Abnormal pulmonary hemodynamics during exercise is associated with exercise capacity in COPD.

BACKGROUND: Pulmonary hypertension (PH) is a frequent complication in COPD and it is associated with decreased exercise capacity and poor prognosis. We hypothesized that even in COPD patients without significant PH at rest, abnormal pulmonary hemodynamics during exercise affect exercise capacity. METHODS: Consecutive COPD patients with clinically indicated right heart catheterization and resting mean pulmonary arterial pressure (mPAP) < 25 mmHg and age- and sex-matched controls with the same limits of pulmonary hemodynamics but no chronic lung disease who underwent clinical work-up including invasive hemodynamic assessment during exercise, were retrospectively analyzed. Chi-square tests were used to evaluate differences between groups for categorical data and Fisher's exact test or Mann-Whitney-U-tests for continuous variables. Associations were analyzed with Spearman rank correlation tests. RESULTS: We included n = 26 COPD patients (female/male: 16/10, 66 ± 11 yr, FEV1: 56 ± 25%predicted) and n = 26 matched controls (FEV1: 96 ± 22%predicted). At rest, COPD patients presented with slightly increased mPAP (21 (18-23) vs. 17 (14-20) mmHg, p = 0.022), and pulmonary vascular resistance (PVR) [2.5 (1.9-3.0) vs. 1.9 (1.5-2.4) WU, p = 0.020] as compared to controls. During exercise, COPD patients reached significantly higher mPAP [47 (40-52) vs. 38 (32-44) mmHg, p = 0.015] and PVR [3.1 (2.2-3.7) vs. 1.7 (1.1-2.9) WU, p = 0.028] values despite lower peak exercise level [50 (50-75) vs. 100 (75-125) Watt, p = 0.002]. The mPAP/cardiac output slope was increased in COPD vs. controls [6.9 (5.5-10.9) vs. 3.7 (2.4-7.4) mmHg/L/min, p = 0.007] and negatively correlated with both peak oxygen uptake (r = - 0.46, p = 0.007) and 6-min walk distance (r = - 0.46, p = 0.001). CONCLUSION: Even in the absence of significant PH at rest, COPD patients reveal characteristic abnormalities in pulmonary hemodynamics during exercise, which may represent an important exercise-limiting factor.

Network Analysis to Risk Stratify Patients With Exercise Intolerance.

RATIONALE: Current methods assessing clinical risk because of exercise intolerance in patients with cardiopulmonary disease rely on a small subset of traditional variables. Alternative strategies incorporating the spectrum of factors underlying prognosis in at-risk patients may be useful clinically, but are lacking. OBJECTIVE: Use unbiased analyses to identify variables that correspond to clinical risk in patients with exercise intolerance. METHODS AND RESULTS: Data from 738 consecutive patients referred for invasive cardiopulmonary exercise testing at a single center (2011-2015) were analyzed retrospectively (derivation cohort). A correlation network of invasive cardiopulmonary exercise testing parameters was assembled using |r|>0.5. From an exercise network of 39 variables (ie, nodes) and 98 correlations (ie, edges) corresponding to P<9.5e-46 for each correlation, we focused on a subnetwork containing peak volume of oxygen consumption (pVo2) and 9 linked nodes. K-mean clustering based on these 10 variables identified 4 novel patient clusters characterized by significant differences in 44 of 45 exercise measurements (P<0.01). Compared with a probabilistic model, including 23 independent predictors of pVo2 and pVo2 itself, the network model was less redundant and identified clusters that were more distinct. Cluster assignment from the network model was predictive of subsequent clinical events. For example, a 4.3-fold (P<0.0001; 95% CI, 2.2-8.1) and 2.8-fold (P=0.0018; 95% CI, 1.5-5.2) increase in hazard for age- and pVo2-adjusted all-cause 3-year hospitalization, respectively, were observed between the highest versus lowest risk clusters. Using these data, we developed the first risk-stratification calculator for patients with exercise intolerance. When applying the risk calculator to patients in 2 independent invasive cardiopulmonary exercise testing cohorts (Boston and Graz, Austria), we observed a clinical risk profile that paralleled the derivation cohort. CONCLUSIONS: Network analyses were used to identify novel exercise groups and develop a point-of-care risk calculator. These data expand the range of useful clinical variables beyond pVo2 that predict hospitalization in patients with exercise intolerance.

Apixaban and risk of myocardial infarction: meta-analysis of randomized controlled trials.

The coagulation system contributes greatly to the evolution of myocardial infarction (MI). Anticoagulation may reduce the occurrence of MI as monotherapy or with concomitant use of aspirin. Activated factor X antagonists (anti-Xa) and direct thrombin inhibitors have promising results in various indications in non-inferiority trials. However, results regarding their cardiovascular safety are heterogeneous. We systematically evaluated the risk of MI and mortality in patients receiving the new-generation oral anti-Xa agent apixaban. Electronic databases were searched to find prospective, randomized, controlled clinical trials (RCT) that evaluated the clinical impact of apixaban. Efficacy measures included frequency of MI, cardiovascular and overall mortality. Outcome parameters of RCTs were pooled with a random-effects model. Between January 2000 and December 2013, 12 RCTs comprising 54,054 patients were identified. Based on the pooled results, there was no increase in the risk of MI in patients treated with apixaban [odds ratio (OR) 0.90; 95 % confidence interval (CI) 0.77-1.05; p = 0.17] compared to different controls. Cardiovascular and overall mortality with apixaban was comparable to the control groups (OR 0.88; 95 % CI 0.72-1.06; p = 0.18, OR 0.89; 95 % CI 0.77-1.03; p = 0.11, respectively). The pooled risk of major bleeding was lower in the apixaban treated groups (OR 0.84; 95 % CI 0.62-1.12; p = 0.23) however this reached significant level only in subgroup analysis of trials with anticoagulant regimes in the control (OR 0.66; 95 % CI 0.51-0.87; p = 0.003). In a broad spectrum of patients and compared to different controls apixaban treatment was not associated with an increase in MI or mortality.

Severe Pulmonary Hypertension in COPD: Impact on Survival and Diagnostic Approach.

BACKGROUND: Severe pulmonary hypertension (PH) is prognostically highly relevant in patients with COPD. The criteria for severe PH have been defined based on hemodynamic thresholds in right heart catheterization. RESEARCH QUESTION: Can noninvasive clinical tools predict severe PH in patients with COPD? How does the mortality risk change with increasing severity of airflow limitation and pulmonary vascular disease? STUDY DESIGN AND METHODS: We retrospectively analyzed all consecutive patients with COPD with suspected PH undergoing in-depth clinical evaluation, including right heart catheterization, in our PH clinic between 2005 and 2018. Clinical variables potentially indicative of severe PH or death were analyzed using univariate and stepwise multivariate logistic regression and Cox regression analysis adjusted for age and sex. RESULTS: We included 142 patients with median FEV1 of 55.0% predicted (interquartile range [IQR], 42.4%-69.4% predicted) and mean pulmonary arterial pressure of 35 mm Hg (IQR, 27-43 mm Hg). A multivariate model combining echocardiographic systolic pulmonary arterial pressure of ≥ 56 mm Hg, N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels of ≥ 650 pg/mL, and pulmonary artery (PA) to ascending aorta (Ao) diameter ratio on chest CT scan of ≥ 0.93 predicted severe PH with high positive and negative predictive values (both 94%). After correction for age and sex, both airflow limitation (P = .002; Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-2 vs stage 3: hazard ratio [HR], 1.56 [95% CI, 0.90-2.71]; GOLD stages 1-2 vs stage 4: HR, 3.45 [95% CI, 1.75-6.79]) and PH severity (P = .012; HR, 1.85 [95% CI, 1.15-2.99]) remained associated independently with survival. The combination of GOLD stages 3 and 4 airflow limitation and severe PH showed the poorest survival (HR for death, 3.26 [95% CI, 1.62-6.57; P = .001] vs GOLD stages 1-2 combined with nonsevere PH). INTERPRETATION: In patients with COPD, the combination of echocardiography, NT-proBNP level, and PA to Ao diameter ratio predicts severe PH with high sensitivity and specificity. The contribution of severe PH and severe airflow limitation to impaired survival is comparable.

Clinical outcomes in patients treated for coronary in-stent restenosis with drug-eluting balloons: Impact of high platelet reactivity.

BACKGROUND: The impact of high platelet reactivity (HPR) on clinical outcomes after elective percutaneous coronary interventions (PCI) with drug-eluting balloons (DEB) due to in-stent restenosis (ISR) is unknown. OBJECTIVE: We sought to evaluate the prognostic importance of HPR together with conventional risk factors in patients treated with DEB. METHODS: Patients treated with DEB due to ISR were enrolled in a single-centre, prospective registry between October 2009 and March 2015. Only patients with recent myocardial infarction (MI) received prasugrel, others were treated with clopidogrel. HPR was defined as an ADP-test >46U with the Multiplate assay and no adjustments were done based on results. The primary endpoint of the study was a composite of cardiovascular mortality, MI, any revascularization or stroke during one-year follow-up. RESULTS: 194 stable angina patients were recruited of whom 90% were treated with clopidogrel. Clinical characteristics and procedural data were available for all patients; while platelet function testing was performed in 152 subjects of whom 32 (21%) had HPR. Patients with HPR had a higher risk for the primary endpoint (HR: 2.45; CI: 1.01-5.92; p = 0.03). The difference was primarily driven by a higher risk for revascularization and MI. According to the multivariate analysis, HPR remained a significant, independent predictor of the primary endpoint (HR: 2.88; CI: 1.02-8.14; p = 0.04), while total DEB length and statin treatment were other independent correlates of the primary outcome. CONCLUSION: HPR was found to be an independent predictor of repeat revascularization and MI among elective patients with ISR undergoing PCI with DEB.

Risk of Myocardial Infarction in Patients with Long-Term Non-Vitamin K Antagonist Oral Anticoagulant Treatment.

UNLABELLED: The relative cardiovascular (CV) safety of oral anticoagulants continues to be debated, and in particular concerns for risk of myocardial infarction (MI) have been raised. We analyzed the risk of MI in patients treated long term with oral anticoagulants (vitamin K antagonists [VKA], direct thrombin inhibitors or activated X factor antagonist) for atrial fibrillation, deep vein thrombosis or pulmonary embolism using a network meta-analysis (NMA). METHODS: Randomized, phase 3 trials comparing novel anticoagulants to VKA were searched. Information on study design and clinical outcomes was extracted. The primary end-point of the analysis was the occurrence of MI or acute coronary syndrome. A Bayesian multiple treatment analysis was performed using fixed-effect and random-effects modeling. RESULTS: Twelve trials including 100,524 randomized patients were analyzed. The odds for MI in NMA were worse with dabigatran when compared to VKA, rivaroxaban, apixaban, and edoxaban (OR: 0.66 CI: 0.49-0.87; OR: 0.56 CI: 0.38-0.82, OR: 0.59 CI 0.40-0.88, and OR: 0.71 CI: 0.50-1.0, respectively).The posterior probability of being the first best choice of treatment was 53.5% for rivaroxaban, 33.8% for apixaban, 9.5% for ximelagatran, 2.0% for edoxaban, 1.2% for VKA, and 0.007% for dabigatran. CONCLUSIONS: There is a considerable heterogeneity regarding CV safety among oral anticoagulants. Differences in risk of MI may influence the choice of treatment. Multiple treatment NMA found 29%-44% higher odds of MI with dabigatran supporting the concerns regarding its CV safety.

Assessment of platelet function in patients receiving tirofiban early after primary coronary intervention.

BACKGROUND: Following percutaneous coronary intervention, combined antiplatelet therapy is necessary. Platelet function testing (PFT) has prognostic value and may be applied in the risk assessment of acute coronary syndrome. In case of combined antiplatelet therapy, PFT may require special laboratory methods, as different antiplatelet agents may influence test results. MATERIALS AND METHODS: Platelet functions were measured in stent thrombosis-segment elevation myocardial infarction patients receiving aspirin, clopidogrel, and tirofiban. The first sampling was obtained immediately after the termination of administration of tirofiban. The second sample was drawn at a randomly assigned time between 1 and 6 h. The third sampling was done after a minimum of 24 h of tirofiban cessation. Adenosine diphosphate (ADP)- and thrombin receptor-activating peptide (TRAP)-induced aggregations were measured. RESULTS: Thirty-seven patients were included. Both TRAP- and ADP-induced aggregation values were significantly lower immediately after tirofiban termination, than after 24 h [TRAP: 26.41 ± 25.00 units (U) vs. 109.86 ± 23.69 U, p < 0.0001; ADP: 17.43 ± 10.10 U vs. 43.92 ± 23.35 U, p ≤ 0.0001]. Elimination half-life of tirofiban and clopidogrel were 1.34 ± 0.49 and 1.269 ± 0.78, respectively. CONCLUSION: ADP-induced residual platelet reactivity is significantly influenced by the presence of concurrent glycoprotein IIb/IIIa inhibitor. In patients receiving combined antiplatelet treatment, ADP-receptor-specific efficiency measurements are valid only after total elimination of GPIIb/IIIa inhibitors.

Novel mechanisms of sildenafil in pulmonary hypertension involving cytokines/chemokines, MAP kinases and Akt.

Pulmonary arterial hypertension (PH) is associated with high mortality due to right ventricular failure and hypoxia, therefore to understand the mechanism by which pulmonary vascular remodeling initiates these processes is very important. We used a well-characterized monocrotaline (MCT)-induced rat PH model, and analyzed lung morphology, expression of cytokines, mitogen-activated protein kinase (MAPK) phosphorylation, and phosphatidylinositol 3-kinase-Akt (PI-3k-Akt) pathway and nuclear factor (NF)-κB activation in order to elucidate the mechanisms by which sildenafil's protective effect in PH is exerted. Besides its protective effect on lung morphology, sildenafil suppressed multiple cytokines involved in neutrophil and mononuclear cells recruitment including cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2α/ß, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-1α, lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1α, and MIP-3α. NF-κB activation and phosphorylation were also attenuated by sildenafil. Furthermore, sildenafil reduced extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK activation while enhanced activation of the cytoprotective Akt pathway in PH. These data suggest a beneficial effect of sildenafil on inflammatory and kinase signaling mechanisms that substantially contribute to its protective effects, and may have potential implications in designing future therapeutic strategies in the treatment of pulmonary hypertension.

Meta-analysis of randomized trials on access site selection for percutaneous coronary intervention in ST-segment elevation myocardial infarction.

INTRODUCTION: Superior outcomes with transradial (TRPCI) versus transfemoral coronary intervention (TFPCI) in the setting of acute ST-segment elevation myocardial infarction (STEMI) have been suggested by earlier studies. However, this effect was not evident in randomized controlled trials (RCTs), suggesting a possible allocation bias in observational studies. Since important studies with heterogeneous results regarding mortality have been published recently, we aimed to perform an updated review and meta-analysis on the safety and efficacy of TRPCI compared to TFPCI in the setting of STEMI. MATERIAL AND METHODS: Electronic databases were searched for relevant studies from January 1993 to November 2012. Outcome parameters of RCTs were pooled with the DerSimonian-Laird random-effects model. RESULTS: Twelve RCTs involving 5,124 patients were identified. According to the pooled analysis, TRPCI was associated with a significant reduction in major bleeding (odds ratio (OR): 0.52 (95% confidence interval (CI) 0.38-0.71, p < 0.0001)). The risk of mortality and major adverse events was significantly lower after TRPCI (OR = 0.58 (95% CI: 0.43-0.79), p = 0.0005 and OR = 0.67 (95% CI: 0.52-0.86), p = 0.002 respectively). CONCLUSIONS: Robust data from randomized clinical studies indicate that TRPCI reduces both ischemic and bleeding complications in STEMI. These findings support the preferential use of radial access for primary PCI.

Optimizing P2Y12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing: impact of prasugrel and high-dose clopidogrel.

OBJECTIVES: This study sought to evaluate the impact of treatment with prasugrel and high-dose clopidogrel on the basis of platelet function testing in patients with acute coronary syndrome (ACS) who are undergoing percutaneous coronary intervention (PCI). BACKGROUND: The clinical impact of treatment with prasugrel in patients with ACS who have high platelet reactivity (HPR) is unknown. METHODS: Patients with ACS who were pre-treated with clopidogrel and undergoing successful PCI were enrolled in a single-center, prospective registry. Platelet function was measured 12 to 36 h after PCI with the Multiplate device (Roche Diagnostics GmbH, Mannheim, Germany). Patients with HPR (>46 U) were switched to prasugrel or treated with high-dose clopidogrel, and those without HPR continued treatment with 75 mg of clopidogrel. RESULTS: A total of 741 consecutive patients were enrolled in the study between September 2011 and August 2012, and 219 of these patients (29.5%) had HPR. Although platelet reactivity decreased after treatment adjustments in those with HPR, prasugrel provided significantly more potent platelet inhibition compared with high-dose clopidogrel (p < 0.0001). Compared with patients without HPR, the risk of all-cause death, myocardial infarction, stent thrombosis, or stroke at 1 year was significantly higher in the high-dose clopidogrel group (hazard ratio [HR]: 2.27; 95% confidence interval [CI]: 1.45 to 3.55; p < 0.0001), and patients who were switched to prasugrel had similar outcomes (HR: 0.90; 95% CI: 0.44 to 1.81; p = 0.76). Bleeding Academic Research Consortium (BARC) type 3/5 bleeding was also more frequent in patients treated with high-dose clopidogrel (HR: 2.09; 95% CI: 1.05 to 4.17; p = 0.04) than in patients switched to prasugrel (HR: 0.45; 95% CI: 0.11 to 1.91; p = 0.28). In a multivariate model, HPR with high-dose clopidogrel, but not with prasugrel, was an independent predictor of the composite ischemic endpoint (HR: 1.90; 95% CI: 1.17 to 3.08; p = 0.01). CONCLUSIONS: Switching patients with ACS who have HPR to treatment with prasugrel reduces thrombotic and bleeding events to a level similar to that of those without HPR; however, there is a higher risk of both thrombotic and bleeding complications with high-dose clopidogrel.