Objective To investigate whether an intervention to improve treatment of depression in older adults in primary care modified the increased risk of death associated with depression.
Design Long term follow-up of multi-site practice randomized controlled trial (PROSPECT—Prevention of Suicide in Primary Care Elderly: Collaborative Trial).
Setting 20 primary care practices in New York City, Philadelphia, and Pittsburgh, USA, randomized to intervention or usual care.
Participants 1226 participants identified between May 1999 and August 2001 through a two stage, age stratified (60-74; ≥75 years) depression screening of randomly sampled patients; enrollment included patients who screened positive and a random sample of patients who screened negative.
Intervention For two years, a depression care manager worked with primary care physicians in intervention practices to provide algorithm based care for depression, offering psychotherapy, increasing antidepressant dose if indicated, and monitoring symptoms, adverse effects of drugs, and adherence to treatment. This paper reports the long term follow-up.
Main outcome measure Mortality risk based on a median follow-up of 98 (range 0.8-116.4) months through 2008.
Results In baseline clinical interviews, 396 people were classified as having major depression, 203 had clinically significant minor depression, and 627 did not meet criteria for depression. At follow-up, 405 patients had died. Patients with major depression in usual care were more likely to die than were those without depression (hazard ratio 1.90, 95% confidence interval 1.57 to 2.31). In contrast, patients with major depression in intervention practices were at no greater risk than were people without depression (hazard ratio 1.09, 0.83 to 1.44). Patients with major depression in intervention practices, relative to usual care, were 24% less likely to have died (hazard ratio 0.76, 0.57 to 1.00; P=0.05). Preliminary data on cause of death are provided. No significant effect on mortality was found for minor depression.
Conclusions Older adults with major depression in practices provided with additional resources to intensively manage depression had a mortality risk lower than that observed in usual care and similar to older adults without depression.
What is already known on this topic
- Prospective studies have consistently shown a relation between depression and increased mortality in older adults
- No randomized trials have reported that a depression management program can decrease risk
- A 24% lower mortality risk was seen after a median of 98 months among patients with major depression in practices provided with resources for depression care management compared with usual care
- The decline in mortality was across all causes of death, but with fewer deaths from cancer among people with major depression in intervention practices
- A depression care manager working with primary care physicians to provide algorithm based care for depression can mitigate the detrimental effects of depression on mortality
What this study adds
nitial9 �ta�spacing:0px’ id=p-70>Our patients presented relatively late after the onset of illness, a median of five days overall (seven days for H5N1). Despite administration of oseltamivir, about 30% of those enrolled remained positive for viral RNA (the primary endpoint) after five days of treatment. Timing of oseltamivir treatment is important as several studies have shown that early treatment confers greater virological and clinical benefits.4 5 6 32 33 34 In particular, later viral clearance has been noted with delayed treatment with oseltamivir compared with treatment within two to three days after onset of symptoms in observational reports from patients with H1N1-pdm09, especially those with severe illness.35 36 37 38 39 40 In the current trial, 73 (22.4%) patients presented within three days of illness, but even in this subpopulation, double dose oseltamivir was not associated with more rapid viral RNA clearance. Over a quarter of patients received neuraminidase inhibitors before enrolment, which could have influenced the effect size and contributed to the low proportion of patients shedding virus at day five in both treatment groups.
Although viral RNA detection in samples from the upper respiratory tract might not accurately reflect viral replication in the lower respiratory tract, especially in those with severe illness,39 prolonged viral RNA detection in upper respiratory tract samples has been shown to correlate with inpatient morbidity and prolonged hospital stay. In our study viral detection on day five was observed at about twofold the frequency in those meeting the criteria for clinical failure, although lack of clinical failure was not a surrogate for cessation of viral detection. Thus in our study the delays in starting treatment with oseltamivir also probably contributed to the substantial rates of admission to intensive care (18%), use of supplemental oxygen (30%), mechanical ventilation (12%), and mortality in hospital of 6.4%. Although our study was not placebo controlled for ethical reasons, other studies indicate that early oseltamivir treatment in people with severe influenza is associated with both clinical benefits and more rapid viral clearance from upper respiratory tract samples.
Possible reasons for findings
It is unclear why double dose oseltamivir does not seem to offer benefit over standard dose in patients with severe influenza. Blood trough concentrations of oseltamivir carboxylate from 75 mg or 150 mg twice daily in influenza exceed the IC50 (inhibitory concentration) of influenza viruses.42 43 Inhibition of viral neuraminidase by oseltamivir might be a saturable process, and maximal inhibition might be achieved with a standard dose; exceeding these concentrations might not produce an additional clinical or virological effect. In this regard, a randomised oseltamivir controlled study of intravenous peramivir (BioCryst Pharmaceuticals, Durham, NC), which reaches over 20-fold higher peak blood concentrations of active metabolite than oseltamivir carboxylate, found similar viral reductions in patients with influenza A virus admitted to hospital.44 Further studies of peramivir and other intravenous neuraminidase inhibitors currently in progress should provide additional evidence regarding this hypothesis.
Infection with avian H5N1 virus, higher baseline viral load, and severity of disease were independently associated with longer viral RNA detection. The association between avian H5N1, severe illness, and prolonged shedding has been well described.14 The clearance kinetics of influenza viruses, both without antiviral treatment and with oseltamivir treatment,32 41 could explain longer viral RNA detection with higher baseline viral loads. It is unclear whether the independent association with disease severity might be related to impaired mechanisms of viral clearance or higher intrinsic rates of viral replication or both in these patients. Severe chronic comorbidities are seen commonly in industrialised countries and are related to prolonged viral shedding but most of our patients lacked these comorbidities.40 41
The heterogeneous population characteristics, geographical differences in recruitment (most patients were from Vietnam but there were no significant differences between Vietnam and other sites), and the variety of infecting viruses in our trial reflect the clinical circumstances in South East Asia during our study but might be viewed as a limitation. Most of these patients were children and had low or normal BMI, and for all patients only about a fifth reported a chronic underlying medical condition. Thus, our findings are applicable primarily to the region where the study was conducted and other settings with similar characteristics of influenza epidemiology. We did not have many adults in our study and results were inconclusive but indicate no difference in efficacy between the two oseltamivir regimens. We would caution the extension of our results to, for example, morbidly obese adults with severe influenza and those who could have underlying chronic illnesses. We conducted several statistical comparisons and inevitably subgroup analyses involved small numbers; thus power was limited and some significant results could have resulted by chance. Additionally, as all patients were randomised to an active treatment, our study was not designed to evaluate the efficacy of oseltamivir in severe influenza nor in H5N1 infections. This large randomised trial did, however, examine an important clinical and public health question and showed a lack of a clinical or virological benefit of double dose compared with standard dose oseltamivir in patients admitted to hospital with severe influenza. Our results and other observational reports from avian H5N110 and H1N1-pdm0911 36 infections do not support routine use of double dose oseltamivir to treat severe influenza. These findings have implications for both clinical management and pandemic preparedness including during the current H7N9 epidemic.16 17 18
What is already known on this topic
- Clinical trials in patients with uncomplicated influenza have shown that treatment with oseltamivir has clinical and virological benefit when administered within 48 hours of onset of symptoms
- Observational studies in severe influenza have shown that oseltamivir treatment, if given early, is associated with reduced mortality and shorter length of hospital stay. Reduced mortality has also been reported for patients with H5N1 influenza treated with oseltamivir
- Several authorities have suggested the use of double dose oseltamivir for severe influenza, although there is no clinical evidence to support this
- In the largest randomised trial on the treatment of severe influenza, no clinical or virological benefit of double dose oseltamivir over standard dose was found
- These findings have implications for both clinical management of severe influenza and for pandemic preparedness of emerging influenza viruses including the current H7N9 epidemic
What this study adds