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ObjectiveTo examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG).MethodsThis study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups.ResultsPatients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, p < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone.ConclusionsThymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone.Clinicaltrialsgov identifierNCT00294658.Classification of evidenceThis study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.

BackgroundThe Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events.MethodsWe did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50-0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed.FindingsOf the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase.InterpretationAt 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis.FundingNational Institutes of Health, National Institute of Neurological Disorders and Stroke.

AimsTo examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial.Methods and resultsTwo thousand five hundred and sixty-nine patients with HFrEF (ejection fraction ≤35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n = 748; enalapril, n = 696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n = 486; enalapril, n = 528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695).ConclusionIn patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses.

BackgroundThymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone.MethodsWe compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period.ResultsA total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P

BackgroundAccording to the 2004 Surgeon General's Report on Health Consequences of Smoking, after >15 years of abstinence, the cardiovascular risk of former smokers becomes similar to that of never-smokers. Whether this health benefit of smoking cessation varies by amount and duration of prior smoking remains unclear.Methods and resultsOf the 4482 adults ≥65 years without prevalent heart failure (HF) in the Cardiovascular Health Study, 2556 were never-smokers, 629 current smokers, and 1297 former smokers with >15 years of cessation, of whom 312 were heavy smokers (highest quartile; ≥32 pack-years). Age-sex-race-adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for centrally adjudicated incident HF and mortality during 13 years of follow-up were estimated using Cox regression models. Compared with never-smokers, former smokers as a group had similar risk for incident HF (aHR, 0.99; 95% CI, 0.85-1.16) and all-cause mortality (aHR, 1.08; 95% CI, 0.96-1.20), but former heavy smokers had higher risk for both HF (aHR, 1.45; 95% CI, 1.15-1.83) and mortality (aHR, 1.38; 95% CI, 1.17-1.64). However, when compared with current smokers, former heavy smokers had lower risk of death (aHR, 0.64; 95% CI, 0.53-0.77), but not of HF (aHR, 0.97; 95% CI, 0.74-1.28).ConclusionsAfter >15 years of smoking cessation, the risk of HF and death for most former smokers becomes similar to that of never-smokers. Although this benefit of smoking cessation is not extended to those with ≥32 pack-years of prior smoking, they have lower risk of death relative to current smokers.

BackgroundWe examined the clinical effectiveness of beta-blockers considered evidenced-based to heart failure and reduced ejection fraction (HFrEF) and their recommended target doses in older adults with HF and preserved ejection fraction (HFpEF).MethodsIn OPTIMIZE-HF (2003-2004) linked to Medicare (2003-2008), of the 10,570 older (age ≥ 65 years, mean, 81 years) adults with HFpEF (EF ≥ 40%, mean 55%), 8373 had no contraindications to beta-blocker therapy. After excluding 4614 patients receiving pre-admission beta-blockers, the remaining 3759 patients were potentially eligible for new discharge prescriptions for beta-blockers and 1454 received them. We assembled a propensity-matched cohort of 1099 pairs of patients receiving beta-blockers and no beta-blockers, balanced on 115 baseline characteristics. Evidence-based beta-blockers for HFrEF, namely, carvedilol, metoprolol succinate, and bisoprolol and their respective guideline-recommended target doses were 50, 200, and 10mg/day.ResultsDuring 6 years of follow-up, new discharge prescriptions for beta-blockers had no association with the primary composite endpoint of all-cause mortality or HF rehospitalization (hazard ratio, 1.03; 95% confidence interval {CI}, 0.94-1.13; p=0.569). This association did not vary by beta-blocker evidence class or daily dose. Hazard ratios for all-cause mortality and HF rehospitalization were 0.99 (95% CI, 0.90-1.10; p=0.897) and 1.17 (95% CI, 1.03-1.34; p=0.014), respectively. The latter association lost significance when higher EF cutoffs of ≥45%, ≥50% and ≥55% were used.ConclusionsInitiation of therapy with beta-blockers considered evidence-based for HFrEF and in target doses recommended for HFrEF had no association with the composite or individual endpoints of all-cause mortality or HF rehospitalization in HFpEF.

BackgroundHeart failure is the leading cause for hospital readmission, the reduction of which is a priority under the Affordable Care Act. Digoxin reduces 30-day all-cause hospital admission in chronic systolic heart failure. Whether digoxin is effective in reducing readmission after hospitalization for acute decompensation remains unknown.MethodsOf the 5153 Medicare beneficiaries hospitalized for acute heart failure and not receiving digoxin, 1054 (20%) received new discharge prescriptions for digoxin. Propensity scores for digoxin use, estimated for each of the 5153 patients, were used to assemble a matched cohort of 1842 (921 pairs) patients (mean age, 76 years; 56% women; 25% African American) receiving and not receiving digoxin, who were balanced on 55 baseline characteristics.ResultsThirty-day all-cause readmission occurred in 17% and 22% of matched patients receiving and not receiving digoxin, respectively (hazard ratio [HR] for digoxin, 0.77; 95% confidence interval [CI], 0.63-0.95). This beneficial association was observed only in those with ejection fraction

BackgroundWhether prediabetes is an independent risk factor for incident heart failure (HF) in non-diabetic older adults remains unclear.MethodsOf the 4602 Cardiovascular Health Study participants, age≥65 years, without baseline HF and diabetes, 2157 had prediabetes, defined as fasting plasma glucose (FPG) 100-125 mg/dL. Propensity scores for prediabetes, estimated for each of the 4602 participants, were used to assemble a cohort of 1421 pairs of individuals with and without prediabetes, balanced on 44 baseline characteristics.ResultsParticipants had a mean age of 73 years, 57% were women, and 13% African American. Incident HF occurred in 18% and 20% of matched participants with and without prediabetes, respectively (hazard ratio {HR} associated with prediabetes, 0.90; 95% confidence interval {CI}, 0.76-1.07; p=0.239). Unadjusted and multivariable-adjusted HRs (95% CIs) for incident HF associated with prediabetes among 4602 pre-match participants were 1.22 (95% CI, 1.07-1.40; p=0.003) and 0.98 (95% CI, 0.85-1.14; p=0.826), respectively. Among matched individuals, prediabetes had no independent association with incident acute myocardial infarction (HR, 1.02; 95% CI, 0.81-1.28; p=0.875), angina pectoris (HR, 0.93; 95% CI, 0.77-1.12; p=0.451), stroke (HR, 0.86; 95% CI, 0.70-1.06; p=0.151) or all-cause mortality (HR, 0.99; 95% CI, 0.88-1.11; p=0.840).ConclusionsWe found no evidence that prediabetes is an independent risk factor for incident HF, other cardiovascular events or mortality in community-dwelling older adults. These findings question the wisdom of routine screening for prediabetes in older adults and targeted interventions to prevent adverse outcomes in older adults with prediabetes.

BackgroundThe prevalence of atrial fibrillation substantially increases after 70 years of age. However, the effect of rate-control versus rhythm-control strategies on outcomes in these patients remains unclear.MethodsIn the randomized Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 4060 patients (mean age 70 years, range 49-80 years) with paroxysmal and persistent atrial fibrillation were randomized to rate-control versus rhythm-control strategies. Of these, 2248 were 70-80 years, of whom 1118 were in the rate-control group. Propensity scores for rate-control strategy were estimated for each of the 2248 patients and were used to assemble a cohort of 937 pairs of patients receiving rate-control versus rhythm-control strategies, balanced on 45 baseline characteristics.ResultsMatched patients had a mean age of 75 years; 45% were women, 7% were nonwhite, and 47% had prior hospitalizations due to arrhythmias. During 3.4 years of mean follow-up, all-cause mortality occurred in 18% and 23% of matched patients in the rate-control and rhythm-control groups, respectively (hazard ratio [HR] associated with rate control, 0.77; 95% confidence interval [CI], 0.63-0.94; P = .010). HRs (95% CIs) for cardiovascular and noncardiovascular mortality associated with rate control were 0.88 (0.65-1.18) and 0.62 (0.46-0.84), respectively. All-cause hospitalization occurred in 61% and 68% of rate-control and rhythm-control patients, respectively (HR 0.76; 95% CI, 0.68-0.86). HRs (95% CIs) for cardiovascular and noncardiovascular hospitalization were 0.66 (0.56-0.77) and 1.07 (0.91-1.27), respectively.ConclusionIn septuagenarian patients with atrial fibrillation, compared with rhythm-control, a rate-control strategy was associated with significantly lower mortality and hospitalization.