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- Galiè, Nazzareno, et al.
(författare)
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Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension
- 2015
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 373:9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce.METHODS: In this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.RESULTS: The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooled-monotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, -67.2% vs. -50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P=0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia.CONCLUSIONS: Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.).
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| 2. |
- Hofstee, Herman M A, et al.
(författare)
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A multicentre study on the reliability of qualitative and quantitative nail-fold videocapillaroscopy assessment.
- 2012
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 51:4, s. 749-755
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To investigate the inter- and intra-observer reliability of both qualitative and quantitative parameters used in the assessment of nail-fold capillaroscopy images.Methods. Fifty mosaic nail-fold images of healthy controls (n = 10), patients with primary RP (n = 10) and SSc (n = 30) were assessed in random order by two blinded observers on two occasions at centres in Sweden, UK and The Netherlands. Each image was therefore scored by six observers twice.Results. Inter- and intra-observer reliability of quantitative parameters showed substantial to almost perfect agreement [inter- and intra-observer weighted κ's for the number of widened capillaries was 0.75 and 0.87 and giant capillaries was 0.84 and 0.92, intra-class correlation coefficients (ICCs) for capillary density was 0.87 and 0.92 and total loop width was 0.94 and 0.98, respectively]. Qualitative parameters including architecture, avascularity, haemorrhage, crossed, ramified and bushy capillaries showed moderate to substantial inter-observer reproducibility (weighted κ ranging from 0.47 to 0.73), and substantial intra-observer repeatability (weighted κ ranging from 0.71 to 0.80), whereas the scoring of tortuous and bizarre capillaries showed poor inter-observer and substantial intra-observer agreement (inter-observer weighted κ's was 0.39 and 0.21 and intra-observer weighted κ's was 0.68 and 0.76, respectively).Conclusion. All quantitative and certain qualitative parameters are highly reliable in terms of inter- and intra-observer agreement. A combination of parameters with the highest reliability should be incorporated into future capillaroscopic scoring systems in studies of prediction and monitoring of SSc spectrum disorders.
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| 6. |
- Lubberink, Mark, et al.
(författare)
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Myocardial Oxygen Extraction Fraction Measured Using Bolus Inhalation of O-15-Oxygen Gas and Dynamic PET
- 2011
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 52:1, s. 60-66
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to determine the accuracy of oxygen extraction fraction (OEF) measurements using a dynamic scan protocol after bolus inhalation of O-15(2). The method of analysis was optimized by investigating potential reuse of myocardial blood flow (MBF), perfusable tissue fraction, and blood and lung spillover factors derived from separate O-15-water and (CO)-O-15 scans. Methods: Simulations were performed to assess the accuracy and precision of OEF for a variety of models in which different parameters from O-15-water and (CO)-O-15 scans were reused. Reproducibility was assessed in 8 patients who underwent one 10-min dynamic scan after bolus injection of 1.1 GBq of O-15-water, two 10-min dynamic scans after bolus inhalation of 1.4 GBq of O-15(2), and a 6-min static scan after bolus inhalation of 0.8 GBq of (CO)-O-15 for region-of-interest definition. Results: Simulations showed that accuracy and precision were lowest when all parameters were determined from the O-15(2) scan. The optimal accuracy and precision of OEF were obtained when fixing MBF, perfusable tissue fraction, and blood spillover to values derived from a O-15-water scan and estimating spillover from the pulmonary gas volume using an attenuation map. Optimal accuracy and precision were confirmed in the patient study, showing an OEF test-retest variability of 13% for the whole myocardium. Correction of spillover from pulmonary gas volume requires correction of the lung time-activity curve for pulmonary blood volume, which could equally well be obtained from a O-15-water rather than (CO)-O-15 scan. Conclusion: Measurement of OEF is possible using bolus inhalation of O-15(2) and a dynamic scan protocol, with optimal accuracy and precision when other relevant parameters, such as MBF, are derived from an additional O-15-water scan.
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| 7. |
- Timmer, S A J, et al.
(författare)
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Right ventricular energetics in patients with hypertrophic cardiomyopathy and the effect of alcohol septal ablation
- 2011
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Ingår i: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164 .- 1532-8414. ; 17:10, s. 827-831
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Diastolic dysfunction in hypertrophic cardiomyopathy (HCM) is accompanied by augmented left ventricular (LV) end-diastolic pressure, above all in the presence of LV outflow tract (LVOT) obstruction. Increased back-pressure may augment right ventricular (RV) afterload and induce an oxidative metabolic imbalance between the 2 ventricles. The aim was to study right-to-left ventricular oxidative metabolism in HCM and the effects of alcohol septal ablation (ASA).METHODS AND RESULTS:Twenty-one HCM patients were enrolled. Eleven healthy subjects served as a control group. Subjects underwent 2-dimensional echocardiography to assess LVOT gradient, left atrial size, and diastolic function. [11C]Acetate positron-emission tomography (PET) was performed to determine RVk2 and LVk2, as a noninvasive index of oxidative metabolism. Seven HCM patients with LVOT obstruction, scheduled to undergo ASA, were also studied 6 months after the procedure. RVk2 was higher in HCM patients than i control subjects (0.081 ± 0.021 min−1 vs. 0.061 ± 0.017 min−1; P = .05), whereas LVk2 was similar between groups. Consequently, RVk2/LVk2 was increased in the patients (0.85 ± 0.19 vs 0.59 ± 0.13; P = .004). In patients with obstructive HCM, ASA reduced RVk2 (0.085 ± 0.021 min−1 to 0.072 ± 0.022 min−1; P = .001). Inasmuch as LVk2 remained unaffected by the procedure, RVk2/LVk2 was decreased after ASA (0.66 ± 0.18; P = .03). The absolute change in LVOT gradient was related to the absolute change in RVk2 (r = 0.77; P = .044).CONCLUSIONS:In HCM patients, RV oxygen consumption is increased in relation to the LV. ASA reduces RV oxygen consumption in HCM patients with LVOT obstruction, suggesting that increased LV loading conditions and diastolic dysfunction play a predominant role in augmenting RV workload in these patients.
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| 8. |
- Wong, Yeun Ying, et al.
(författare)
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Right ventricular failure in idiopathic pulmonary arterial hypertension is associated with inefficient myocardial oxygen utilization
- 2011
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Ingår i: Circulation Heart Failure. - 1941-3289 .- 1941-3297. ; 4:6, s. 700-706
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn idiopathic pulmonary arterial hypertension (IPAH), increased right ventricular (RV) power is required to maintain cardiac output. For this, RV O2 consumption (MVO2) must increase by augmentation of O2 supply and/or improvement of mechanical efficiency–ratio of power output to MVO2. In IPAH with overt RV failure, however, there is evidence that O2 supply (perfusion) reserve is reduced, leaving only increase in either O2 extraction or mechanical efficiency as compensatory mechanisms. We related RV mechanical efficiency to clinical and hemodynamic parameters of RV function in patients with IPAH and associated it with glucose metabolism.Methods and ResultsThe patients included were in New York Heart Association (NYHA) class II (n=8) and class III (n=8). They underwent right heart catheterization, MRI, and H215O-, 15O2-, C15O-, and 18FDG-PET. RV power and O2 supply were similar in both groups (NYHA class II versus class III: 0.54±0.14 versus 0.47±0.12 J/s and 0.109±0.022 versus 0.128±0.026 mL O2/min per gram, respectively). RV O2 extraction was near-significantly lower in NYHA class II compared with NYHA class III (63±17% versus 75±16%, respectively, P=0.10). As a result, MVO2 was significantly lower (0.066±0.012 versus 0.092±0.010 mL O2/min per gram, respectively, P=0.006). RV efficiency was reduced in NYHA class III (13.9±3.8%) compared with NYHA class II (27.8±7.6%, P=0.001). Septal bowing, measured by MRI, correlated with RV efficiency (r=−0.59, P=0.020). No relation was found between RV efficiency and glucose uptake rate. RV mechanical efficiency and ejection fraction were closely related (r=0.81, P<0.001).ConclusionsRV failure in IPAH was associated with reduced mechanical efficiency that was partially explained by RV mechanical dysfunction but not by a metabolic shift.
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| 9. |
- Wong, Yeun Ying, et al.
(författare)
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Supine-exercise-induced oxygen supply to the right myocardium is attenuated in patients with severe idiopathic pulmonary arterial hypertension
- 2011
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 97:24, s. 2069-2074
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundImpaired right ventricular (RV) myocardial blood flow (MBF) has been associated with RV dysfunction and fatal RV failure in idiopathic pulmonary hypertension during stress. MBF and O2 extraction from myocardial capillaries (O2 extraction fraction (OEF)) influence myocardial O2 supply.ObjectiveTo determine how the baseline RV OEF affects the amount of MBF increase induced by supine exercise, the authors hypothesise that higher baseline OEF (H-OEF) results in limited O2 extraction during exercise and that MBF must therefore be increased to obtain sufficient O2.MethodsIn 18 patients with idiopathic pulmonary hypertension, baseline OEF, resting MBF and exercise-induced MBF at 40% of maximal cardiopulmonary exercise testing load were measured using positron emission tomography and [15O]O2, [15O]H2O and [15O]CO.ResultsFor the whole population, exercise increased RV MBF from 0.68±0.16 to 1.13±0.38 ml/min/g (p<0.0001). The MBF exercise-to-rest ratio (reserve) was 1.7±0.7. The median baseline OEF was 0.73 at which the patient population was split into H-OEF and lower baseline OEF (L-OEF). Baseline MBF values (0.61±0.11 and 0.74±0.17 ml/min/g, respectively) were similar, and exercise induced a significant MBF increase in both groups (p=0.0001). However, exercise-induced increase in MBF was significantly less in the H-OEF group than in the L-OEF group (0.97±0.30 and 1.30±0.39 ml/min/g, respectively, p<0.05). Moreover, H-OEF patients had lower baseline stroke volume and cardiac output than the L-OEF group (52±19 ml and 4.0±1.1 l/min vs 78±18 ml and 5.5±0.9 l/min, respectively, both p<0.05).ConclusionsH-OEF patients were hemodynamically poorer and showed a lower exercise-induced MBF increase compared to L-OEF patients, suggesting exercise-induced O2 supply limitation.
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| 10. |
- Wong, Yeun Ying, et al.
(författare)
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Systolic pulmonary artery pressure and heart rate are main determinants of oxygen consumption in the right ventricular myocardium of patients with idiopathic pulmonary arterial hypertension
- 2011
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 13:12, s. 1290-1295
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Tidskriftsartikel (refereegranskat)abstract
- AimsIncreased afterload in idiopathic pulmonary arterial hypertension (IPAH) causes right ventricular (RV) hypertrophy and failure. Since RV remodelling occurs with alterations in RV oxygen metabolism, increasing our understanding in the factors determining RV O2 consumption in IPAH is necessary. In the left ventricle, it is known that heart rate and systolic blood pressure are the main determinants of myocardial O2 consumption (MVO2). However, the normal right heart has lower oxygen extraction and perfusion than the left myocardium, and RV energy metabolism is changed in hypertrophy. Therefore, it is not obvious that the relationsships of pressure and heart rate to MVO2 hold for the overloaded human right heart. We hypothesize that systolic pulmonary artery pressure (PAP) and heart rate (HR) are the major determinants of RV MVO2 in IPAH.Methods and resultsIn 18 IPAH patients (New York Heart Association class II and III), RV MVO2 was determined using positron emission tomography and 15O tracers. PAP and HR were measured during right heart catheterization. RV MVO2 was found to be related to systolic PAP (R2 = 0.54, P < 0.001), and inversely to stroke volume (R2 = 0.32, P = 0.015) and HR (R2 = 0.32, P = 0.014). Relationships of MVO2 to the rate pressure product (RPP), i.e. systolic pressure × HR, and wall stress were R2 = 0.55, P < 0.001, and R2 = 0.30, P = 0.020, respectively. Multiple regression of MVO2 on HR and systolic PAP gave R2 = 0.59, P = 0.001.ConclusionSystolic PAP and HR are the major determinants of RV MVO2 in IPAH. A further increase of HR and PAP with IPAH progression suggests a compromised RV myocardial oxygen availability.
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