Thalassaemia major (TM) patients need regular blood transfusions that lead to accumulation of iron and death from heart failure. Deferiprone has been reported to be superior to deferoxamine for the ...removal of cardiac iron and improvement in left ventricular (LV) function but little is known of their relative effects on the right ventricle (RV), which is being increasingly recognised as an important prognostic factor in cardiomyopathy. Therefore data from a prospective randomised controlled trial (RCT) comparing these chelators was retrospectively analysed to assess the RV responses to these drugs.
In the RCT, 61 TM patients were randomised to receive either deferiprone or deferoxamine monotherapy, and CMR scans for T2* and cardiac function were obtained. Data were re-analysed for RV volumes and function at baseline, and after 6 and 12 months of treatment.
From baseline to 12 months, deferiprone reduced RV end systolic volume (ESV) from 37.7 to 34.2 mL (p=0.008), whilst RV ejection fraction (EF) increased from 69.6 to 72.2% (p=0.001). This was associated with a 27% increase in T2* (p<0.001) and 3.1% increase in LVEF (p<0.001). By contrast, deferoxamine showed no change in RVESV (38.1 to 39.1 mL, p=0.38), or RVEF (70.0 to 69.9%, p=0.93) whereas the T2* increased by 13% (p<0.001), but with no change in LVEF (0.32%; p=0.66). Analysis of between drugs treatment effects, showed significant improvements favouring deferiprone with a mean effect on RVESV of -1.82 mL (p=0.014) and 1.16% for RVEF (p=0.009). Using regression analysis the improvement in RVEF at 12 months was shown to be greater in patients with lower baseline EF values (p<0.001), with a significant difference in RVEF of 3.5% favouring deferiprone over deferoxamine (p=0.012).
In this retrospective analysis of a prospective RCT, deferiprone monotherapy was superior to deferoxamine for improvement in RVEF and end-systolic volume. This improvement in the RV volumes and function may contribute to the improved cardiac outcomes seen with deferiprone.
Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson disease (PD). Following STN-DBS, speech intelligibility can deteriorate, limiting its beneficial ...effect. Here we prospectively examined the short- and long-term speech response to STN-DBS in a consecutive series of patients to identify clinical and surgical factors associated with speech change.
Thirty-two consecutive patients were assessed before surgery, then 1 month, 6 months, and 1 year after STN-DBS in 4 conditions on- and off-medication with on- and off-stimulation using established and validated speech and movement scales. Fifteen of these patients were followed up for 3 years. A control group of 12 patients with PD were followed up for 1 year.
Within the surgical group, speech intelligibility significantly deteriorated by an average of 14.2%±20.15% off-medication and 16.9%±21.8% on-medication 1 year after STN-DBS. The medical group deteriorated by 3.6%±5.5% and 4.5%±8.8%, respectively. Seven patients showed speech amelioration after surgery. Loudness increased significantly in all tasks with stimulation. A less severe preoperative on-medication motor score was associated with a more favorable speech response to STN-DBS after 1 year. Medially located electrodes on the left STN were associated with a significantly higher risk of speech deterioration than electrodes within the nucleus. There was a strong relationship between high voltage in the left electrode and poor speech outcome at 1 year.
The effect of STN-DBS on speech is variable and multifactorial, with most patients exhibiting decline of speech intelligibility. Both medical and surgical issues contribute to deterioration of speech in STN-DBS patients.
This study provides Class III evidence that STN-DBS for PD results in deterioration in speech intelligibility in all combinations of medication and stimulation states at 1 month, 6 months, and 1 year compared to baseline and to control subjects treated with best medical therapy.
Risk stratification of patients with nonischemic dilated cardiomyopathy is primarily based on left ventricular ejection fraction (LVEF). Superior prognostic factors may improve patient selection for ...implantable cardioverter-defibrillators (ICDs) and other management decisions.
To determine whether myocardial fibrosis (detected by late gadolinium enhancement cardiovascular magnetic resonance LGE-CMR imaging) is an independent and incremental predictor of mortality and sudden cardiac death (SCD) in dilated cardiomyopathy.
Prospective, longitudinal study of 472 patients with dilated cardiomyopathy referred to a UK center for CMR imaging between November 2000 and December 2008 after presence and extent of midwall replacement fibrosis were determined. Patients were followed up through December 2011.
Primary end point was all-cause mortality. Secondary end points included cardiovascular mortality or cardiac transplantation; an arrhythmic composite of SCD or aborted SCD (appropriate ICD shock, nonfatal ventricular fibrillation, or sustained ventricular tachycardia); and a composite of HF death, HF hospitalization, or cardiac transplantation.
Among the 142 patients with midwall fibrosis, there were 38 deaths (26.8%) vs 35 deaths (10.6%) among the 330 patients without fibrosis (hazard ratio HR, 2.96 95% CI, 1.87-4.69; absolute risk difference, 16.2% 95% CI, 8.2%-24.2%; P < .001) during a median follow-up of 5.3 years (2557 patient-years of follow-up). The arrhythmic composite was reached by 42 patients with fibrosis (29.6%) and 23 patients without fibrosis (7.0%) (HR, 5.24 95% CI, 3.15-8.72; absolute risk difference, 22.6% 95% CI, 14.6%-30.6%; P < .001). After adjustment for LVEF and other conventional prognostic factors, both the presence of fibrosis (HR, 2.43 95% CI, 1.50-3.92; P < .001) and the extent (HR, 1.11 95% CI, 1.06-1.16; P < .001) were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation (by fibrosis presence: HR, 3.22 95% CI, 1.95-5.31, P < .001; and by fibrosis extent: HR, 1.15 95% CI, 1.10-1.20, P < .001), SCD or aborted SCD (by fibrosis presence: HR, 4.61 95% CI, 2.75-7.74, P < .001; and by fibrosis extent: HR, 1.10 95% CI, 1.05-1.16, P < .001), and the HF composite (by fibrosis presence: HR, 1.62 95% CI, 1.00-2.61, P = .049; and by fibrosis extent: HR, 1.08 95% CI, 1.04-1.13, P < .001). Addition of fibrosis to LVEF significantly improved risk reclassification for all-cause mortality and the SCD composite (net reclassification improvement: 0.26 95% CI, 0.11-0.41; P = .001 and 0.29 95% CI, 0.11-0.48; P = .002, respectively).
Assessment of midwall fibrosis with LGE-CMR imaging provided independent prognostic information beyond LVEF in patients with nonischemic dilated cardiomyopathy. The role of LGE-CMR in the risk stratification of dilated cardiomyopathy requires further investigation.
Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal.
We aimed to evaluate the ...safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease.
LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion ≥ 1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC ≤ ULN at week 12. The key secondary endpoint was the proportion achieving mUFC ≤ ULN at week 36 (after 24 weeks' open-label osilodrostat).
Seventy-three patients (median age, 39 years range, 19-67; mean/median mUFC, 3.1 × ULN/2.5 × ULN) received randomized treatment with osilodrostat (n = 48) or placebo (n = 25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC ≤ ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P < 0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC ≤ ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%).
Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable.
In this pre-specified subanalysis of the SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure) trial, which examined the effects of ...nebivolol in elderly heart failure (HF) patients, we explored the effects of left ventricular ejection fraction (EF) on outcomes, including the subgroups impaired EF (< or =35%) and preserved EF (>35%).
Beta-blockers are established drugs in patients with HF and impaired EF, but their value in preserved EF is unclear.
We studied 2,111 patients; 1,359 (64%) had impaired (< or =35%) EF (mean 28.7%) and 752 (36%) had preserved (>35%) EF (mean 49.2%). The effect of nebivolol was investigated in these 2 groups, and it was compared to explore the interaction of EF with outcome. Follow-up was 21 months; the primary end point was all-cause mortality or cardiovascular hospitalizations.
Patients with preserved EF were more often women (49.9% vs. 29.8%) and had less advanced HF, more hypertension, and fewer prior myocardial infarctions (all p < 0.001). During follow-up, the primary end point occurred in 465 patients (34.2%) with impaired EF and in 235 patients (31.2%) with preserved EF. The effect of nebivolol on the primary end point (hazard ratio HR of nebivolol vs. placebo) was 0.86 (95% confidence interval: 0.72 to 1.04) in patients with impaired EF and 0.81 (95% confidence interval: 0.63 to 1.04) in preserved EF (p = 0.720 for subgroup interaction). Effects on all secondary end points were similar between groups (HR for all-cause mortality 0.84 and 0.91, respectively), and no p value for interaction was <0.48.
The effect of beta-blockade with nebivolol in elderly patients with HF in this study was similar in those with preserved and impaired EF.
The purpose of this study was to compare the safety and efficacy of percutaneous coronary intervention (PCI) with stenting against coronary artery bypass grafting (CABG) in patients with diabetes and ...symptomatic multivessel coronary artery disease.
CABG is the established method of revascularization in patients with diabetes and multivessel coronary disease, but with advances in PCI, there is uncertainty whether CABG remains the preferred method of revascularization.
The primary outcome was a composite of all-cause mortality, myocardial infarction (MI), and stroke, and the main secondary outcome included the addition of repeat revascularization to the primary outcome events. A total of 510 diabetic patients with multivessel or complex single-vessel coronary disease from 24 centers were randomized to PCI plus stenting (and routine abciximab) or CABG. The primary comparison used a noninferiority method with the upper boundary of the 95% confidence interval (CI) not to exceed 1.3 to declare PCI noninferior. Bare-metal stents were used initially, but a switch to Cypher (sirolimus drug-eluting) stents (Cordis, Johnson & Johnson, Bridgewater, New Jersey) was made when these became available.
At 1 year of follow-up, the composite rate of death, MI, and stroke was 10.5% in the CABG group and 13.0% in the PCI group (hazard ratio HR: 1.25, 95% CI: 0.75 to 2.09; p=0.39), all-cause mortality rates were 3.2% and 3.2%, and the rates of death, MI, stroke, or repeat revascularization were 11.3% and 19.3% (HR: 1.77, 95% CI: 1.11 to 2.82; p=0.02), respectively. When the patients who underwent CABG were compared with the subset of patients who received drug-eluting stents (69% of patients), the primary outcome rates were 12.4% and 11.6% (HR: 0.93, 95% CI: 0.51 to 1.71; p=0.82), respectively.
The CARDia (Coronary Artery Revascularization in Diabetes) trial is the first randomized trial of coronary revascularization in diabetic patients, but the 1-year results did not show that PCI is noninferior to CABG. However, the CARDia trial did show that multivessel PCI is feasible in patients with diabetes, but longer-term follow-up and data from other trials will be needed to provide a more precise comparison of the efficacy of these 2 revascularization strategies. (The Coronary Artery Revascularisation in Diabetes trial; ISRCTN19872154).
Aims The PREDICT Study is a prospective cohort study designed to evaluate coronary artery calcification score (CACS) as a predictor of cardiovascular events in type 2 diabetes (T2DM). Methods and ...results A total of 589 patients with no history of cardiovascular disease and with established T2DM had CACS measured, as well as risk factors, including plasma lipoprotein, apolipoprotein, homocysteine and C-reactive protein concentrations, homeostasis model assessment insulin resistance (HOMA-IR), and urine albumin creatinine ratio. Participants were followed for a median of 4 years and first coronary heart disease (CHD) and stroke events were identified as primary endpoints. There were 66 first cardiovascular events (including 10 strokes). CACS was a highly significant, independent predictor of events (P < 0.001), with a doubling in CACS being associated with a 32% increase in risk of events (29% after adjustment). Hazard ratios relative to CACS in the range 0–10 Agatston units (AU) were: CACS 11–100 AU, 5.4 (P = 0.02); 101–400 AU 10.5 (P = 0.001); 401–1000 AU, 11.9 (P = 0.001), and >1000 AU, 19.8 (P < 0.001). Only HOMA-IR predicted primary endpoints independently of CACS (P = 0.01). The areas under the receiver operator characteristic curve for United Kingdom Prospective Diabetes Study (UKPDS) risk engine primary endpoint risk and for UKPDS risk plus CACS were 0.63 and 0.73, respectively (P = 0.03). Conclusion Measurement of CACS is a powerful predictor of cardiovascular events in asymptomatic patients with T2DM and can further enhance prediction provided by established risk models.
To determine whether variation in gastroscopy rates in English general practice populations is associated with inequality in oesophagogastric (OG) cancer outcome.
Retrospective observational study of ...the Hospital Episode Statistics (HES) dataset for England (2006-2008) linked to death registration.
were validated using independent local and national data. General practices with new cases of OG cancer were included. Practices were grouped into tertiles according to standardised elective gastroscopy rate per capita (low, medium or high). Outcome measures for cancer cases were: emergency admission during diagnostic pathway, major surgical resection and mortality at 1 year. Covariates were: age group, gender, comorbidity, general practice average deprivation and patient deprivation.
22 488 incident cases of OG cancer from 6513 general practices were identified. Patients registered with the low tertile group of practices had the lowest rate of major surgery, highest rate of emergency admission and highest mortality. The inequality was widest for the most socioeconomically deprived cases. After adjustment for covariates in logistic regression, the gastroscopy rate (low, medium or high) at the patient's general practice was an independent predictor of emergency admission, major surgery and mortality.
There is wide variation in the rate of gastroscopy among general practice populations in England. On average, OG cancer patients belonging to practices with the lowest rates of gastroscopy are at greater risk of poor outcome. These findings suggest that initiatives or current guidelines aimed at limiting the use of gastroscopy may adversely affect cancer outcomes.
Background:Respiratory muscle weakness is an important clinical problem. Tests of varying complexity and invasiveness are available to assess respiratory muscle strength. The relative precision of ...different tests in the detection of weakness is less clear, as is the value of multiple tests.Methods:The respiratory muscle function tests of clinical referrals who had multiple tests assessed in our laboratories over a 6-year period were analysed. Thresholds for weakness for each test were determined from published and in-house laboratory data. The patients were divided into three groups: those who had all relevant measurements of global inspiratory muscle strength (group A, n = 182), those with full assessment of diaphragm strength (group B, n = 264) and those for whom expiratory muscle strength was fully evaluated (group C, n = 60). The diagnostic outcome of each inspiratory, diaphragm and expiratory muscle test, both singly and in combination, was studied and the impact of using more than one test to detect weakness was calculated.Results:The clinical referrals were primarily for the evaluation of neuromuscular diseases and dyspnoea of unknown cause. A low maximal inspiratory mouth pressure (Pimax) was recorded in 40.1% of referrals in group A, while a low sniff nasal pressure (Sniff Pnasal) was recorded in 41.8% and a low sniff oesophageal pressure (Sniff Poes) in 37.9%. When assessing inspiratory strength with the combination of all three tests, 29.6% of patients had weakness. Using the two non-invasive tests (Pimax and Sniff Pnasal) in combination, a similar result was obtained (low in 32.4%). Combining Sniff Pdi (low in 68.2%) and Twitch Pdi (low in 67.4%) reduced the diagnoses of patients with diaphragm weakness to 55.3% in group B. 38.3% of the patients in group C had expiratory muscle weakness as measured by maximum expiratory pressure (Pemax) compared with 36.7% when weakness was diagnosed by cough gastric pressure (Pgas), and 28.3% when assessed by Twitch T10. Combining all three expiratory muscle tests reduced the number of patients diagnosed as having expiratory muscle weakness to 16.7%.Conclusion:The use of single tests such as Pimax, Pemax and other available individual tests of inspiratory, diaphragm and expiratory muscle strength tends to overdiagnose weakness. Combinations of tests increase diagnostic precision and, in the population studied, they reduced the diagnosis of inspiratory, specific diaphragm and expiratory muscle weakness by 19–56%. Measuring both Pimax and Sniff Pnasal resulted in a relative reduction of 19.2% of patients falsely diagnosed with inspiratory muscle weakness. The addition of Twitch Pdi to Sniff Pdi increased diagnostic precision by a smaller amount (18.9%). Having multiple tests of respiratory muscle function available both increases diagnostic precision and makes assessment possible in a range of clinical circumstances.
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