet therapy. The primary endpoint was clinically driven target-vessel revascularization within 24 months. Safety endpoints of cardiac death, non-fatal myocardial infarction (MI), and definite/probable stent thrombosis (ST) were also assessed. We used inverse probability weighted proportional hazards Cox regressions adjusting for known confounders. RESULTS: Demographics, clinical presentation, and risk factors were comparable between the groups, but patients receiving SCC-BMS underwent less complex procedures. The risk for clinically driven TVR was increased om the SCC-BMS group compared to the UC-BMS group (cumulative incidence, 10.6% vs. 8.4%; adjusted relative hazard [HR], 1.49 [95% CI, 1.05-2.10]). No differences in safety endpoints were detected, cardiac death (1.6% vs. 2.8%; HR, 0.62 [CI, 0.30-1.27]), non-fatal MI (3.2% vs. 2.5%; HR, 1.56 [CI, 0.83-2.91]), and definite/probable ST (0.8% vs. 1.1%; HR, 1.17 [CI, 0.39-3.50]). Differences in strut thickness between the two stents did not explain the association between stent type and clinically driven TVR. CONCLUSIONS: In patients requiring stenting of large coronary arteries, use of the newer generation SCC-BMS was associated with a higher risk of clinically driven repeat revascularization compared to the UC-BMS with no signs of an offsetting safety benefit.

Drug-eluting stents in large coronary vessels improve both safety and efficacy compared with bare-metal stents in women: a pooled analysis of the BASKET-PROVE I and II trials.

Background: Drug-eluting stents (DES) have proven superior to bare-metal stents (BMS) in terms of safety and efficacy. However, inference to the female subgroup has been limited by low enrolment rates of women in clinical trials. The objective of this study was to investigate the safety and efficacy of DES versus BMS in women and men. Methods: In a pooled analysis of two all-comers randomised trials (Basel Stent Kosten-Effektivitäts Trial-Prospective Validation Examination (BASKET-PROVE) and BASKET-PROVE II) (n=4605), we examined safety and efficacy of DES versus BMS according to sex. Patients were followed 2 years for a composite endpoint of cardiac death, non-fatal myocardial infarction (MI) and clinically driven target-vessel revascularisation not related to MI. Results: Among the 1076 women and 3529 men included in the analysis, 65.6% of the women and 67.2% of the men were randomised to receive DES. At baseline, men had more complex coronary artery disease than women. After 2 years, DES reduced rates of major adverse cardiac events (MACE) compared with BMS in both women (cumulative incidence, 6.1% vs 14.7%; adjusted HR 0.36 (95% CI 0.24 to 0.54)) and men (7.7 vs 12.1%, HR 0.62 (0.50 to 0.77)), although the reduction in MACE rates was more pronounced in women (adjusted p=0.02 for sex-stent interaction). Event rates were lower in DES for both safety and efficacy outcomes, with the largest effect seen for non-MI TVR, in both women (2.3 vs 9.2%, adjusted HR 0.24 (0.13 to 0.44)) and men (4.0 vs 7.8%, adjusted HR 0.48 (0.36 to 0.64)) (adjusted p=0.049 for sex-stent interaction). Conclusions: In patients requiring stenting of large coronary arteries, DES were associated with improved safety in women and superior efficacy in both sexes as compared with BMS.

Prognostic Significance of Longitudinal Clinical Congestion Pattern in Chronic Heart Failure: Insights From TIME-CHF Trial.

BACKGROUND: The relationship between longitudinal clinical congestion pattern and heart failure outcome is uncertain. This study was designed to assess the prevalence of congestion over time and to investigate its impact on outcome in chronic heart failure. METHODS: A total of 588 patients with chronic heart failure older than 60 years of age with New York Heart Association (NYHA) functional class ≥II from the TIME-CHF study were included. The endpoints for this study were survival and hospitalization-free heart failure survival. Orthopnea, NYHA ≥III, paroxysmal nocturnal dyspnea, hepatomegaly, peripheral pitting edema, jugular venous distension, and rales were repeatedly investigated and related to outcomes. These congestion-related signs and symptoms were used to design a 7-item Clinical Congestion Index. RESULTS: Sixty-one percent of patients had a Clinical Congestion Index ≥3 at baseline, which decreased to 18% at month 18. During the median [interquartile range] follow-up of 27.2 [14.3-39.8] months, 17%, 27%, and 47% of patients with baseline Clinical Congestion Index of 0, 1-2, and ≥3 at inclusion, respectively, died (P <.001). Clinical Congestion Index was identified as an independent predictor of mortality at all visits (P <.05) except month 6 and reduced hospitalization-free heart failure survival (P <.05). Successful decongestion was related to better outcome as compared to persistent congestion or partial decongestion (log-rank P <0.001). CONCLUSIONS: The extent of congestion as assessed by means of clinical signs and symptoms decreased over time with intensified treatment, but it remained present or relapsed in a substantial number of patients with heart failure and was associated with poor outcome. This highlights the importance of appropriate decongestion in chronic heart failure.

Competing risks of major bleeding and thrombotic events with prasugrel-based dual antiplatelet therapy after stent implantation - An observational analysis from BASKET-PROVE II.

BACKGROUND: Dual antiplatelet therapy (DAPT) prevents thrombotic events after coronary stent implantation but may induce bleedings, specifically in elderly patients. However, a competitive risk analysis is lacking. OBJECTIVES: To assess the determinants of major bleeding and the balance between the competing risks of major bleeding and thrombotic events during prasugrel-based DAPT after stent implantation. METHODS: Overall, 2,291 patients randomized to drug-eluting or bare metal stents and treated with prasugrel 10mg/day for 1 year were followed over 2 years for major bleeding (BARC 3/5) and thrombotic events (cardiac death, myocardial infarction, definitive/probable stent thrombosis). Prasugrel dose was reduced to 5mg in patients >75 years and/or <60kg. Predictors of major bleeding and competing risks of major bleeding and thrombotic events were assessed. RESULTS: Two-year rates of major bleeding and thrombotic events were 2.9% and 9.0%, respectively. The only independent predictor of major bleeding was age (hazard ratio per year increase 1.05 [1.02,1.07], p<0.001). The relationship between major bleeding and age was non-linear, with lowest hazard ratios at 57 years and an exponential increase only above 65 years. In contrast, the relationship between thrombotic events and age was linear and continuously increasing with older age. While the competing risk of thrombotic events was higher than that of major bleeding in younger patients, the two risks were similar in older patients. After discontinuation of prasugrel, bleeding events leveled off in all patients, while thrombotic events continued to increase. CONCLUSIONS: In prasugrel-based DAPT, age is the strongest risk factor for major bleeding, increasing exponentially >65 years. In younger patients, thrombotic events represent a higher risk than bleeding, while thrombotic and bleeding risks were similar in older patients. Important clinical implications relate to prasugrel dose in the elderly, duration of DAPT and the competing risk balance necessitating individualized treatment decisions.

Novel concept to guide systolic heart failure medication by repeated biomarker testing-results from TIME-CHF in context of predictive, preventive, and personalized medicine.

BACKGROUND: It is uncertain whether repeated measurements of a multi-target biomarker panel may help to personalize medical heart failure (HF) therapy to improve outcome in chronic HF. METHODS: This analysis included 499 patients from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF), aged ≥ 60 years, LVEF ≤ 45%, and NYHA ≥ II, who had repeated clinical visits within 19 months follow-up. The interaction between repeated measurements of biomarkers and treatment effects of loop diuretics, spironolactone, ß-blockers, and renin-angiotensin system (RAS) inhibitors on risk of HF hospitalization or death was investigated in a hypothesis-generating analysis. Generalized estimating equation (GEE) models were used to account for the correlation between recurrences of events in a patient. RESULTS: One hundred patients (20%) had just one event (HF hospitalization or death) and 87 (17.4%) had at least two events. Loop diuretic up-titration had a beneficial effect for patients with high interleukin-6 (IL6) or high high-sensitivity C-reactive protein (hsCRP) (interaction, P = 0.013 and P = 0.001), whereas the opposite was the case with low hsCRP (interaction, P = 0.013). Higher dosage of loop diuretics was associated with poor outcome in patients with high blood urea nitrogen (BUN) or prealbumin (interaction, P = 0.006 and P = 0.001), but not in those with low levels of these biomarkers. Spironolactone up-titration was associated with lower risk of HF hospitalization or death in patients with high cystatin C (CysC) (interaction, P = 0.021). ß-Blockers up-titration might have a beneficial effect in patients with low soluble fms-like tyrosine kinase-1 (sFlt) (interaction, P = 0.021). No treatment biomarker interactions were found for RAS inhibition. CONCLUSION: The data of this post hoc analysis suggest that decision-making using repeated biomarker measurements may be very promising in bringing treatment of heart failure to a new level in the context of predictive, preventive, and personalized medicine. Clearly, prospective testing is needed before this novel concept can be adopted. CLINICAL TRIAL REGISTRATION: isrctn.org, identifier: ISRCTN43596477.

Is the clinical presentation of chronic heart failure different in elderly versus younger patients and those with preserved versus reduced ejection fraction?

BACKGROUND: Whether the clinical presentation and in particular prevalence of symptoms and signs of heart failure (HF) is different in elderly versus younger patients and in those with reduced (HFrEF) versus preserved (HFpEF) left ventricular ejection fraction (LVEF) is a matter of ongoing debate. AIMS: To compare detailed clinical characteristics of these important subgroups and to develop a prediction rule for the differentiation of HFpEF and HFrEF based on clinical parameters. METHODS: The analysis was based on the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) comprising 622 patients ≥60 years with HF including the whole LVEF spectrum. RESULTS: In the groups ≥75 years and with HFpEF typical symptoms and clinical signs of HF were more prevalent as compared to those <75 years or with HFrEF, respectively. The burden of comorbidities was higher in the older age group. HFrEF could not be differentiated from HFpEF by symptom history and clinical examination alone. However, a combination of age, presence of pulmonary rales, systolic blood pressure, cause of heart failure, osteoporosis, current smoking, NT-proBNP, haemoglobin, QRS width and heart rhythm allowed to identify HFrEF versus HFpEF with a sensitivity of 81% and specificity of 90% (c-statistics 0.91). CONCLUSIONS: More symptoms and signs of HF were present both in the older age group and in patients with HFpEF. HFpEF versus HFrEF could be differentiated by a set of simple clinical, laboratory and ECG parameters but not by symptom history and physical examination alone.

Second generation drug-eluting stents versus bare-metal stents for percutaneous coronary intervention of the proximal left anterior descending artery: An analysis of the BASKET-PROVE I and II trials.

OBJECTIVES: To compare mid-term outcomes between patients undergoing proximal left anterior descending artery (LAD) percutaneous coronary intervention (PCI) with second generation drug-eluting stent (DES) or bare-metal stent (BMS). BACKGROUND: PCI with BMS and first-generation DES have shown to be safe options for the treatment of proximal LAD stenosis, however associated with considerable reintervention rates. Overall, second-generation DES has proven to be superior to BMS and first-generation DES, nevertheless, its effect for proximal LAD PCI has not previously been reported. METHODS: We analyzed 2-year outcomes of 1,100 patients from the BASKET-PROVE I and II trials, referred for proximal LAD PCI with second generation DES (n = 680) or BMS (n = 420). RESULTS: The cumulative 2-year incidence of major adverse cardiac events (MACE, composite of cardiac death, myocardial infarction (MI) and target vessel revascularization (TVR)) was lower in second generation DES than in BMS treated patients (7.3% vs. 12.3%; HR 0.57, 95% CI 0.39/0.85), mainly driven by a reduced rate of TVR (3.7% vs. 10.0%; HR 0.35, CI 0.21/0.58). No difference was found in cardiac death (1.9% vs. 1.9%; HR 1.01, CI 0.42/2.44) and MI (4.4% vs. 4.7%; HR 0.93, CI 0.53/1.64). The benefit of DES use seemed to be more prominent in female patients with a reduction in MACE (P for interaction = 0.025). CONCLUSIONS: In patients with proximal LAD stenosis, treatment with second-generation DES was associated with reduced 2-year rates of adverse cardiac events and TVR compared to BMS, with reintervention rates similar to those earlier reported from bypass surgery.

Predictors and prognostic impact of silent coronary artery disease in asymptomatic high-risk patients with diabetes mellitus.

AIMS: Evaluation of predictors of silent coronary artery disease (SCAD) in high-risk asymptomatic diabetic patients and to evaluate their two-year outcome. METHODS AND RESULTS: Four hundred diabetic patients without prior CAD but at high CAD risk underwent myocardial perfusion scintigraphy (MPS) in this prospective multicentre outcome trial. MPS were abnormal in 22% of patients. Male sex (OR 2.223, 1.152-4.290; p=0.017), diabetes duration (OR 1.049,1.015-1.085; p=0·005), peripheral artery disease (OR 2.134, 1·150-3.961; p=0.016), smoking (OR 2.064, 1.109-3.839; p=0·022), systolic blood pressure (OR 1.014, 1.00-1.03, p=0·056), brain natriuretic peptide (OR 1.002, 1.001-1.004, p=0·005) independently predicted an abnormal MPS: if <2 and >3 predictors were present, 3.2% and 47% patients had an abnormal MPS, respectively (p<0·001). Two-year major adverse cardiac event rates increased from 2·9% to 14·6%, cardiac death rates from 0·6% to 4·1% in patients with summed stress scores ≤10 and >10%, respectively (each p<0.045). CONCLUSIONS: Male sex, diabetes duration, peripheral artery disease, smoking, elevated systolic blood pressure and increased brain-natriuretic peptides independently predicted SCAD. In presence of >3 predictors, almost 50% of patients had an abnormal MPS. They may benefit from screening by MPS since the extent of the MPS abnormality discriminated clearly between a favourable compared to a bad 2-year outcome. However, even highest risk patients without objective evidence of CAD had a benign prognosis without need for specific evaluation or therapy. TRIAL REGISTRATION NUMBER: ISRCTN87953632.

Prasugrel vs. clopidogrel in contemporary Western European patients with acute coronary syndromes receiving drug-eluting stents: Comparative cost-effectiveness analysis from the BASKET-PROVE cohorts.

BACKGROUND: Clinical and cost-effectiveness of prasugrel vs. clopidogrel in acute coronary syndrome (ACS) was only evaluated using TRITON-TIMI 38 event rates. A comparative analysis of both drugs in contemporary European ACS patients is lacking. METHODS: To address this issue, cardiac and bleeding events of 2 "sister" multicenter stent trials, BASKET-PROVE (BP) I with clopidogrel and BPII with prasugrel (for 12months each) were used in a hybrid analysis. Medication costs were 2015 sales prices, event costs modelled for Denmark (DNK), Germany (GER) and Switzerland (SUI) and quality adjusted life years (QALY) by EQ-5D-3L questionnaire. RESULTS: In BPI and II, 1012 and 985 ACS-patients received drug eluting stents, respectively, followed-up for 2years. Compared to clopidogrel, prasugrel-treated patients had no more major cardiac events (5.2% vs. 6.4%, p=0.422) nor cardiac deaths (1.6% vs. 1.0%, p=0.255), but more major bleedings (4.0% vs. 1.7%, p<0.001) and altogether no difference in QALYs (-0.027 (95%CI: -0.064/0.011)). Prasugrel caused higher total expenditures per patient: 1116.3 (DNK), 1063.5 (GER) and 880.8 (SUI) EURO, respectively. Accordingly, incremental cost-effectiveness was negative for prasugrel vs. clopidogrel with ratios of -45,907 (DNK), -39,909 (GER) and -33,435 (SUI) EURO/QALY gained, making clopidogrel an economically dominant strategy, even after accounting for the non-randomized comparison. CONCLUSION: Findings of this contemporary European ACS-cohort showed markedly lower cardiac event rates than TRITON-TIMI 38 and no significant difference in 2-year QALYs between prasugrel and clopidogrel-treated patients. At current drug prices, clopidogrel use resulted in an economically dominant treatment strategy in Western European patients.

Prognostic Usefulness of Cardiac Stress Test Modalities in Patients With Type 2 Diabetes Mellitus Who Underwent Myocardial Perfusion Scintigraphy (from the Basel Asymptomatic High-Risk Diabetics' Outcome Trial).

Our study aimed to assess predictors of the stress test technique used and to evaluate the impact of exercise level achieved on risk stratification in patients with asymptomatic type 2 diabetes without a previous coronary artery disease. Little is known whether co-morbidities of these patients predict the stress technique and whether physical performance provides risk stratification: 400 patients underwent clinical evaluation and myocardial perfusion scintigraphy (MPS) using physical or pharmacological stress. Physical patients were divided into 2 groups: achieving <6 and ≥6 METs, respectively. The mean follow-up time was 2 years. Major cardiac events (MACEs) included myocardial infarction and/or cardiac death. Independent predictors of pharmacological stress were a body mass index of >30 kg/m2 (hazard ratio 1.076, 95% confidence interval 1.027 to 1.127, p = 0.002) and a peripheral arterial disease (hazard ratio 2.888, 95% confidence interval 1.446 to 5.769, p = 0.003). Pharmacological patients had more MACE than physical patients (3.2% vs 1.0%, p = 0.03). Patients achieving <6 METs had a similar MACE rate as pharmacological patients (3.0% vs 3.2%, p = not significant) and more MACE than patients achieving ≥6 METs (3.0% vs 0.4%, p = 0.01). In patients achieving <6 METs and in pharmacological patients, MPS added an incremental prognostic value to pretest information (p values for global chi-square 0.012 and 0.04, respectively). In high-risk asymptomatic diabetic patients, co-morbidities were predictive of the stress technique used. Pharmacological patients had more MACE, similar to those unable to achieve 6 METs. MPS provided an incremental prognostic value in pharmacological patients and in patients with <6METs. In contrast, patients who were able to achieve ≥6 METs were at low risk and do not need further risk stratification.

Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF).

AIMS: While the conditions of heart failure (HF) with reduced (HFrEF, LVEF < 40%) and preserved (HFpEF, LVEF ≥ 50%) left ventricular ejection fraction (LVEF) are well characterized, it is unknown whether patients with HF and mid-range LVEF (HFmrEF, LVEF 40-49%) have to be regarded as a separate clinical entity. The aim of this study was to characterize these three populations and to compare outcome and response to therapy. METHODS AND RESULTS: The analysis was based on the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) comprising a population with established HF including the whole spectrum of LVEF. Of the 622 patients, 108 (17%) were classified as having HFmrEF. This group was in general found to be 'intermediate' regarding clinical characteristics with a comparable and high burden of comorbidities and equally impaired quality of life but was more likely to have coronary artery disease as compared with the HFpEF group. During a median follow-up of 794 days, mortality was 39.7% without significant differences between groups. N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided as compared with standard therapy resulted in improved survival free of HF hospitalizations in HFrEF and HFmrEF, but not in HFpEF. CONCLUSION: Although the 'intermediate' clinical profile of HFmrEF between HFrEF and HFpEF would support the conclusion that HFmrEF is a distinct clinical entity, we hypothesize that HFmrEF has to be categorized as HFrEF because of the high prevalence of coronary artery disease and the similar benefit of NT-proBNP-guided therapy in HFrEF and HFmrEF, in contrast to HFpEF.

N-Terminal Pro-B-Type Natriuretic Peptide-Guided Therapy in Chronic Heart Failure Reduces Repeated Hospitalizations-Results From TIME-CHF.

BACKGROUND: Although heart failure (HF) patients are known to experience repeated hospitalizations, most studies evaluated only time to first event. N-Terminal B-type natriuretic peptide (NT-proBNP)-guided therapy has not convincingly been shown to improve HF-specific outcomes, and effects on recurrent all-cause hospitalization are uncertain. Therefore, we investigated the effect of NT-proBNP-guided therapy on recurrent events in HF with the use of a time-between-events approach in a hypothesis-generating analysis. METHODS AND RESULTS: The Trial of Intensified Versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized 499 HF patients, aged ≥60 years, left ventricular ejection fraction ≤45%, New York Heart Association functional class ≥I,I to NT-proBNP-guided versus symptom-guided therapy for 18 months, with further follow-up for 5.5 years. The effect of NT-proBNP-guided therapy on recurrent HF-related and all-cause hospitalizations and/or all-cause death was explored. One hundred four patients (49 NT-proBNP-guided, 55 symptom-guided) experienced 1 and 275 patients (133 NT-proBNP-guided, 142 symptom-guided) experienced ≥2 all-cause hospitalization events. Regarding HF hospitalization, 132 patients (57 NT-proBNP-guided, 75 symptom-guided) experienced 1 and 122 patients (57 NT-proBNP-guided, 65 symptom-guided) experienced ≥2 events. NT-proBNP-guided therapy was significant in preventing 2nd all-cause hospitalizations (hazard ratio [HR] 0.83; P = .01), in contrast to nonsignificant results in preventing 1st all-cause hospitalization events (HR 0.91; P = .35). This was not the case regarding HF hospitalization events (HR 0.85 [P = .14] vs HR 0.73 [P = .01]) The beneficial effect of NT-proBNP-guided therapy was seen only in patients aged <75 years, and not in those aged ≥75 years (interaction terms with P = .01 and P = .03 for all-cause hospitalization and HF hospitalization events, respectively). CONCLUSION: NT-proBNP-guided therapy reduces the risk of recurrent events in patients <75 years of age. This included all-cause hospitalization by mainly reducing later events, adding knowledge to the neutral effect on this end point when shown using time-to-first-event analysis only. CLINICAL TRIAL REGISTRATION: isrctn.org, identifier: ISRCTN43596477.

Quality of life as predictor for the development of cardiac ischemia in high-risk asymptomatic diabetic patients.

BACKGROUND: Ischemia induced by psychological stress and depression is a common phenomenon in stable coronary artery disease (CAD). We evaluated the quality of life (QoL) of diabetic patients screened for CAD and assessed the prognostic value of mental and physical QoL scores to predict the development of new cardiac ischemia. METHODS: Prospective multicentre outcome study. The study comprised 400 asymptomatic diabetic patients without history or symptoms of CAD. They underwent myocardial perfusion single-photon emission computed tomography (MPS) and assessment of QoL by two questionnaires: Hospital Depression and Anxiety Scale (HADS-D and HADS-A) and Medical Outcomes Study Short Form 36 (SF-36) at baseline and after 2 years. Patients with normal MPS received usual care; those with abnormal MPS received medical or combined invasive and medical management. RESULTS: Only mental QoL scores but not physical QoL scores or traditional cardiovascular risk factors were predictive of new ischemia (n = 11/306) during follow-up. The prognostic value for new ischemia as quantified by the area under the receiver operating characteristics curve (AUC) amounted to 0.784 (95% confidence interval (CI) 0.654-0.914, P = 0.002) for HADS-D and to 0.737 (95% CI 0.580-0.893, P = 0.011) for HADS-A. This finding was confirmed by SF-36 mental sum score (AUC 0.688, 95% CI 0.539-0.836, P = 0.036), but not SF-36 physical sum score. QoL scores did not change after 2 years in patients with ischemia at baseline. CONCLUSIONS: QoL scores assessing mental health, particularly depression and anxiety, predicted the development of new cardiac ischemia in asymptomatic diabetic patients. The study is limited by a small number of events (new ischemia) and so the results should be considered hypothesis generating rather than conclusive.

Long-term outcomes in patients with rheumatologic disorders undergoing percutaneous coronary intervention: a BAsel Stent Kosten-Effektivitäts Trial-PROspective Validation Examination (BASKET-PROVE) sub-study.

AIMS: Rheumatologic disorders are characterised by inflammation and an increased risk of coronary artery disease (CAD). However, the association between rheumatologic disorders and long-term prognosis in CAD patients undergoing percutaneous coronary intervention (PCI) is unknown. Thus, we aimed to examine the association between rheumatologic disorders and long-term prognosis in CAD patients undergoing PCI. METHODS AND RESULTS: A post-hoc analysis was performed in 4605 patients (age: 63.3 ± 11.0 years; male: 76.6%) with ST-segment elevation myocardial infarction (STEMI; n = 1396), non-STEMI ( n = 1541), and stable CAD ( n = 1668) from the all-comer stent trials, the BAsel Stent Kosten-Effektivitäts Trial-PROspective Validation Examination (BASKET-PROVE) I and II trials. We evaluated the association between rheumatologic disorders and 2-year major adverse cardiac events (MACEs; cardiac death, nonfatal myocardial infarction (MI), and target vessel revascularisation (TVR)) by Cox regression analysis. Patients with rheumatologic disorders ( n = 197) were older, more often female, had a higher prevalence of renal disease, multi-vessel coronary disease, and bifurcation lesions, and had longer total stent lengths. During the 2-year follow-up, the MACE rate was 8.6% in the total cohort. After adjustment for potential confounders, rheumatologic disorders were associated with MACEs in the total cohort (adjusted hazard ratio: 1.55; 95% confidence interval (CI): 1.04-2.31) driven by the STEMI subgroup (adjusted hazard ratio: 2.38; 95% CI: 1.26-4.51). In all patients, rheumatologic disorders were associated with all-cause death (adjusted hazard ratio: 2.05; 95% CI: 1.14-3.70), cardiac death (adjusted hazard ratio: 2.63; 95% CI: 1.27-5.43), and non-fatal MI (adjusted hazard ratio: 2.64; 95% CI: 1.36-5.13), but not with TVR (adjusted hazard ratio: 0.81; 95% CI: 0.41-1.58). CONCLUSIONS: The presence of rheumatologic disorders appears to be independently associated with worse outcome in CAD patients undergoing PCI. This calls for further studies and focus on this high-risk group of patients following PCI.

Frequency of Cardiac Death and Stent Thrombosis in Patients With Chronic Obstructive Pulmonary Disease Undergoing Percutaneous Coronary Intervention (from the BASKET-PROVE I and II Trials).

Chronic obstructive pulmonary disease (COPD) is associated with long-term all-cause death after percutaneous coronary intervention with bare-metal stents. Regarding other outcomes, previous studies have shown conflicting results and the impact of drug-eluting stent (DES) in this population is not well known. We analyzed 4,605 patients who underwent percutaneous coronary intervention with bare-metal stents (33.1%) or DES (66.9%) from the Basel Stent Kosten-Effektivitats Trial-Prospective Validation Examination trials I and II. COPD patients (n = 283, 6.1%), were older and had more frequently a smoking or cardiovascular event history. At 2-year follow-up, cumulative event rates for patients with versus without COPD were the following: major adverse cardiac events (MACE: composite of cardiac death, nonfatal myocardial infarction, and target vessel revascularization): 15.2% versus 8.1% (p <0.001); all-cause death: 11.7% versus 2.4% (p <0.001); cardiac death: 5.7% versus 1.2% (p <0.001); myocardial infarction: 3.5% versus 1.9% (p = 0.045); definite/probable/possible stent thrombosis: 2.5% versus 0.9% (p = 0.01); and major bleeding: 4.2% versus 2.1% (p = 0.014). After adjusting for confounders including smoking status, COPD remained an independent predictor for MACE (hazard ratio [HR] 1.80, 95% confidence interval [CI] 1.31 to 2.49), all-cause death (HR 3.62, 95% CI 2.41 to 5.45), cardiac death (HR 3.12, 95% CI 1.74 to 5.60), and stent thrombosis (HR 2.39, 95% CI 1.03 to 5.54). We did not find evidence of an interaction between COPD and DES implantation (p for interaction = 0.29) for MACE. In conclusion, COPD is associated with increased 2-year rates of all-cause death, cardiac death, and stent thrombosis after stent implantation. DES use appears to be beneficial also in patients with COPD.

Predicting hospitalization and mortality in patients with heart failure: The BARDICHE-index.

BACKGROUND: Prediction of events in chronic heart failure (CHF) patients is still difficult and available scores are often complex to calculate. Therefore, we developed and validated a simple-to-use, multidimensional prognostic index for such patients. METHODS: A theoretical model was developed based on known prognostic factors of CHF that are easily obtainable: Body mass index (B), Age (A), Resting systolic blood pressure (R), Dyspnea (D), N-termInal pro brain natriuretic peptide (NT-proBNP) (I), Cockroft-Gault equation to estimate glomerular filtration rate (C), resting Heart rate (H), and Exercise performance using the 6-min walk test (E) (the BARDICHE-index). Scores were given for all components and added, the sum ranging from 1 (lowest value) to 25 points (maximal value), with estimated risk being highest in patients with highest scores. Scores were categorized into three groups: a low (≤8 points); medium (9-16 points), or high (>16 points) BARDICHE-score. The model was validated in a data set of 1811 patients from two prospective CHF-cohorts (median follow-up 887days). The primary outcome was 5-year all-cause survival. Secondary outcomes were 5-year survival without all-cause hospitalization and 5-year survival without CHF-related hospitalization. RESULTS: There were significant differences between BARDICHE-risk groups for mortality (hazard ratio=3.63 per BARDICHE-group, 95%-CI 3.10-4.25), mortality or all-cause hospitalization (HR=2.00 per BARDICHE-group, 95%-CI 1.83-2.19), and mortality or CHF-related hospitalization (HR=3.43 per BARDICHE-group, 95%-CI 3.01-3.92; all P<10-50). Outcome was predicted independently of left ventricular ejection fraction (LVEF) and gender. CONCLUSIONS: The BARDICHE-index is a simple multidimensional prognostic tool for patients with CHF, independently of LVEF.

Impact of stent diameter and length on in-stent restenosis after DES vs BMS implantation in patients needing large coronary stents-A clinical and health-economic evaluation.

AIMS: The British National Institute of Clinical Excellence (NICE) guidelines recommend to use drug-eluting stents (DES) instead of bare-metal stents (BMS) only in lesions >15 mm in length or in vessels <3 mm in diameter. We analyzed the impact of stent length and stent diameter on in-stent restenosis (ISR) in the BASKET-PROVE study population and evaluated the cost-effectiveness of DES compared to BMS. METHODS/RESULTS: The BASKET-PROVE trial compared DES vs BMS in large coronary arteries (≥3 mm). We calculated incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves with regard to quality-adjusted life years (QALYs) gained and target lesion revascularizations (TLRs) avoided. A total of 2278 patients were included in the analysis. A total of 74 ISR in 63 patients were observed. In-stent restenosis was significantly more frequent in segments treated with a BMS compared to segments treated with a DES (5.4% vs 0.76%; P<.001). The benefit of a DES compared to a BMS regarding ISR was consistent among the subgroups of stent length >15 mm and ≤15 mm, respectively. With the use of DES in short lesions, there was only a minimal gain of 0.005 in QALYs. At a threshold of 10 000 CHF per TLR avoided, DES had a high probability of being cost-effective. CONCLUSION: In the BASKET-PROVE study population, the strongest predictor of ISR is the use of a BMS, even in patients in need of stents ≥3.0 mm and ≤15 mm lesion length and DES were cost-effective. This should prompt the NICE to reevaluate its recommendation to use DES instead of BMS only in vessels <3.0 mm and lesions >15 mm length.