Dupilumab in Persistent Asthma with Elevated Eosinophil Levels.


Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels.


We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol-defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of asthma control. Effects on various type 2 helper T-cell (Th2)–associated biomarkers and safety and tolerability were also evaluated.


A total of 52 patients were assigned to the dupilumab group, and 52 patients were assigned to the placebo group. Baseline characteristics were similar in the two groups. Three patients had an asthma exacerbation with dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28; P<0.001). Significant improvements were observed for most measures of lung function and asthma control. Dupilumab reduced biomarkers associated with Th2-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and headache occurred more frequently with dupilumab than with placebo.


In patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers.

Source: NEJM






Dual Antiplatelet Therapy in Acute Transient Ischemic Attack and Minor Stroke.

Some patients with stroke and transient ischemic attack (TIA) of the brain are at high risk for early recurrent stroke, usually due to arterial thromboembolism.1,2 Aspirin reduces the risk of early recurrent stroke by only 12% (95% confidence interval [CI], 3 to 20).3 Adding clopidogrel to aspirin in patients with acute coronary syndromes reduces the risk of recurrent vascular events by 20% (95% CI, 10 to 28) but increases the risk of major bleeding by 38% (95% CI, 13 to 67).4 For patients with acute ischemic stroke, who are prone to early spontaneous hemorrhagic transformation of infarcted brain, adding clopidogrel to aspirin may cause more major bleeding than may otherwise occur in acute coronary syndromes. Among 731 patients with acute ischemic stroke or TIA (onset within the previous 3 days) enrolled in five small trials, the addition of clopidogrel to aspirin was associated with nonsignificant trends toward a reduction in recurrent stroke (4.5% with clopidogrel and aspirin, as compared with 6.6% with aspirin alone) and an increase in major bleeding (1.1% and 0%, respectively).5

Wang and colleagues now report in the Journal the impressive results of the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial.6 Among 5170 Chinese patients with acute minor ischemic stroke or TIA (onset within the previous 24 hours) at high risk for recurrence, the addition of clopidogrel to aspirin reduced the relative risk of recurrent stroke at 90 days by 32% (8.2% vs. 11.7%; hazard ratio, 0.68; 95% CI, 0.57 to 0.81; absolute risk reduction, 3.5 percentage points). The effect was consistent among 11 predefined subgroups. There was no difference between the group that received both clopidogrel and aspirin and the group that received aspirin alone in the incidence of moderate or severe hemorrhage (0.3% in each group; P=0.73) or hemorrhagic stroke (0.3% in each group; P=0.98).

The CHANCE investigators completed a large, scientifically rigorous trial that proves the concept that dual antiplatelet therapy can be more effective than single antiplatelet therapy in preventing early recurrent stroke in patients with acute symptomatic atherothrombosis (predominantly intracranial) of the brain. Moreover, the absolute benefits of dual antiplatelet therapy can be substantial in patients at high risk for recurrent stroke1; treating 29 patients for 90 days with clopidogrel plus aspirin for the first 21 days, followed by clopidogrel alone from day 22 to day 90, prevented one stroke, as compared with aspirin alone. Indeed, most of the absolute benefit of clopidogrel plus aspirin is realized within the first few days after TIA and ischemic stroke, when the underlying atherosclerotic plaque is most unstable and the risk of recurrence is highest.

The safety results show that dual antiplatelet therapy can be given without excess harm in patients with acute focal brain ischemia, provided that patients have a low risk of hemorrhagic transformation — no fresh brain infarction (i.e., TIA) or a very small volume of fresh brain infarction (i.e., minor ischemic stroke). The CHANCE investigators had to screen 41,561 patients with stroke or TIA to find 5170 appropriate patients (12.4%). Hence, the results cannot be generalized to most patients; the study excluded patients with major ischemic stroke, who are at risk for hemorrhagic transformation, and patients with TIA due to isolated sensory, visual, or vertiginous syndromes, who are at low risk for recurrence.1 The results may also not apply to non-Chinese patients with different forms of underlying arterial disease (e.g., a higher prevalence of extracranial large-artery atherosclerosis) and different prevalences of genetic polymorphisms of liver cytochrome P-450 (CYP) isozymes, which metabolize clopidogrel to its active metabolites. The absolute benefits of clopidogrel plus aspirin observed in this trial may also not be realized in persons and populations at lower absolute risk for recurrent stroke, such as those with a low prevalence of risk factors for recurrent stroke and those with access to effective secondary stroke prevention. Finally, the results of this trial cannot be generalized beyond 90 days after ischemic stroke, when the cumulative risks of bleeding with clopidogrel plus aspirin, as compared with aspirin or clopidogrel alone, offset the benefits.7-9

The implication of this trial is that Chinese patients with acute TIA or minor ischemic stroke (onset within the previous 24 hours) who are at high risk for recurrence should be regarded as a medical emergency. They should be treated immediately with clopidogrel plus aspirin for 21 days, followed by clopidogrel alone, for a total of 90 days, before continuing long-term treatment with clopidogrel, aspirin, or the combination of aspirin and extended-release dipyridamole. A bolus loading dose of at least 162 mg of aspirin and 300 mg of clopidogrel is required on day 1 to rapidly inhibit platelet aggregation, given that starting with daily doses of 75 mg of aspirin and clopidogrel takes several days to produce maximal inhibition of platelet aggregation. The benefits of dual antiplatelet therapy are greatest in the first days after TIA and ischemic stroke.

I think that clinicians should continue to enroll non-Chinese patients with acute TIA and minor ischemic stroke into ongoing large clinical trials of the safety and efficacy of dual and triple antiplatelet therapy.10,11 Moreover, I hope that researchers will evaluate new antiplatelet agents (e.g., ticagrelor and prasugrel) and new anticoagulant agents (e.g., rivaroxaban) that are effective in atherothrombotic acute coronary syndrome in patients with acute TIA and minor ischemic stroke due to arterial thromboembolism.

Source: NEJM


Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack.

Transient ischemic attack (TIA) and acute minor ischemic stroke are common and often lead to disabling events. In China, there are approximately 3 million new strokes every year, and approximately 30% of them are minor ischemic strokes.1,2 The incidence of TIA in China has not been determined, but on the basis of the incidence in other countries, there are probably more than 2 million TIAs annually in China.3-5 The risk of another stroke occurring after a TIA or minor stroke is high, with approximately 10 to 20% of patients having a stroke within 3 months after the index event; most of these strokes occur within the first 2 days.5-8

The role of antiplatelet therapy for secondary stroke prevention has been well established. However, aspirin is the only antiplatelet agent that has been studied in the acute phase of stroke, during which its benefit is modest.9,10 Aspirin and clopidogrel synergistically inhibit platelet aggregation,11,12 and such dual therapy reduces the risk of recurrent ischemic events in patients with the acute coronary syndrome.13,14 Large-scale trials of secondary prevention of ischemic events after stroke have not shown a benefit of the combination of clopidogrel and aspirin.15-17 However, these trials did not study the early, high-risk period after stroke, they included some patients with strokes of moderate severity, and they included few if any patients with TIA. Three small pilot trials have shown trends toward a benefit of the combination therapy and minimal safety concerns in patients with minor stroke or TIA.18-20

We conducted the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial to test the hypothesis that 3 months of treatment with a combination of clopidogrel and aspirin would reduce the risk of recurrent stroke, as compared with aspirin alone, among patients with acute high-risk TIA or minor ischemic stroke.


In this large-scale trial involving patients with high-risk TIA or minor ischemic stroke, we found that the addition of clopidogrel to aspirin within 24 hours after symptom onset reduced the risk of subsequent stroke by 32.0%, as compared with aspirin alone. Event rates during this early period were very high, and clopidogrel was associated with an absolute risk reduction of 3.5 percentage points, equivalent to a number needed to treat of 29 patients to prevent one stroke over a period of 90 days. Combination therapy with clopidogrel and aspirin, as compared with aspirin alone, was not associated with an increased incidence of hemorrhage, although there was a worrisome trend in overall bleeding toward more events with the combination therapy.

The results of our trial differ from those of other trials of combination therapy with clopidogrel and aspirin after cerebral ischemic events.7,8,17 One possible explanation is that, unlike previous trials, our trial targeted a population at particularly high risk for recurrent ischemia and at low risk for hemorrhage. Previous trials included patients with more severe strokes than our trial did, and they did not enroll patients in the first hours after an index minor stroke or TIA, during which the risk of recurrent ischemia is particularly high. This may explain why other trials did not show a reduction in the risk of ischemic events but did show an increased risk of hemorrhage.

In our study, the curves for survival free of stroke were particularly steep in the first few days, during which the curves representing the treatment groups diverged dramatically. Subsequently, the rates of stroke were similar. This suggests that the requirement for randomization within 24 hours after the onset of symptoms, with nearly half the patients enrolled within 12 hours (and treated shortly thereafter), was important. Although we did not see a relative difference in the efficacy outcome between patients randomly assigned to a study group within 12 hours and those assigned after a longer interval, absolute event rates were higher among those who were enrolled within 12 hours. In clinical practice, treatment with clopidogrel and aspirin as soon as possible after symptom onset is likely to produce the greatest absolute benefit, since ischemic event rates are highest in the initial hours after symptoms appear.

Our trial was conducted entirely in China, a country with approximately 150 to 250 deaths from stroke per 100,000 persons per year, which is five times as high as the rate in the United States.23Although diagnostic tools and therapies commonly used in the United States and Europe are available in most hospitals in China, some patients cannot afford this level of care.24,25 Secondary prevention practices are also less rigorous in China, where rates of treatment of hypertension, diabetes, and hyperlipidemia are low, as shown in our study population (Table S3 in theSupplementary Appendix). Furthermore, the distribution of stroke subtypes in China differs from that in more developed countries; China has a higher incidence of large-artery intracranial atherosclerosis25 and a higher prevalence of genetic polymorphisms that affect the metabolism of clopidogrel.26 The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial (ClinicalTrials.gov number, NCT00991029), sponsored by the National Institutes of Health, which is similar to our trial, is now enrolling patients at sites primarily in the United States.27 The POINT trial is assessing a higher loading dose of clopidogrel (600 mg) and a narrower time window (treatment within 12 hours after symptom onset) than were used in our study.

Several common clinical conditions mimic TIA, including seizures, migraine, peripheral vertigo, syncope, and anxiety.28 To minimize the risk of enrolling patients with TIA mimics, we excluded all patients with isolated sensory symptoms, isolated visual changes, or isolated dizziness or vertigo without evidence of acute infarction on baseline CT or MRI of the head. In addition, enrollment of patients with TIA was limited to those with a high ABCD2 score (≥4) to increase the likelihood that spells were due to true TIAs and to ensure that we were enrolling patients who were at high risk for subsequent ischemic events.29 The risk of subsequent stroke in the trial was high for this patient population, suggesting that our strategy was successful. Our findings may not apply to other populations of patients with ischemic events.

In conclusion, our study shows that among patients with high-risk TIA or minor ischemic stroke who are initially seen within 24 hours after symptom onset, treatment with clopidogrel plus aspirin for 21 days, followed by clopidogrel alone for a total of 90 days, is superior to aspirin alone in reducing the risk of subsequent stroke events. The combination of clopidogrel with aspirin did not cause more hemorrhagic events in this patient population than aspirin alone.

Source: NEJM

The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults.



There are limited data regarding the relationship between cannabinoids and metabolic processes. Epidemiologic studies have found lower prevalence rates of obesity and diabetes mellitus in marijuana users compared with people who have never used marijuana, suggesting a relationship between cannabinoids and peripheral metabolic processes. To date, no study has investigated the relationship between marijuana use and fasting insulin, glucose, and insulin resistance.


We included 4657 adult men and women from the National Health and Nutrition Examination Survey from 2005 to 2010. Marijuana use was assessed by self-report in a private room. Fasting insulin and glucose were measured via blood samples after a 9-hour fast, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated to evaluate insulin resistance. Associations were estimated using multiple linear regression, accounting for survey design and adjusting for potential confounders.


Of the participants in our study sample, 579 were current marijuana users and 1975 were past users. In multivariable adjusted models, current marijuana use was associated with 16% lower fasting insulin levels (95% confidence interval [CI], −26, −6) and 17% lower HOMA-IR (95% CI, −27, −6). We found significant associations between marijuana use and smaller waist circumferences. Among current users, we found no significant dose-response.


We found that marijuana use was associated with lower levels of fasting insulin and HOMA-IR, and smaller waist circumference.


In this large, cross-sectional study, we found that subjects who reported using marijuana in the past month had lower levels of fasting insulin and HOMA-IR, as well as smaller waist circumference and higher levels of HDL-C. These associations were attenuated among those who reported using marijuana at least once, but not in the past 30 days, suggesting that the impact of marijuana use on insulin and insulin resistance exists during periods of recent use.

There have been discrepant findings on the relationship between marijuana use and BMI. A study of young adults examining associations between marijuana use and cardiovascular risk factors reported no significant trend between marijuana use and BMI,5 whereas analyses of 2 large nationally representative surveys found lower BMI and decreased prevalence of obesity.46 Few studies have explored possible underlying explanations for these associations. However, a recent analysis using NHANES III data showed that marijuana users had a lower prevalence of diabetes mellitus compared with nonusers;7similar results have been found with administration of cannabidiol in a mouse model.11 In the present study, we demonstrate a significant association between current marijuana use and lower levels of fasting insulin and insulin resistance in multivariable adjusted analyses even after excluding participants with prevalent diabetes mellitus.

Particular focus has been given to the plant cannabinoid (-)-trans-Δ9-tetrahydrocannabinol, which acts as a partial agonist at both the cannabinoid type 1 and 2 receptors, and cannabidiol, which has lower affinity for the cannabinoid receptors but appears to antagonize both cannabinoid type 1 and 2.1213 In addition, it has been found that repeated administration of cannabinoids reduces cannabinoid type 1 receptor density, producing a tolerance to its physiologic effects.1214 Thus, a dose-response relationship may be expected; however, we did not find any evidence of this in the present study.

Although not completely elucidated, the mechanisms by which cannabinoids affect peripheral metabolism via these receptors have been studied extensively; the cannabinoid type 1 receptor antagonist, rimonabant, was found to improve insulin sensitivity in wild-type mice, but not in adiponectin knockout mice, suggesting that adiponectin at least partially mediates the improvement in insulin sensitivity;15 adiponectin has been reported to improve insulin sensitivity.16 This rimonabant-induced improvement in insulin resistance has been confirmed in human studies.17 Furthermore, in a randomized clinical trial, rimonabant was significantly associated with an increase in plasma adiponectin levels, as well as weight loss and a reduction in waist circumference.18 Cannabis itself, when administered to obese rats, was associated with weight reduction and an increase in the weight of pancreata, implying beta-cell protection.19 In addition, cannabinoid type 1 knockout mice are resistant to diet-induced obesity, suggesting that the role of this receptor is central in the metabolic processes leading to obesity.20 Given that 2 of the main active phytocannabinoids in marijuana, (-)-trans-Δ9-tetrahydrocannabinol and cannabidiol, are classified as partial agonists and antagonists, respectively, and are thus capable of producing antagonistic effects at the cannabinoid receptors, it is possible that the associations observed in the aforementioned studies, as well as in the present study, are due at least in part to this adiponectin-mediated mechanism.

In our analyses, we presented alternative models, controlling for BMI as a potential confounder of the relationship between marijuana use and the remainder of the cardiometabolic parameters. We generated this model because of the potential for BMI to affect marijuana use and independently affect the cardiometabolic parameters. On the other hand, BMI may be a mediator of the association between marijuana use and the cardiometabolic outcomes, and thus was excluded from our primary multivariable model.


With the recent trends in legalization of marijuana in the United States, it is likely that physicians will increasingly encounter patients who use marijuana and should therefore be aware of the effects it can have on common disease processes, such as diabetes mellitus. We found that current marijuana use is associated with lower levels of fasting insulin, lower HOMA-IR, and smaller waist circumference.

Source: http://www.amjmed.com


Use of 5α-reductase inhibitors for lower urinary tract symptoms and risk of prostate cancer in Swedish men: nationwide, population based case-control study.


Objective To assess the association between 5α-reductase inhibitor (5-ARI) use in men with lower urinary tract symptoms and prostate cancer risk.

Design Nationwide, population based case-control study for men diagnosed with prostate cancer in 2007-09 within the Prostate Cancer data Base Sweden 2.0.

Setting The National Prostate Cancer Register, National Patient Register, census, and Prescribed Drug Register in Sweden, from which we obtained data on 5-ARI use before date of prostate cancer diagnosis.

Participants 26 735 cases and 133 671 matched controls; five controls per case were randomly selected from matched men in the background population. 7815 men (1499 cases and 6316 controls) had been exposed to 5-ARI. 412 men had been exposed to 5-ARI before the diagnosis of a cancer with Gleason score 8-10.

Main outcome measures Risk of prostate cancer calculated as odds ratios and 95% confidence intervals by conditional logistic regression analyses.

Results Risk of prostate cancer overall decreased with an increasing duration of exposure; men on 5-ARI treatment for more than three years had an odds ratio of 0.72 (95% confidence interval 0.59 to 0.89; P<0.001 for trend). The same pattern was seen for cancers with Gleason scores 2-6 and score 7 (both P<0.001 for trend). By contrast, the risk of tumours with Gleason scores 8-10 did not decrease with increasing exposure time to 5-ARI (for 0-1 year of exposure, odds ratio 0.96 (95% confidence interval 0.83 to 1.11); for 1-2 years, 1.07 (0.88 to 1.31); for 2-3 years, 0.96 (0.72 to 1.27); for >3 years, 1.23 (0.90 to 1.68); P=0.46 for trend).

Conclusions Men treated with 5-ARI for lower urinary tract symptoms had a decreased risk of cancer with Gleason scores 2-7, and showed no evidence of an increased risk of cancer with Gleason scores 8-10 after up to four years’ treatment.


In this nationwide, population based, case-control study, increasing duration of exposure to 5-ARI was associated with a decreased risk of prostate cancer overall, and this decrease was restricted to cancers with Gleason scores 2-6 and 7. There was no significant association in risk of cancers with Gleason scores 8-10. Our data, together with previous studies, suggest that the net balance between benefit and harm for 5-ARI use is favourable in men with lower urinary tract symptoms based on prostatic enlargement.

What is known on this topic

  • Several studies have shown that 5α-reductase inhibitors decrease the risk of prostate cancer with Gleason scores 2-7
  • However, the effect of 5α-reductase inhibitors on the risk of cancers with Gleason scores 8-10 is uncertain
  • Men receiving up to four years’ treatment of 5α-reductase inhibitors for lower urinary tract symptoms showed no evidence of an increased risk of prostate cancer with Gleason scores 8-10

What this study adds

Source: BMJ

Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis.


Objectives To summarise evidence on the associations of maternal anaemia and prenatal iron use with maternal haematological and adverse pregnancy outcomes; and to evaluate potential exposure-response relations of dose of iron, duration of use, and haemoglobin concentration in prenatal period with pregnancy outcomes.

Design Systematic review and meta-analysis

Data sources Searches of PubMed and Embase for studies published up to May 2012 and references of review articles.

Study selection criteria Randomised trials of prenatal iron use and prospective cohort studies of prenatal anaemia; cross sectional and case-control studies were excluded.

Results 48 randomised trials (17 793 women) and 44 cohort studies (1 851 682 women) were included. Iron use increased maternal mean haemoglobin concentration by 4.59 (95% confidence interval 3.72 to 5.46) g/L compared with controls and significantly reduced the risk of anaemia (relative risk 0.50, 0.42 to 0.59), iron deficiency (0.59, 0.46 to 0.79), iron deficiency anaemia (0.40, 0.26 to 0.60), and low birth weight (0.81, 0.71 to 0.93). The effect of iron on preterm birth was not significant (relative risk 0.84, 0.68 to 1.03). Analysis of cohort studies showed a significantly higher risk of low birth weight (adjusted odds ratio 1.29, 1.09 to 1.53) and preterm birth (1.21, 1.13 to 1.30) with anaemia in the first or second trimester. Exposure-response analysis indicated that for every 10 mg increase in iron dose/day, up to 66 mg/day, the relative risk of maternal anaemia was 0.88 (0.84 to 0.92) (P for linear trend<0.001). Birth weight increased by 15.1 (6.0 to 24.2) g (P for linear trend=0.005) and risk of low birth weight decreased by 3% (relative risk 0.97, 0.95 to 0.98) for every 10 mg increase in dose/day (P for linear trend<0.001). Duration of use was not significantly associated with the outcomes after adjustment for dose. Furthermore, for each 1 g/L increase in mean haemoglobin, birth weight increased by 14.0 (6.8 to 21.8) g (P for linear trend=0.002); however, mean haemoglobin was not associated with the risk of low birth weight and preterm birth. No evidence of a significant effect on duration of gestation, small for gestational age births, and birth length was noted.

Conclusions Daily prenatal use of iron substantially improved birth weight in a linear dose-response fashion, probably leading to a reduction in risk of low birth weight. An improvement in prenatal mean haemoglobin concentration linearly increased birth weight.


In meta-analyses of randomised trials of prenatal iron use, we found evidence of significant reductions in maternal anaemia, iron deficiency, iron deficiency anaemia, and risk of low birth weight. Dose-response analysis showed a linear decrease in maternal anaemia with higher doses of iron, up to 66 mg/day. Higher doses of iron were associated with a linear increase in birth weight and decrease in risk of low birth weight. With iron up to 66 mg/day, we found a non-linear association with birth weight but a linear reduction in risk of low birth weight. Furthermore, higher mean haemoglobin concentration in the prenatal period linearly increased birth weight with a dose-response relation. We did not find any evidence of reduction in risk of preterm birth as a result of iron use; however, meta-analysis of cohort studies indicated a higher risk of preterm birth with first or second trimester anaemia and with lower mean haemoglobin concentration.

What is already known on this topic

  • Synthesis of evidence from observational studies indicates an association between prenatal anaemia and risk of preterm birth, but evidence on other birth outcomes is inconsistent
  • Evidence from randomised trials on the effect of prenatal iron use on adverse birth outcomes is also inconclusive
  • This comprehensive meta-analysis of randomised trials suggests that prenatal iron use is associated with a significant increase in birth weight and reduction in risk of low birth weight
  • A dose-response relation of higher iron dose with increasing birth weight and decreasing risk of low birth weight exists
  • An exposure-response relation also exists between increasing mean haemoglobin concentration in the prenatal period and higher birth weight


Source: BMJ


Detection of mild to moderate influenza A/H7N9 infection by China’s national sentinel surveillance system for influenza-like illness: case series.



Objective To characterise the complete case series of influenza A/H7N9 infections as of 27 May 2013, detected by China’s national sentinel surveillance system for influenza-like illness.

Design Case series.

Setting Outpatient clinics and emergency departments of 554 sentinel hospitals across 31 provinces in mainland China.

Cases Infected individuals were identified through cross-referencing people who had laboratory confirmed A/H7N9 infection with people detected by the sentinel surveillance system for influenza-like illness, where patients meeting the World Health Organization’s definition of influenza-like illness undergo weekly surveillance, and 10-15 nasopharyngeal swabs are collected each week from a subset of patients with influenza-like illness in each hospital for virological testing. We extracted relevant epidemiological data from public health investigations by the Centers for Disease Control and Prevention at the local, provincial, and national level; and clinical and laboratory data from chart review.

Main outcome measure Epidemiological, clinical, and laboratory profiles of the case series.

Results Of 130 people with laboratory confirmed A/H7N9 infection as of 27 May 2013, five (4%) were detected through the sentinel surveillance system for influenza-like illness. Mean age was 13 years (range 2-26), and none had any underlying medical conditions. Exposure history, geographical location, and timing of symptom onset of these five patients were otherwise similar to the general cohort of laboratory confirmed cases so far. Only two of the five patients needed hospitalisation, and all five had mild or moderate disease with an uneventful course of recovery.

Conclusion Our findings support the existence of a “clinical iceberg” phenomenon in influenza A/H7N9 infections, and reinforce the need for vigilance to the diverse presentation that can be associated with A/H7N9 infection. At the public health level, indirect evidence suggests a substantial proportion of mild disease in A/H7N9 infections.


Summary and clinical implications of results

The complete case series of A/H7N9 infections detected to date through China’s national sentinel surveillance system for influenza-like illness has provided contrasting clinical presentations to the generally more severe presentations of A/H7N9 cases reported so far.7 9 The five patients detected by the surveillance system were much younger, on average, than the cohort of people with laboratory confirmed infections (13 years v about 60 years). But both groups otherwise shared similar epidemiological characteristics—including exposure history, geographical location, and calendar time of disease onset. However, none of the five patients had any chronic underlying medical conditions, unlike many in the general cohort of confirmed cases.7 9 16 Our report expands on a preliminary assessment of six people with A/H7N9 infections who were identified either through the routine sentinel surveillance system for influenza-like illness or through enhanced surveillance among inpatients with atypical pneumonia, established as part of the response to A/H7N9.14 17

Our findings reinforce the need for vigilance to the diverse presentation that can be associated with A/H7N9 infection. This vigilance is important not only in the interest of direct patient care, but also in terms of public health, because a large proportion of unidentified cases with mild infection in the community may be a source of infection to other susceptible people if A/H7N9 develops the capacity for human to human transmission, thus making an epidemic potentially much more difficult to control.

What is already known on this topic

  • The “clinical iceberg” phenomenon of milder cases that escape detection is a common feature of influenza
  • Most reports of infection from the novel influenza A/H7N9 virus have so far presented a severe clinical picture
  • It remains unknown whether the clinical iceberg phenomenon applies to A/H7N9
  • Evidence suggests that there is an important proportion of mild disease, and supports the existence of a clinical iceberg phenomenon in influenza A/H7N9 infections
  • Our findings reinforce the need for vigilance to the diverse presentation that can be associated with influenza A/H7N9 infections


Source: BMJ

Do we need tougher drug patent laws?

History has witnessed numerous drug patent wars, but in April 2013, the Indian Supreme Court did something which captured the attention of the international media. It denied a patent to the beta crystalline form of Imatinib mesylate, a life saving anticancer drug, to the Swiss pharmaceutical company Novartis. The verdict was noteworthy because this drug is patented in more than 38 countries including the US, Russia, and China. Today this drug is being manufactured by generic drug companies in India. Is this a victory against the monopoly of pharmaceutical giants, or has India set a dangerous precedent which will discourage the innovation of future drugs?

As a researcher myself, I understand the importance of patent protection for any intellectual property. Patents give exclusive rights to the innovators for a limited period of time which acts as an incentive for future research and development (R&D). According to estimates, a company spends between US$ 500 million to US$ 2 billion for the discovery, research, testing, and marketing of a new drug. [1] In addition, patents encourage innovators to make their discoveries available for public use.

So why did the court rule against these relevant arguments?

Patentability of a product relies heavily on its novelty. The court argued that the product was not unique, but merely a tweaked version of an already known compound, noting that Imatinib was patented in many countries in 1996. Many researchers are making similar observations about other pharmacological agents and accusing the companies of “evergreening,” a practice which enables them to claim a new patent by slightly modifying the chemical composition of a known drug. Recently an article in the BMJ pointed out that about 85-90% of all new drugs since the mid 90s provide few or no clinical advantages for patients. [2] Even Brian Druker, who developed the beta version of Imatinib, believes in the need for novel, and not just modified drugs.

After the court’s decision, Novartis said it would pull out all R&D investments from India. It should be noted that India has never been a home to new drug discoveries as its priority is to provide cheap medicines to as many people possible. In other words, India has a different role to play in the pharmaceutical industry. India is a major market for manufacturing drugs in their generic form and providing them cheaply to patients in India as well as in other developing and poor countries. For instance, a 400mg pill of the drug in question is being manufactured by Novartis at US$99 each and the same by a generic drug manufacturer at a cost of around US$9. [3] No wonder Médecins Sans Frontières and other charitable health organisations hailed the court’s decision. This brings us to the question of affordability. 81% of the Indians live on less than US$2.5 a day. Predatory pricing and a market monopoly will make healthcare costlier for those living in the developing world as well as for those struggling in the developed. We do not want life saving drugs to be luxury goods.

It has been argued that stricter patent laws will encourage innovation. This is true to some extent as innovators will then be forced to push their limits to develop novel and better products. But we cannot afford to overstretch the strings. If the innovators are denied of their deserved rights and royalties, the intent to discover and invent will die. Some suggested that pharmaceutical companies should act morally and take into account the economic condition of the country they are selling in before pricing their products.

Coming back to our initial question: do we need tougher drug patent laws? There is no simple answer to this. Patients’ interests come first and they must be provided with the best medicines at an affordable price but we also need to incentivise the innovative thinking. A consensus on this patent vs patient issue can only be achieved by debate and discussion.

Source: BMJ

What does Tamiflu do, and how will we know?

Jonathan Nguyen-Van-Tam, virologist and researcher from the University of Nottingham, told a group of triallists and virologists last week “we must remember why we’re here—because of the controversies. The clinical world doesn’t believe that Tamiflu works. We should assess whether the regulatory approval/product insert for Tamiflu is valid.”

That group, the MUltiparty Group for Advice on Science (MUGAS) was at a workshop in Brussels on 18 June organised by the European Scientific Working group on Influenza (ESWI) and supported by an unrestricted grant from Roche. Led by several of the original Tamiflu regulatory triallists, the workshop heard plenty of evidence to challenge current claims about Tamiflu’s effects. MUGAS decided to plan and conduct individual participant data (IPD) meta-analyses of the randomised trial data—and observational data. That’s quite a remarkable turnaround, given the strength of claims made by some of the same people over the past decade.

BMJ readers will already be very familiar with growing concerns about oseltamivir’s effectiveness. Earlier this year Professor Harlan Krumholz and co-authors concluded in an editorial in the BMJ that “Despite government claims, we should acknowledge the uncertainty surrounding oseltamivir’s effectiveness and the gaps in publicly available evidence. On the basis of the available data, at best the drug shortens symptoms by about a day when used within the first two days of symptoms, but it has no effect on hospital admissions. In addition, trial data from which to draw conclusions about complications and transmission of flu are lacking.”

WHO made particularly firm claims about oseltamivir in August 2009 during the swine flu (H1N1) pandemic. WHO then stated that, “The guidelines represent the consensus reached by an international panel of experts who reviewed all available studies on the safety and effectiveness of these drugs…Evidence reviewed by the panel indicates that oseltamivir, when properly prescribed, can significantly reduce the risk of pneumonia (a leading cause of death for both pandemic and seasonal influenza) and the need for hospitalization.”

That expert panel advising WHO was anonymous: all its members had signed a confidentiality agreement. But at least one member was identified later as Professor Arnold Monto of the University of Michigan, who coauthored several trials of neuraminidase inhibitors back in the 1990s. The same Professor Monto is one of the four convenors of MUGAS, along with Professor Ab Osterhaus (of Erasmus MC University in Rotterdam, a scientific advisor to Roche, another oseltamivir triallist), Professor Menno de Jong (of Academic Medical Center Amsterdam, virologist and researcher) and Professor Rich Whitley (of University of Alabama at Birmingham, professor of pediatric infectious diseases and an adviser on flu to the Obama administration).

Barry Clinch, Principal Clinical Scientist at F. Hoffmann-La Roche, presented at the MUGAS workshop an overview of all studies in the company’s oseltamivir research programme. His slides showed that in all, 18,928 patients had taken part in trials, observational studies of treatment, and studies of prophylaxis; around 11,500 of them treated with oral oseltamivir. Randomised controlled trials (RCTs) had included 4799 adults and 1368 children and, along with some open label studies, a total of 8078 patients had taken part. All but one of the 12 RCTs took place in the late 1990s. Roche’s lab researchers had also done experimental flu studies and clinical pharmacology studies.

Clinch confirmed that investigators were told to always report admissions to hospital during the Roche trials, but warned that “caution should be exercised in interpreting results on hospitalisation.” This is because there were such low event rates: for example in trial WV15671 just 1 of 201 participants was hospitalised. The main intention to treat analyses in the 12 Roche RCTs (for all patients enrolled with flu-like illness and who had at least 1 dose of trial medication) failed to find statistically significant evidence that hospitalisation rates were reduced by oseltamivir when compared against placebo. For the ITTI population (the subset with flu confirmed by culture or >4 fold rise in antibody titre) the overall P value was 0.06 but this was grossly underpowered.

Presenting the key oseltamivir trials that yielded data on flu complications, Clinch explained that a standard case report form was used to collected data on “Secondary illness.” “We didn’t ask physicians to actively look for complications,” he said. “They simply reported them if they thought patients had, for example, sinusitis, otitis media, bronchitis, pneumonia or other chest infections.” Clinicians could also say if patients needed antibiotics or X rays—thereby implying that there might be some secondary illness—but there was no requirement to confirm diagnoses without anything more than a clinical diagnosis. “To be honest, we weren’t that stringent at the time,” acknowledged Clinch. (And, of course, at that time Roche was testing oseltamivir primarily as another antiviral for seasonal flu, not as a lifesaver in a pandemic.) Only two trial protocols required reporting of clinically diagnosed complications (coded as bronchitis, pneumonia, lower respiratory tract complication, or antibiotic prescription occurring >48h after start of treatment with oseltamivir) as a formal secondary endpoint: those among older and at risk participants. Statistical analyses of these outcomes were exploratory, said Clinch.

The ensuing questions and discussion among the MUGAS review board members (some of whom co-authored some of the trials in question) confirmed that “secondary illness” was indeed only a clinical diagnosis, that in most of the trials its reporting was ad hoc, and that Roche does not know the extent of any missing data. Decisions to give antibiotics were made for nonspecified clinical reasons, and, as someone pointed out, antibiotic usage rates will have varied a lot from site to site because of geographical variations in prescribing behaviour.

However, some of the MUGAS virologists said we know from Roche’s original observational studies and from subsequent case series from the H1N1 pandemic that oseltamivir does reduce complications. Do we? Not yet, although Professor Van Tam’s group has conducted a systematic review and IPD meta-analysis of published andunpublished observational study data during the H1N1 pandemic that will be submitted soon for publication. This study was sponsored by Roche but Professor Van Tam said the data agreement gives Roche no access to the data. The authors plan, however, to share the data with other investigators on request.

When asked what proportion of the original Roche oseltamivir research programme had results in the public domain, Clinch said “about 90% in one form or another.” Virologist Fred Hayden, co-author of several Roche trials, asked: “the contentious area is the 8-10 unpublished trials done some time ago. Are there any plans to publish those?” Clinch replied “it’s a good question…we’d like MUGAS to discuss that. Roche has no objection to that.” Professor Osterhaus said that MUGAS wants to analyse the IPD from those trials and to publish the resulting papers in peer reviewed journals.

So, of course, does the Cochrane Acute Respiratory Infections Group, which has been struggling for years to get the unpublished trial data from Roche. That data release has now begun, and the Cochrane group is poring over the partly redacted Clinical Study Reports right now.

So it’s from famine to feast, with two different groups working towards meta-analyses of the unpublished patient-level data on the effects of oseltamivir in flu. Will they come to the same conclusions?

Source: BMJ

Reporting of industry funded study outcome data: comparison of confidential and published data on the safety and effectiveness of rhBMP-2 for spinal fusion.


Objective To investigate whether published results of industry funded trials of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion match underlying trial data by comparing three different data sources: individual participant data, internal industry reports, and publicly available journal publications and conference abstracts.

Data collection and synthesis The manufacturer of rhBMP-2 products (Medtronic; Minneapolis, MN) provided complete individual participant data and internal reports for all its studies of rhMBP-2 in spinal fusion. We identified publications and conference abstracts through comprehensive literature searches. We compared outcomes provided in the individual participant data against outcomes reported in publications. For effectiveness outcomes, we compared meta-analyses of randomised controlled trials based on each of the three data sources. For adverse events, meta-analysis of the published aggregate data was not possible and we compared the number and type of adverse events reported between data sources.

Results 32 publications reported outcomes from 11 of the 17 existing manufacturer sponsored studies. For individual randomised controlled trials, 56% (9/16) to 88% (15/17) of effectiveness outcomes known to have been collected were reported in the published literature. Meta-analyses of effectiveness data were almost identical for pain outcomes and similar for fusion across the three data sources. A minority of adverse event data known to have been collected were reported in the published literature. Several journal articles reported only “serious,” “related,” or “unanticipated” adverse events, without defining these terms. Others reported a small proportion of the collected adverse event categories. Around 23% (533/2302) of the total adverse events collected in published randomised controlled trials have been reported in the literature, with randomised controlled trials evaluating the licensed preparation (Infuse) reporting around 11% (122/1108) of collected adverse events.

Conclusions The published literature only partially represents the total data known to have been collected on the effects of rhBMP-2. This did not lead to substantially different results for meta-analysis of effectiveness outcomes. In contrast, reporting of adverse event data in trial publications was inadequate and inconsistent to the extent that any systematic review based solely on the publicly available data would not be able to properly evaluate the safety of rhBMP-2. Analysis of individual participant data enabled the most complete, detailed, and in-depth analysis and was not more resource intensive than extracting, collating, and analysing aggregate data from multiple trial publications and conference abstracts. Confidential internal reports presented considerably more adverse event data than publications, and in the absence of individual participant data access to these reports would support more accurate and reliable investigation, with less time and effort than relying on incomplete published data.


Controversy around use of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion began with suggestions that inadequate peer review and editorial oversight were responsible for an apparent absence of adverse events from early peer reviewed publications of industry sponsored studies. A subsequent investigation led by the editor in chief of The Spine Journal14 found fewer reported adverse events in academic publications of industry sponsored studies than in related study data available in FDA summaries and public meeting documents. The FDA materials available for that investigation appear to be partial outcome data from a subset of industry funded studies evaluating Infuse/LT-CAGE, Infuse/MASTERGRAFT, and AMPLIFY rhBMP-2 matrix preparations. Our investigation was able to explore this issue in greater depth having individual participant data on all recorded effectiveness and safety outcomes as well as internal reports provided for all Medtronic funded studies of rhBMP-2 for spinal fusion. Given their previous confidentiality, high degree of detail, and availability for all known studies, we consider the combination of individual participant data and internal reports to be the most comprehensive and trustworthy source of Medtronic trial evidence available to date.

Source: BMJ