COPD treatment: time to change our algorithm?

For the past decade, clinicians have largely followed a set of similar algorithms for chronic obstructive pulmonary disease (COPD) therapy, initiating treatment with an inhaled longacting antimuscarinic (LAMA) and adding combination therapy with a longacting β agonist (LABA) plus an inhaled corticosteroid when symptom or exacerbation control is inadequate. This algorithm is also in accordance with the Global initiative for chronic Obstructive Lung Disease (GOLD) 2007 consensus statement.1 However, the GOLD 2013 consensus statement challenges clinicians to rethink this routine.2 A wide range of treatment options are proposed including LAMA/LABA dual therapy, which is recommended as a treatment alternative for group B (high symptoms/low risk), C (low symptoms/high risk), and D (high symptom/high risk) patients. However, few data have been available to support the efficacy of this combination therapy over single agent bronchodilator therapy. Good data already exist for the efficacy of LAMA monotherapy for symptom control and exacerbation reduction3 as well as for the efficacy of LABA monotherapy for symptom control,4 but scarce data have been available for whether dual agent therapy has additional benefit in terms of either symptom control or exacerbation reduction.

In The Lancet Respiratory Medicine, Jadwiga Wedzicha and colleagues5 present data from the SPARK study, a randomised, three-group, double-blind study in COPD comparing once-daily indacaterol plus glycopyrronium combination therapy (QVA149) versus glycopyrronium alone versus open-label tiotropium. The primary endpoint examined was superiority of QVA149 versus glycopyrronium in reducing the frequency of moderate to severe COPD exacerbations, with the comparison of QVA149 versus tiotropium as a major secondary endpoint. Inclusion criteria were post-bronchodilator forced expiratory volume in 1 s (FEV1) less than 50% and at least one exacerbation in the previous 12 months. This study showed a 12% reduction in the rate of moderate to severe exacerbations for QVA149 compared with glycopyrronium (rate ratio [RR] 0·88, 95% CI 0·77—0·99, p=0·038). The 10% reduction in moderate to severe exacerbations for QVA149 compared with tiotropium was not significant (RR 0·90, 95% CI 0·79—1·02, p=0·096). QVA149 also resulted in significantly higher trough FEV1 as compared to glycopyrronium (differences 70—80 mL, p<0·0001) and tiotropium (differences 60—80 mL, p<0·0001) and resulted in 8—9 unit improvements in St George’s Respiratory Questionnaire score (SGRQ) total score as opposed to 6 units with glycopyrronium and 5—6 units with tiotropium, both significant differences.

The real question is how these data should influence prescribing practices for COPD. These data support better lung function improvement, better symptom control, and greater exacerbation reduction with LAMA/LABA therapy as opposed to LAMA therapy alone in patients with severe to very severe disease. In reality, such patients are likely to be on some form of therapy before they progress to this level of disease severity. Hence for the patient already on LAMA therapy, the addition of a LABA, particularly if exacerbation reduction is a goal, as a next step in therapy is supported by these data.

These data must be interpreted in light of the fact that about 75% of patients were on concomitant inhaled corticosteroids, which has several implications. First, the magnitude of exacerbation reduction seen was 12%, which is arguably clinically significant but might have been attenuated owing to concomitant inhaled corticosteroid use. These results mirror the magnitude of reduction seen with tiotropium in the UPLIFT study,3 in which concomitant inhaled corticosteroid plus LABA therapy was allowed. Second, the high rates of concomitant inhaled corticosteroid use also mean that these data perhaps provide less support for the GOLD recommendation of LABA/LAMA as dual therapy for either groups C or D and perhaps provide greater support for triple therapy (addition of LABA to LAMA plus inhaled corticosteroids) for C and D patients.

In further thinking about how these data inform prescribing practices, one should also note that 22% of patients studied had two or more moderate or severe exacerbations in the previous year. Previous data suggest that group D patients who are judged to be at high risk by both FEV1 and exacerbation criteria are at even greater risk of moderate and severe exacerbations than are those meeting a single criterion, suggesting good efficacy in a relatively high risk population.6 On the other hand, another interesting finding of the study was that the greatest reduction was seen in mild exacerbations—15% with QVA149 compared with glycopyrronium and 16% compared with tiotropium—with mild exacerbations defined as an event with increase in symptoms but self-managed by the patient. Although exacerbation events requiring therapy are more frequently studied, the importance of untreated events should not be underestimated. Even events unreported to a health-care provider have been shown to be associated with significantly worse health status,7 which might explain the improvements in SGRQ score seen with QVA149 therapy.

Overall, these data support greater efficacy for dual bronchodilator therapy with QVA149 as compared with LAMA monotherapy. In view of the lack of data in the past, the use of combination LABA/LAMA therapy has not been embraced by medical practitioners for use in COPD, but these new data suggest dual therapy is an important therapeutic option when trying to maximise symptom improvement and exacerbation reduction.

Source: Lancet

 

New options for second-line therapy of advanced renal cancer.

Several drugs targeting VEGF or mTOR pathways have been approved for treatment of advanced renal-cell carcinoma because of improvements noted in progression-free survival (PFS) in phase 3 trials.1 Validation of prognostic models showed that treatment with such drugs can lead to a median overall survival of around 43 months for patients in favourable risk categories and 23 months for patients in intermediate risk categories.2 With few exceptions, patients on first-line therapy progress and proceed to need one or more subsequent lines of targeted therapy. In a population-based study,3 patients in a favourable risk group had progression on first-line VEGF-targeted therapy after a median of 16·6 months (compared with 15 months for patients in an intermediate risk group) and progression after 6·2 months on second-line targeted therapy (5·5 months for intermediate risk). Two phase 3 trials4, 5 assessed outcomes after failure of a previous VEGF-targeted therapy to establish evidence for the mTOR-inhibitor everolimus and the selective inhibitor of VEGF receptors 1—3, axitinib. The AXIS trial5 is the only study that directly compared two active compounds (axitinib vs sorafenib) after failure of an approved first-line regimen. In AXIS, more than a third of patients had received cytokines and over half had received sunitinib as first-line therapy. Axitinib led to an improvement in median PFS compared with sorafenib in the intention-to-treat analysis. However, the difference in PFS for patients after sunitinib treatment based on investigator and independent review committee assessments was only slight. Data for overall survival, a secondary endpoint, were immature before the first report was published in 2011. Because guidelines and clinical practice favour targeted therapy in preference to cytokines as first-line treatment,1 axitinib is regarded as a treatment option for second-line therapy of advanced renal-cell carcinoma.5

In The Lancet Oncology, Robert Motzer and colleagues6 now report mature overall survival data for the AXIS trial. Such an analysis is important because crossover between the two study arms was not allowed. No significant differences in overall survival were noted between patients in both treatment arms who received the same first-line regimen (median overall survival 20·1 months [95% CI 16·7—23·4] with axitinib vs 19·2 months [17·5—22·3] with sorafenib; hazard ratio 0·969, 95% CI 0·800—1·174, p=0·3744). More than half the patients in each arm continued with a third-line treatment after progression on study drug and treatment after progression was allowed. This design confounded overall survival results and raises questions as to whether PFS is meaningful in this setting.7 Third-line therapy partly explains the long time interval noted between progression on second-line treatment and overall survival. However, inclusion of patients with a less aggressive tumour biology might have contributed to this outcome. Only a third of patients in the AXIS trial were Memorial Sloan Kettering Cancer Center (MSKCC) poor risk at entry,5 suggesting that individuals with rapid deterioration of performance or accelerated progression during first-line therapy are less likely to enter trials than are patients with more favourable risk profiles.

For patients previously treated with sunitinib in Motzer and colleagues’ study,6 median time on first-line therapy was about 10 months, with a median overall survival for all risk groups of 15·2 months (95% CI 12·8—18·3) for axitinib and 16·5 months (13·7—19·2) for sorafenib. Patients who received cytokines had first-line therapy for about 6 months and a median overall survival of 29·4 months (24·5—not assessable) for axitinib and 27·8 months (23·1—34·5) for sorafenib. After correction for the different length of first-line therapies, overall survival seemed to be increased by about 7—9 months in patients who had cytokines before VEGF-targeted therapy. Resistance to previous VEGF-targeted therapy, which might not be apparent in patients previously untreated with such an approach, cannot fully explain this difference. Motzer and colleagues noted a putative association of overall survival with length of previous sunitinib treatment for both axitinib and sorafenib, although there was substantial overlap in the 95% CIs.6 A retrospective Database Consortium analysis of 464 patients who had received two lines of VEGF-targeted therapies reported no correlation between first-line PFS and second-line PFS.8 Rather, a significant difference in multivariate analysis of baseline prognostic factors in favour of cytokine versus sunitinib pretreatment (HR 0·503, 95% CI 0·395—0·641; p<0·0001) suggested that patients with less advanced disease were most likely to start treatment with cytokines.6 However, information about the distribution of prognostic factors between patients who were pretreated with cytokines and sunitinib, which could have important implications for treatment sequences, is not provided in Motzer and colleagues’ study.

Data from trials and population-based analyses suggest that a ceiling has almost been reached in terms of outcome with present targeted therapies and prognosis that relies on models based on clinical factors.2 The mature AXIS data add axitinib to the choices for second-line treatment with similar outcome and different toxicity profiles.4—6 Despite prognostic factors assessed in the updated analysis and a correlation of development of hypertension during axitinib and sorafenib treatment with overall survival, the choice for a second-line drug or even treatment beyond progression at failure of first-line treatment remains an educated guess. The outcome of this study proves once again that renal-cell carcinoma is a heterogenous cancer9 that needs further research into predictive biomarkers to tailor treatment choices.

Source: Lancet

 

MR-guided focused ultrasound thalamotomy for essential tremor: a proof-of-concept study.

Background

Essential tremor is the most common movement disorder and is often refractory to medical treatment. Surgical therapies, using lesioning and deep brain stimulation in the thalamus, have been used to treat essential tremor that is disabling and resistant to medication. Although often effective, these treatments have risks associated with an open neurosurgical procedure. MR-guided focused ultrasound has been developed as a non-invasive means of generating precisely placed focal lesions. We examined its application to the management of essential tremor.

Methods

Our study was done in Toronto, Canada, between May, 2012, and January, 2013. Four patients with chronic and medication-resistant essential tremor were treated with MR-guided focused ultrasound to ablate tremor-mediating areas of the thalamus. Patients underwent tremor evaluation and neuroimaging at baseline and 1 month and 3 months after surgery. Outcome measures included tremor severity in the treated arm, as measured by the clinical rating scale for tremor, and treatment-related adverse events.

Findings

Patients showed immediate and sustained improvements in tremor in the dominant hand. Mean reduction in tremor score of the treated hand was 89·4% at 1 month and 81·3% at 3 months. This reduction was accompanied by functional benefits and improvements in writing and motor tasks. One patient had postoperative paraesthesias which persisted at 3 months. Another patient developed a deep vein thrombosis, potentially related to the length of the procedure.

Interpretation

MR-guided focused ultrasound might be a safe and effective approach to generation of focal intracranial lesions for the management of disabling, medication-resistant essential tremor. If larger trials validate the safety and ascertain the efficacy and durability of this new approach, it might change the way that patients with essential tremor and potentially other disorders are treated.

Source: Lancet

Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study.

Background

Extracranial arterial dilatation has been hypothesised to be the cause of pain in patients who have migraine without aura. To test that hypothesis, we aimed to measure extracranial and intracranial arteries during attacks of migraine without aura.

Methods

In this cross-sectional study, we recruited patients aged 18—60 years from the Danish Headache Centre and via announcements on a Danish website. We did magnetic resonance angiography during spontaneous unilateral migraine attacks. Primary endpoints were difference in circumference of extracranial and intracranial arterial segments comparing attack and attack-free days and the pain and the non-pain side. The extracranial arterial segments measured were the external carotid (ECA), the superficial temporal (STA), the middle meningeal (MMA), and the cervical part of the internal carotid (ICAcervical) arteries. The intracranial arterial segments were the cavernous (ICAcavernous) and cerebral (ICAcerebral) parts of the internal carotid, the middle cerebral (MCA), and the basilar (BA) arteries. This study is registered atClinicaltrials.gov, number NCT01471314.

Findings

Between Oct 12, 2010, and Feb 8, 2012, we recruited 78 patients, of whom 19 women had a scan during migraine and were included in the final analysis. On migraine compared with non-migraine days, we detected no statistically significant dilatation of the extracranial arteries on the pain side (ECA, mean difference 1·2% [95% CI −5·7 to 8·2] p=0·985, STA 3·6% [—3·7 to 11·0] p=0·532, MMA 1·7% [—1·7 to 5·2] p=0·341, and ICAcervical 2·3% [—0·3 to 4·9] p=0·093); the intracranial arteries were more dilated during attacks (MCA, 13·0% [6·4 to 19·6] p=0·001, ICAcerebral 11·5% [5·6 to 17·3] p=0·0004, and ICAcavernous 11·4% [5·3 to 17·5] p=0·001), except for the BA (1·6% [—2·7 to 5·9] p=0·621). Compared with the non-pain side, during attacks we detected dilatation on the pain side of the intracranial arteries (MCA, mean difference 10·5% [0·7—20·3] p=0·044, ICAcerebral (14·4% [4·6—24·1] p=0·013), and ICAcavernous (9·1% [3·9—14·4] p=0·003) but not of the extracranial arteries (ECA, 2·1% [—3·8 to 9·2] p=0·238, STA, 3·6% [—3·7 to 10·8] p=0·525, MMA, 2·7% [—1·3 to 5·6] p=0·531, and ICAcervical, 5·0% [—0·5 to 10·4] p=0·119).

Interpretation

Migraine pain was not accompanied by extracranial arterial dilatation, and by only slight intracranial dilatation. Future migraine research should focus on the peripheral and central pain pathways rather than simple arterial dilatation.

Source: Lancet

 

Idiopathic REM sleep behaviour disorder in the development of Parkinson’s disease.

Parkinson’s disease is a progressive neurodegenerative disorder associated with Lewy body disease pathology in central and peripheral nervous system structures. Although the cause of Parkinson’s disease is not fully understood, clinicopathological analyses have led to the development of a staging system for Lewy body disease-associated pathological changes. This system posits a predictable topography of progression of Lewy body disease in the CNS, beginning in olfactory structures and the medulla, then progressing rostrally from the medulla to the pons, then to midbrain and substantia nigra, limbic structures, and neocortical structures. If this topography and temporal evolution of Lewy body disease does occur, other manifestations of the disease as a result of degeneration of olfactory and pontomedullary structures could theoretically begin many years before the development of prominent nigral degeneration and the associated parkinsonian features of Parkinson’s disease. One such manifestation of prodromal Parkinson’s disease is rapid eye movement (REM) sleep behaviour disorder, which is a parasomnia manifested by vivid dreams associated with dream enactment behaviour during REM sleep. Findings from animal and human studies have suggested that lesions or dysfunction in REM sleep and motor control circuitry in the pontomedullary structures cause REM sleep behaviour disorder phenomenology, and degeneration of these structures might explain the presence of REM sleep behaviour disorder years or decades before the onset of parkinsonism in people who develop Parkinson’s disease.

Source: Lancet

Highly potent human haemopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region.

Abstract

Background

Haemopoietic stem cells (HSCs) are used in the clinic to treat various haematological disorders. These cells emerge during early embryogenesis and maintain haemopoiesis in the adult organism. In the vertebrate embryo, HSCs develop in multiple locations. Little is known about the embryonic development of human HSCs.

Methods

Human embryonic and fetal tissues were obtained after elective termination of pregnancy. Preconditioned immunodeficient mice were used as recipients for human HSCs. Transplanted mice were bled every 1—2 months to assess human HSC contribution.

Findings

We have found that human HSCs emerge first in the aorta-gonad-mesonephros (AGM) region and only later appear in the yolk sac, liver, and placenta. Transplantation of human AGM region cells into immunodeficient mice provides long-term high-level multilineage haemopoietic repopulation. We have shown that, despite the low number of HSCs in the human AGM region, their self-renewal potential is enormous. A single HSC derived from the AGM region generates around 600 daughter HSCs in primary recipients, which disseminate throughout the entire recipient bone marrow and are retransplantable.

Interpretation

We provide a systematic spatiotemporal analysis of HSC emergence in the early human embryo and identify the AGM region as the primary source of powerful HSCs with enormous self-renewal capacity. This high potency of the first HSCs sets a new standard for in-vitro generation of HSCs from pluripotent stem cells for the purpose of regenerative medicine.

Source: Lancet

 

Rapid pediatric weight gain beneficial in low-income countries .

Previous studies have suggested that rapid weight gain during the first 2 years of life is associated with an increased risk for obesity and insulin resistance later in life. However, a new study with an emphasis on countries with low or middle income suggests that higher birth weight and early growth during the first 2 years of life led to improvements in height and levels of education.

“Our results challenge several programs in countries of low and middle income. … Traditional school feeding programs that increase BMI with little effect on height might be doing more harm than good in terms of future health,” researcher Linda S. Adair, PhD, of the Gillings School of Global Public Health at the University of North Carolina at Chapel Hill, said in a press release.

The researchers collected data for 8,362 patients from five prospective birth cohort studies from Brazil, Guatemala, India, the Philippines and South Africa who had at least one adult outcome of interest.

They wrote that a higher birth weight was consistently related to an adult BMI of >25 kg/m2 (OR=1.28; 95% CI, 1.21-1.35) and a reduced tendency for short adult stature (OR=0.49; 95% CI, 0.44-0.54) and of not completing secondary school (OR=0.82; 95% CI, 0.78-0.87).

Additional data indicate that faster linear growth at age 2 years (OR=0.23; 95% CI, 0.20-0.52) and mid-childhood (OR=0.39; 95% CI, 0.36-0.43) was associated with a reduced risk for short adult stature and of not completing secondary school at age 2 years (OR=0.74; 95% CI, 0.67-0.78) and mid-childhood (OR=0.87; 95% CI, 0.83-0.92).

However, faster linear growth increased the likelihood for children being overweight at age 2 years (OR=1.24; 95% CI, 1.17-1.31) and mid-childhood (OR=1.12; 95% CI, 1.06-1.18), in addition to elevated BP at age 2 years (OR=1.12; 95% CI, 1.06-1.19) and mid-childhood (OR=1.07; 95% CI, 1.01-1.13), researchers wrote.

Moreover, faster relative weight gain was associated with an increased risk for adult overweight status at age 2 years (OR=1.51; 95% CI, 1.43-1.60) and mid-childhood (OR=1.76; 95% CI, 1.69-1.91), in addition to elevated BP at age 2 years (OR=1.07; 95% CI, 1.01-1.13) and mid-childhood (OR=1.22; 95% CI, 1.15-1.30), they wrote.

Linear growth and relative weight gain were not linked to dysglycemia. However, higher birth weight was related to a decreased risk for the disorder (OR=0.89; 95% CI, 0.81-0.98), according to data.

In an accompanying commentary, Zulfiqar A. Bhutta, MBBS, PhD, of the division of women and child health at Aga Khan University in Karachi, Pakistan, wrote that aside from study limitations, Adair and colleagues’ findings have clear implications.

“As shown by an analysis of evidence-based interventions, a focus on improvements in nutrition in pregnancy and linear growth in the first 2 years of life could lead to substantial reductions in stunting and improved survival,” Bhutta wrote.

According to Bhutta, there should be well-designed prospective studies with appropriate interventions and follow-up, including elements of child development, education, employment and earnings, as outcomes.

For more information:

Adair LS. Lancet. 2013;doi:10.1016/S0140-6736(13)60103-8.

Bhutta ZA. Lancet. 2013;doi:10.1016/S0140-6736(13)60716-3.

Source: http://www.healio.com

Study Finds Concerns Around Current Infection Control Practices.

Multidrug-resistant Mycobacterium abscessus is frequently transmitted between patients with cystic fibrosis, suggesting that current infection control is not adequate, according to a Lancet study.

Researchers analyzed 168 isolates from 31 patients with pulmonary M. abscessus infection at a U.K cystic fibrosis center. Within clusters ofM. abscessus subspecies massiliense, isolates from different patients were often more closely related to each other than were isolates from within a single individual, suggesting transmission of the bacteria between patients. In addition, some isolates were resistant to macrolides and aminoglycosides in patients previously unexposed to those antibiotics, supporting the notion of cross-infection. The authors say transmission is likely occurring indirectly, such as through fomite contamination or lung function testing.

The authors conclude that their findings raise “several important questions about current infection control measures used in treatment centers, the potential for cross-infection in other patient groups and with other … species, and whether mandatory notification of infections with M. abscessus complex and routine whole genome sequencing might be required to identify and control the spread.”

Source: Lancet 

 

Major Psychiatric Disorders Linked to Genes Involved with Brain’s Calcium Balance.

Five major psychiatric illneses — autism, ADHD, bipolar disorder, depression, and schizophrenia — seem related to calcium-signaling pathways in the brain, according to a Lancet study.

Researchers performed genome-wide analyses on some 30,000 patients with the disorders and a roughly equal number of controls. They identified four genetic variants — all related to calcium signaling — that were significantly associated with the presence of one of the five disorders.

Commentators, noting the importance of calcium signaling to nerve growth and development, conclude that the results could help identify new targets for psychotropic drugs.

Source: Lancet

 

Extended Duration of Tamoxifen Therapy Enhances Breast Cancer Survival .

Ten years of adjuvant tamoxifen therapy in women with estrogen receptor–positive breast cancer is associated with lower rates of recurrence and breast cancer mortality than 5 years of treatment, according to a Lancet article.

Researchers followed outcomes in some 6800 women with receptor-positive disease who’d completed 5 years of tamoxifen therapy, half of whom were allocated to 5 additional years of treatment.

Recurrences and breast cancer mortality were both significantly lower among those on continued therapy, with reductions being even more pronounced after 9 years. During years 5–14, mortality was 12.2% for those allocated to continue treatment versus 15.0% for controls (absolute mortality reduction, 2.8%). The incidence of pulmonary embolism (but not of death from it) was higher in the continued-treatment group, and the risk of endometrial cancer was also higher with longer treatment, including an absolute increase in mortality risk of 0.2%.

A commentator writes that confirmation of these results by meta-analysis with other tamoxifen trials “should herald a change of practice.”

Source: Lancet