Capacity 1 trial results

The phase 2 and phase 3 Japanese trials of pirfenidone were not included in this analysis because they differed from the three multinational trials in study design and end-point selection.

In addition, the Japanese trials had higher patient drop-out rates and more missing data than the multinational trials. Finally, certain outcome measures in the multinational trials were assessed differently compared with the Japanese trials, including FVC and progression-free survival [ 3 , 4 ]. The primary objectives of the analysis were to obtain the most precise estimates of the magnitude of the pirfenidone treatment effect in patients with IPF, and to further interrogate the effect of pirfenidone in subpopulations defined on the basis of demographics and baseline measures of disease status.

In the pooled analysis, clinical efficacy outcomes are reported at 3-month intervals from baseline to month Safety outcomes are based on analysis of data at week 52 in all three studies.

The statistical analysis plan for the pooled analysis was finalised prior to unblinding of results from the ASCEND study. Inferential statistics are reported for the purpose of informing assessments of the variability of the treatment effect. Supportive analyses were also conducted to assess the robustness of the effect of treatment on FVC; these included the mean change from baseline to month 12 in FVC and the cumulative distribution of FVC change from baseline to month For the rank ANCOVA analyses, missing values due to death were assigned the worst ranks based on the time of death from randomisation.

Missing values for reasons other than death were imputed with the average value from three patients with the smallest sum of squared differences at each visit with nonmissing data.

For the analysis of mean change from baseline in FVC, missing values due to death were assigned the worst possible value i. Each interaction was tested individually without correction for multiplicity.

Differences between treatment groups were evaluated using the log-rank test. Adverse events were coded to preferred terms in the Medical Dictionary for Regulatory Activities, version Demographics and baseline characteristics were generally well balanced across studies and treatment groups table 1. A total of Study treatment was discontinued prematurely in 97 Sensitivity analyses using alternative imputation methods for missing data showed that the magnitude of treatment effect on the change in FVC at month 12 was highly consistent across analyses see online supplementary table S3.

For each point along the cumulative distribution of change from baseline, FVC outcomes favoured pirfenidone over placebo. Consistent with the categorical analysis, the treatment effect emerged by the first FVC assessment at month 3 and persisted throughout the duration of observation. FVC outcomes. Subgroup analysis of FVC outcomes showed a consistent magnitude of treatment effect across all strata for each demographic variable and baseline measure of disease status figure 2.

Secondary outcomes. Figure 4 summarises the overall efficacy results in the pooled population. Additionally, analysis of outcomes by study revealed generally similar treatment effects across all three independent studies, with no statistical evidence of an interaction between treatment and study figure 5.

Consistent with previous studies in patients with IPF, nearly all patients in both treatment groups experienced at least one adverse event during the 1-year observation period More patients in the pirfenidone group compared with placebo experienced an adverse event that led to early discontinuation of treatment 74 The most common adverse events are summarised in table 2.

Gastrointestinal and skin-related adverse events occurred more frequently in the pirfenidone group than the placebo group. Consistent with prior observations, these were generally mild to moderate in severity and infrequently led to premature discontinuation of treatment.

All such elevations were reversible and without clinical sequelae. Safety outcomes according to baseline measures of disease severity are summarised in table 3. In both the pirfenidone and placebo groups, patients with more severe physiologic impairment at baseline had a higher incidence of grade 3 and grade 4 adverse events, serious adverse events, and adverse events leading to treatment discontinuation.

However, there was no evidence of a more pronounced effect of disease severity on the risk of adverse events in the pirfenidone group compared with placebo. IPF is a heterogeneous disease with markedly variable rates of disease progression [ 9 ]. As a result, precise estimation of the magnitude of treatment effect on measures of disease progression is challenging, particularly in individual clinical trials of moderate size.

Analysis of pooled data from multiple clinical trials with similar study designs, patient populations and outcomes allows for more precise estimation of the magnitude of effect associated with a given treatment [ 10 ]. In the present analysis, we used pooled data from three similar phase 3 trials evaluating pirfenidone in patients with IPF to derive the most precise estimates to date of the magnitude of treatment effect on measures of pulmonary function and disease status.

Additionally, Analysis of FVC change in subgroups defined on the basis of demographics and baseline measures of disease status showed that the magnitude of the pirfenidone treatment benefit was also consistent across subpopulations. Collectively, these findings demonstrate that the pirfenidone treatment benefit is observed across the continuum of baseline disease severity and subsequent rates of FVC progression.

Safety outcomes in the pooled population were consistent with the known safety profile of pirfenidone. Gastrointestinal and skin-related events were the most commonly reported adverse events in the pirfenidone group; these were typically mild to moderate in severity and rarely led to treatment discontinuation.

The studies are registered with ClinicalTrials. All patients in both studies were analysed. Interpretation: The data show pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis. Funding: InterMune.

There was substantial variation in capacity to provide critical care among provinces and territories. The median number of mechanical ventilators per province was IQR to Per , population in and , there were 0. ICU beds capable of invasive mechanical ventilation per , Canadian population according to health region. ICUs and ventilation capacity according to population across provinces. There was considerable concentration of ICU resources for mechanical ventilation in teaching hospitals as compared with community hospitals.

Complementary qualitative data acquired in our survey shed important insights into critical care capacity in Canada. Some hospitals with small ICUs that is, fewer than six ICU beds commented that despite their capacity for ongoing ventilation, it was common practice to attempt to transfer patients to larger ICUs after a variable period of time many days to a week. Many hospitals commented that lack of personnel especially nurses prevented the full utilization of ICU beds and ventilator capacity.

We found substantial variation in the numbers of ICU beds, as well as the capacity for mechanical ventilation and specialized support for respiratory failure among ICUs in Canada. These findings were not fully explained by the size of the population. This variation in capacity may result in differential decision-making about who can receive ICU support, and which services can be supported in specific hospitals and regions during times of increased demand [ 3 , 5 ]. Prior work by our group using health administrative data from the Canadian Institute for Health Information estimated that there were ICUs, 3, total adult ICU beds representing 3.

However, these data were based on a more liberal definition of critical care beds, did not include data from Quebec, did not include any interprovincial comparisons, did not estimate the capacity to treat critically ill patients requiring mechanical ventilation, and were generated one decade ago. Our assessment of ICU beds per , population places Canada near the median of high-income and Organization for Economic Co-operation and Development countries, notably above the United Kingdom but well below the United States, Germany, and Belgium [ 8 , 7 , 20 , 21 , 22 ].

Without knowledge of Canadian critical care capacity, and in the absence of provincial, national, or international targets for population-based critical care resources, there has been limited national attention to ensuring optimal distribution among regions.

The results of this survey highlight expected north—south geography-based capacity trends, but also an unanticipated apparent east—west gradient with relative increased capacity among the Atlantic Provinces, in comparison with central and western Canada. Some members of our group have previously reported wide variation in ICU capacity within British Columbia and an inverse relationship between ICU beds, population density, and population growth, highlighting the potential for mismatch in demand and capacity in Canada [ 11 ].

Some variation in distribution of healthcare services is probably a consequence of differential regional models of healthcare delivery. Many systems of intra-provincial regionalization of care that are responsive to population density, geographic barriers, or evolved regional care systems also may lead to differences in the distribution of critical care services.

Moreover, despite provincial administration of most healthcare services, there is also some well-established inter-provincial ICU care, with regionalized trauma services, specialized care delivery for northern territories among bordering provinces, and populations of one province that are closest to a specialized healthcare center in a neighboring province.

This study has important limitations. First, this survey was carried out using existing national and provincial databases of hospitals, and it is possible that some acute care hospitals may have been missed. However, we subsequently employed snowball sampling and web and map searching techniques to identify all hospitals and ICUs in each province, and then sought out a combination of physician, nurse, respiratory therapist, and hospital administrator leaders to derive current ICU beds and ventilator capacity at each hospital.

After compiling local data, each participant and provincial health authority was given the opportunity to critique the aggregate estimates to improve accuracy. Second, population denominator-based comparisons may not be the optimal mechanism for normalization in all regions with varying population density, age demographic differences, geographic barriers, and distinct systems of regionalized care for some tertiary and quaternary services such as trauma and transplantation.

However, our results indicate relatively wide variability in ICU capacity among provinces and therefore may provide helpful inter-provincial comparisons. Third, this study focused on a very narrow spectrum of services needed to provide critical care — ICUs, beds, ventilators, and specialized supports for respiratory failure.

It was beyond the scope of this survey to evaluate personnel dieticians, nurses, pharmacists, physicians, physiotherapists, respiratory therapists, social workers or other resources that are essential to the care of critically ill patients.

Indeed, lack of available critical care clinical staff is among the most common reason for limitations in bed availability [ 25 - 27 ]. Future resource planning must address this key knowledge gap. Fourth, ICU resources are not static, and this survey represents a period prevalence of approximately 3 months at the hospital level and approximately 1 year among all sites, in a period after the H1N1 pandemic where knowledge of ICU capacity may have been greatest.

Our results highlight the need to examine capacity both in relation to local needs and in comparison with other regions. It is important to note that the organization of critical care within Canada has not been static since conducting this survey. Since the severe acute respiratory syndrome experience, the Ministry of Health and Long-term Care in Ontario has maintained a Critical Care Strategy to oversee a similar cataloguing of critical care services including twice-daily clinical updates of every patient in ICUs into a centralized electronic database that facilitates critical care inter-facility transportation services, reporting on quality metrics and decision-making on surge capacity [ 29 ].

British Columbia and Nova Scotia have recently formed Critical Care Working Groups within the Ministry of Health to coordinate data collection and reporting, improvement of care processes, transportation of critically ill patients, and improvement of staffing models in ICUs. One of the lessons learned from the severe acute respiratory syndrome and influenza A H1N1 pandemics is that infectious outbreaks do not respect regional health boundaries [ 30 , 31 ] and that individual regions may be clinically overwhelmed while others are unaffected.

Of relevance to surge planning, we were able to quantify the excess numbers of invasive mechanical ventilators relative to ICU beds, highlighting capacity that may exist beyond existing ICU beds. The ability to provide advanced oxygenation with one of three modes of support was available in a minority of hospitals.

Furthermore, this expertise was unevenly distributed across provinces, and was focused at university-affiliated teaching hospitals. However, we were unable to gauge experience with specialized ventilation alongside capacity.

We did not determine capacity for other techniques such as prone ventilation, which may be less dependent upon specific technology, more dependent upon generation of a local experience base, and have a greater evidence base for efficacy than either early high-frequency ventilation or use of inhaled nitric oxide [ 32 ]. This variable and uneven distribution of expertise observed in this study demands that we evolve a system in which excess capacity in one region may aid another, either through safe transportation of patients or short-term movement of equipment or personnel to existing or temporary facilities [ 33 ].

ICU resources vary widely across Canadian provinces, and during times of increased demand may result in geographic differences in the ability to care for critically ill patients. These results may guide future decision-making, but must also be complemented by estimates of current and future healthcare personnel supply and projections of demand for critical care from an aging population [ 34 ]. Greater ongoing knowledge of regional critical care resources may help us respond to increases in demand from unpredictable events such as infectious outbreaks or regional medical emergencies.

While some regional imbalances may persist, there should be deliberate planning for mechanisms to deal with both unexpected and day-to-day surge in demand. Mechanisms are needed to rapidly share and deploy resources — both equipment and personnel — across provincial boundaries to deliver a more equitable, coordinated, and responsive system of healthcare for critically ill Canadians. We identified all ICU beds and mechanical ventilators for critically ill patients in Canada.

During times of increased demand, variability in ICU resources may result in geographic differences in the ability to care for critically ill patients. These results highlight the need to evolve inter-jurisdictional resource, and provide background data for the development of appropriate critical care capacity benchmarks. Ahern, Dr. The Public Health Agency of Canada assisted in collection and analysis of the data. The funders had no role in the interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication.

Additional file 1: 3. Competing interests. RF and PJ participated in the design of the study. RAF and PA performed the statistical analysis. All authors read and approved the final manuscript.

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