Download national prospective study

Safety of BDZes and opioids
in very severe
respiratory disease
: national prospective study
Magnus P Ekström medical doctor, research fellow1 2, Anna BornefalkHermansson biostatistician3,
Amy P Abernethy associate professor 4 5, David C Currow professor 5
1Department of Clinical Sciences, Division of Respiratory Medicine and
Allergology, Lund University, SE-221 00 Lund, Sweden; 2Department of
Medicine, Blekinge Hospital, SE-37185 Karlskrona, Sweden; 3Uppsala
Clinical Research Center, Uppsala University Hospital, SE-752 37 Uppsala,
Sweden; 4Division of Medical Oncology, Department of Medicine, Duke
University Medical Center, Durham, USA; 5Discipline, Palliative and
Supportive
Services, Flinders University, SA-5041 Adelaide, Australia
R1. 이성곤
Abstract(1)
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Objective: To evaluate the safety of BDZes & opioids in pts c very severe COPD
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Design: Population based longitudinal consecutive cohort study.
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Setting: Centres prescribing long term O2 therapy in Sweden.
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Patients: 2249 pts starting long term O2 therapy for COPD in Sweden btw 2005 & 2009
in the national Swedevox Register.
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Main outcome measures: Effects of BDZes & opioids (rates of admission to hospital & mortality,
adjusted for age, sex, arterial blood gases, BMI, performance status,
previous admissions, comorbidities, & concurrent drugs.)
Abstract(2)
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Results: admitted to hospital :1681 (76%)
/ 1129 (50%) died under observation. (No pt. lost to f/u).
① BDZes & opioids: not a/w admission↑: hazard ratio(HR) 0.98
② BDZes: a/w increased mortality (1.21, 1.05 to 1.39)
c a dose response trend.
③ Opioids: also had a dose response relation with mortality:
1) Lower dose opioids (≤30 mg po morphine/day)
- not a/w increased mortality
2) Higher dose opioids (HR 1.21, 1.02 to 1.44).
④ BDZes + opioids:
*lower doses  not a/w increased admissions or mortality
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Conclusions : “Lower dose opioids”
 not a/w increased Adm. or deaths & might be safe for Sx.↓
Introduction
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Breathlessness: major cause of impaired activity & QOL,
(as many as a 5th > 65aged.)
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COPD: m/c cause of breathlessness, morbidity, and mortality. [300million]
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Randomised trials: Morphine(opioid) → relieve chronic refractory
breathlessness.
cf) BDZes → Breathlessness↓? Safety?
:used to treat anxiety & opioids to treat pain ← severe COPD.
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BDZes & opioids alone or in combination S/E:
①Respiratory depression ②Confusion ③Falls ④Premature death
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No serious adverse events or Adm. to hospital a/w Tx.
c low doses of opioid.
 Safety? BDZes & opioids are limited:
∵ [178 pts pool] or [small short term]
Methods
1) Nationwide prospective consecutive cohort study c longitudinal f/u of pts
starting long term O2 therapy for COPD
[200508’~20090630, national Swedevox Register.(NPR)]
2) To increase the specificity of the Dx.: included only pts aged ≥45
3) The exclusion criterion was a Dx. of lung cancer at the start of O2
therapy(baseline).
4) For 4 years before baseline from the NPR for OPD, IPD
(Comorbidity & hospital Adm.)
: ≥ 99% of all Adms in the study period
& about 80% of all hospital based OPD care 2001~ in Sweden.
5) All dispensed prescriptions(2005.7~) the Swedish Prescribed Drug Register.
** Categorization: Anatomical Therapeutic Chemical Classification System (ATC codes)
20 as antidepressants (N06A), benzodiazepines (N05BA), weakopioids (N02AA59, N02AX02),
Strong opioids (N02A except weak), & sleeping pills (N05C),
& as previously described.
** V/S: Obtained from the Swedish Causes of Death Register.
Statistical analysis(1)
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Drug exposure: at least 1 dispensed prescription ~ 91 days before baseline.
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Exposure to BDZes & opioids : coded dichotomously (treated v non-treated),
*Baseline dose: WHO defined daily doses/~91 day period before baseline.
*Same cut off value for BDZes: Corresponded to the median dose among the exposed.
I. Benzodiazepines (1625 dispensed prescriptions)
: ①oxazepam (74%) ②diazepam (17%) ③alprazolam (8%).
II. Sleeping pills
: ① zopiclone (46%) ② propiomazine(22%) ③zolpidem (18%) ④flunitrazepam (7%).
III. Opioids (1417 prescriptions) - 45 (2%) used both
1) weak opioids [275 (12%)] : ① tramadol (31% of all opioids) ② codeine (19%),
③dextropropoxyphene (15%)
2) strong opioids [189 (8%)] ① oxycodone (15%) ② morphine (11%) ③fentanyl (5%).
(no recorded prescriptions of nebulised opioids.)
Statistical analysis(2)
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Potential confounders evaluated in the analyses at baseline
: age, sex, PaO2 & PaCO2 in pts breathing air, FEV1, smoking status,
BMI, WHO performance status(=ECOG), Charlson comorbidity index, anxiety/depression,
DM, number of cardiovascular Dx. (CVA, HF, HTN, IHD, pph. a. dz, pul. embolism, etc)
osteoporosis, renal failure, number of previous adm. to hospital, Tx with antidepressants,
sleeping pills, whether long term O2 therapy was started in hospital,
and the number of adm. within 4 years before baseline.
 Drug effects on the rates of adm. to hospital : HR & estimated by using Fine-Gray regression,
(which accounts for the competing risk of death.)
* Final adm. model: adjusted for WHO performance status, number of previous adm.,
number of cardiovascular Dx., DM, osteoporosis, & Tx. with oral glucocorticoids.
a/w mortality were expressed as HR & estimated with Cox regression.
* Mortality(observation time: date of start long term oxygen~ death)
: [Censoring - withdrawal of long term oxygen therapy or 20091231.]
Adjusted: age, sex, PaO2 air, PaCO2 air, WHO performance status, BMI, anaemia, number of
cardiovascular Dx., renal failure, and oral glucocorticoids.
Statistical analysis(3)
• Sleeping pills did not predict adm. to hospital or mortality or affect
the estimates for BDZes & opioids.
** Evaluated interactions
1) [btw. the effect of BDZes, opioids & concurrent Tx.]
2) [btw. drugs and comorbid]
 presence of hypercapnia (PaCO2 air >6.5 kPa), being naive to
these drugs (no exposure during the year before baseline), having
comorbid anxiety/depression
(ICD-9 (international classifications of diseases, ninth revision) codes:
296, 298, 300, 311; ICD-10 (10th revision): F30, F48), and comorbid
injury (mainly fractures) (ICD-9: 800,829,830, 999; ICD-10: M84,
S02, S12, S22, S32, S42, S52, S62, S72, S82, S92, T02, T10,
T12)..
- Statistical analyses were performed with Stata version
(StataCorp LP; College Station, TX, USA).
Results
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2249 patients (1410, 59% women).
1) BDZes: 535 (24%) pts
2) Opioids: 509 (23%),
3) Both types: 200 (9%)
**Compared with non-users, pts taking BDZes or opioids
: more likely to be women and had lower functional status,
PaCO2↑(RA), & more previous admissions to hospital,
oral glucocorticoids, osteoporosis, injuries, and depression/anxiety.
** Exposure to benzodiazepines and opioids throughout follow-up
was higher among patients with baseline exposure (table 2⇓);
the median percentage of exposed time during follow-up was
100% (interquartile range 88-100) for benzodiazepines and
100% (IQR, 60-100) for opioids. Patients unexposed at baseline had
low rates of exposed time during subsequent follow-up (table2).⇓
24%
9%
9%
23%
-88 -60
+60+88
I. Admission to hospital
II.Mortality
III.Sensitivity analysis
I. Admission to hospital
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Tx. with BDZes or opioids was not a/w Adm. rates↑ ;
:HR 0.98 (95% confidence interval 0.87 to 1.10) / 0.98 (0.86 to 1.10), respectively.
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No dose-response relations
: Higher dose Tx.(>0.3 defined daily doses/day)- Not ↑ rate of adm.
*BDZes/opioid (subdistribution HR 0.90, 0.76 to 1.06)/(1.01, 0.86 to 1.18).
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Concurrent Tx. (BDZes + opioids): a/w a lower rate of admission,
interaction (influenced mainly by WHO performance)
(subdistribution HR 0.67, 95% confidence interval 0.51 to 0.87; P=0.003).
1) WHO statuses 1 & 2: Non-significant upward trend
2) WHO statuses 3 & 4: Rates of adm. ↓
* No interactions btw drug effects & the presence of hypercapnia.
II. Mortality
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During a median f/u of 1.1 years (IQR 0.6-2.0 years), 138 (6%) pts
withdrew from long term O2 therapy mainly because of improved
oxygenation, & 1129 (50%) pts died.
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Adjusted mortality estimates.
1)*BDZes: a/w adjusted mortality↑
(HR 1.21, 95% confidence interval 1.05 to 1.39).
Dose relation btw higher BDZ doses & mortality↑
(HR 1.01, 1.00 ~ 1.03; P=0.082)
2) Opioids : a linear dose-response a/w mortality ↑
(HR 1.01, 95% confidence interval 1.00 to 1.03; P=0.038)
★Lower dose opioids (≤30 mg of oral morphine equivalents/day)
: not a/w increased mortality (1.03, 0.84 to 1.26)
3) Concurrent use: Opioid high?  ↑
Discussion(1)
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Supportive role of lower dose opioids
 treating breathlessness that is refractory to Tx.
• Other studies:
1) Palliative care found no associations btw. opioids
& increased rates of respiratory depression or death.
2) Large meta-analysis of parenteral opioids in postoperative pts:
in whom the highest rates of toxicity are likely to be seen, the rate of hypoventilation
after 10 mg IM morphine was 0.6% ≒ placebo.
3) Randomised controlled trials
: lower dose BDZes not a/w serious adverse events or impaired blood gas
4) Observational studies,: BDZes have been a/w increased risk of admission to hospital
 falls and of developing more frequent & severe pn.
5) Present study: Both BDZes & opioids were less likely to be admitted to hospital.
Discussion(2)
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Major strength: Large population based consecutive cohort of old
severely ill pts with respiratory failure caused by COPD, many of whom
had hypercapnia. (No pts was lost to f/u)
*Limitation
① Cannot r/o residual confounding:
i) unmeasured covariates
ii) Ix. for BDZes & opioids :absence of randomisation.
② Dispensed prescriptions vs consumed drugs.
**Titration up to 30 mg morphine daily: might safely improve breathlessness
in over 60% of pts, with a mean decrease of 35% in the intensity of dyspnea
**In conclusion:
1) BDZes & higher dose opioids: adjusted mortality↑
2) Lower dose opioids: not a/w risk of hospital adm.↑ or death
(in pts with respiratory failure a/w COPD.)