Safety of human albumin—serious adverse events reported worldwide in 1998–2000{dagger}

J.-L. Vincent*,1, M. M. Wilkes2 and R. J. Navickis2

1 Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles, Route de Lennik 808,B-1070 Brussels, Belgium. 2 Hygeia Associates, Grass Valley, California, USA

Corresponding author. E-mail: jlvincen@ulb.ac.be
{dagger}Declaration of interest. This investigation was supported by an unrestricted grant from the Plasma Protein Therapeutics Association. The sponsor played no role in the analysis and interpretation of data or the preparation and submission of the manuscript. Hygeia Associates is an independent organization specializing in the statistical analysis of biomedical research data and is in no way affiliated with the sponsor, either directly or indirectly. None of the co-investigators in this study has any conflict of interest to declare.

Accepted for publication: July 7, 2003


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Previous pharmacovigilance studies have indicated a low rate of adverse events in patients receiving human albumin. However, the incidence of adverse events is likely to have been underestimated because of under-reporting. A more accurate estimate may be possible during a period such as 1998–2000, when awareness regarding albumin safety was heightened by publication of a meta-analysis.

Methods. All serious adverse event reports received, and total doses of albumin distributed worldwide from the beginning of 1998 to the end of 2000 by 10 major suppliers of therapeutic human albumin were compiled.

Results. Distributed albumin doses totalled 1.62 x 107. The total numbers of non-fatal and fatal serious adverse events reported were 198 and 13, respectively. The incidence of all reported serious non-fatal and fatal adverse events was 5.28 per 106 doses (CI 1.60–17.4 per 106 doses). For non-fatal serious adverse events only, the observed incidence was 4.65 per 106 doses (CI 1.34–16.2 per 106 doses). No patient death was classified as probably related to albumin administration. The observed incidence of fatal serious adverse events possibly related to albumin was 0.185 per 106 doses (CI 0.0597–0.574 per 106 doses). The observed incidence of all non-fatal and fatal serious adverse events was significantly higher during the 1998–2000 period as compared with 1990–1997 (incidence rate ratio 4.98; CI 3.94–6.29), probably chiefly as a result of reduced under-reporting.

Conclusions. Although the observed incidence of adverse events is likely to be an underestimate, nevertheless both non-fatal and fatal serious adverse events in albumin recipients appear to be rare. These results add further support to the excellent safety record of human albumin.

Br J Anaesth 2003; 91: 625–30

Keywords: complications, adverse drug reaction; complications, hospital mortality; pharmacoepidemiology audit; protein, albumin


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In a previous pharmacovigilance study encompassing 1 x 108 albumin doses distributed worldwide in the period 1990–1997, the observed incidence of spontaneously reported serious adverse events was 1.29 per 106 doses.1 No deaths were judged to be probably attributable to albumin, and the incidence of fatal adverse events possibly related to albumin was 5.24 per 108 doses. However, under-reporting is a recognized limitation of pharmacovigilance studies based upon spontaneous adverse event reporting.2

Adverse event reporting may abruptly increase after publication of data calling attention to a potential safety problem with a particular therapeutic agent.3 A 1998 meta-analysis of 24 randomized trials suggested 6% excess mortality among albumin recipients.4 The meta-analysis received widespread attention in medical journals and the mass media.5 6 Excess albumin-associated mortality could not be confirmed in a 2001 meta-analysis of 42 randomized trials including all 24 trials from the 1998 meta-analysis plus an additional 18 trials.7 Nevertheless, during the period from 1998 to the end of 2000 there was clearly heightened awareness of the meta-analytic evidence that albumin might be harmful, and increased reporting of adverse events related to albumin might be anticipated for this period. This possibility was investigated in the present study.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Data sources
Data for this study were provided by 10 major suppliers of human albumin for therapeutic use: Alpha Therapeutic Corp., Los Angeles, CA, USA; Aventis Behring, Marburg, Germany; Baxter BioScience, Westlake Village, CA, USA; Bayer AG, Leverkusen, Germany; Biotest Pharma GmbH, Dreieich, Germany; Grupo Grifols S.A., Parets del Vallës, Spain; Kedrion S.p.A., Lucca, Italy; Octapharma AG, Lachen, Switzerland; Pharmacia & Upjohn, Stockholm, Sweden; and ZLB Bioplasma AG, Bern, Switzerland. All participating suppliers were member organizations of the Plasma Protein Therapeutics Association, Annapolis, MD, USA, which coordinated data collection. Data on all serious adverse events spontaneously reported worldwide to the par ticipating suppliers were compiled for the period January 1, 1998 to December 31, 2000. A standardized questionnaire was completed by each supplier designed to elicit data on the number and description of adverse events and quantity of albumin distributed during the study period, as well as outcomes and the putative relationship between the adverse events and albumin administration.

Adverse event reports
The primary adverse event reports were compiled in accordance with the standard pharmacovigilance programmes of the individual suppliers. Although the primary adverse event report forms differed between countries, the information solicited on the forms was generally similar. In accordance with the definition of the International Conference on Harmonization,8 adverse events were classified as serious if they involved: (i) death; (ii) a life-threatening clinical condition; (iii) hospitalization or extended hospitalization; (iv) disability; (v) congenital anomaly; or (vi) intervention to prevent permanent impairment or damage. The attributability of adverse events to albumin was categorized as probable, possible, unrelated, or unknown, based upon evaluation by qualified healthcare professionals of the pharmacovigilance programme for the supplier receiving the adverse event report. In this study, albumin was introduced into the stream of international commerce, and data were not available as to the proportion distributed in particular countries.

Statistical analysis
Adverse events associated with administration of therapeutic agents can be modelled as a Poisson process.9 10 The study data were analysed by mixed-effects Poisson regression using the GLLAMM programme.11 The albumin supplier was entered in the model as a random effect to accommodate heterogeneity in reporting rates between the geographical distribution regions of the suppliers. In addition to estimation of adverse event incidence rates, the model was used to calculate incidence rate ratios for the 1998–2000 period compared with the 1990–1997 period. The incidence rate ratio is equal to the incidence of adverse events during 1998–2000 divided by the incidence of adverse events during 1990–1997. Incidence rate ratios >1 indicate a greater adverse event incidence during 1998–2000, and the absence of 1 in the 95% CI indicates that the effect is statistically significant, as an incidence rate ratio of 1 would signify no difference in incidence.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
For all 10 albumin suppliers, the combined total quantity of albumin distributed worldwide from 1998 to the end of 2000 was 6.48 x 105 kg, corresponding to 1.62 x 107 doses of 40 g each. For this 3 yr period, the median number of doses distributed annually per supplier was 3.98 x 105 (interquartile range 2.27–7.77 x 105), compared with 4.89 x 105 (interquartile range 1.16–11.2 x 105) for 1990–1997. This 18.8% decline was not statistically significant (P=0.20 by Wilcoxon matched-pairs signed-ranks test).

The combined total numbers of non-fatal and fatal serious adverse events spontaneously reported to the 10 suppliers were 198 and 13, respectively. The putative relationship reported between albumin and both non- fatal and fatal serious adverse events is summarized in Figure 1. Of the non-fatal serious adverse events, 7.1% were classified as probably related to albumin. Three of the fatalities were judged to be possibly related to albumin administration and the rest were judged to be unrelated (Table 1).



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Fig 1 Putative relationship of albumin to non-fatal and fatal serious adverse events.

 

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Table 1 Fatal adverse events
 
The observed incidence of all non-fatal and fatal serious adverse events was 5.28 per 106 doses (CI 1.60–17.4 per 106 doses), as indicated in Table 2. The observed incidence of non-fatal serious adverse events was approximately six times that of fatal adverse events. The incidence of adverse events observed in the 1998–2000 period was significantly higher than that during 1990–1997 (Table 2). For all non-fatal and fatal serious adverse events the incidence rate ratio for these two periods was 4.98 (CI 3.94–6.29), indicating that the incidence for 1998–2000 was approximately five times that for 1990–1997. The increase predominantly reflected a higher incidence of non-fatal serious adverse events during 1998–2000.


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Table 2 Incidence of serious adverse events. Incidence rates were estimated separately in each category and subcategory by mixed effects Poisson regression. Consequently, sums of rates in subcategories do not exactly equal overall category totals. The incidence rate ratio is incidence of adverse events during 1998–2000 divided by the incidence of adverse events during 1990–1997. Data are point estimate (95% CI)
 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The present study covering 1998–2000 confirms the observations previously reported for 1990–1997,1 namely that both non-fatal and fatal serious adverse events spontaneously reported in albumin recipients are rare, even during a period of heightened awareness regarding possible excess mortality when under-reporting is less likely. It is noteworthy that for the entire period from 1990 to the end of 2000, during which a total of 112 million albumin doses were distributed worldwide, no death probably related to albumin was documented.

A major strength of this study was the availability from suppliers of accurate data on the quantity of albumin distributed, allowing the adverse event incidence rate to be calculated. Data for quantity of therapeutic agent used provide the denominator in incidence rate calculations and are frequently lacking in pharmacovigilance studies.12

A major limitation of spontaneous adverse event reporting in general and the present study in particular is the uncertain extent of under-reporting. The impact of under-reporting is likely to have been mitigated by two features of our study: the exclusive focus on serious adverse events which are less subject to under-reporting than non-serious adverse events; and the collection of data during a period of increased awareness, which is also expected to reduce under-reporting. Nevertheless, despite heightened awareness, the incidence of adverse events we observed may still be an underestimate because of residual under-reporting. One potential contributor to under-reporting is the lapse of time after the introduction of a therapeutic agent, a phenomenon termed the Weber effect in recognition of the work by Dr J. C. P. Weber in the UK during the early 1980s.9 13 Thus, reporting of adverse events may be less likely in the case of agents such as albumin that have been in clinical use for a protracted period. However, in an investigation of adverse event reporting after introduction of five non-steroidal anti-inflammatory drugs, there was no evidence of a consistent decline in adverse event reporting rates for four of the five drugs examined.14 Hence, the Weber effect may not operate in all clinical contexts. In addition to the Weber effect, factors that may influence under-reporting include the identity of the particular therapeutic agent, the type of adverse event involved, and reporting practices in particular clinical settings and countries.

The seriousness of adverse events is a major determinant of reporting. In a study based on prescription-event monitoring data for 15 newly marketed drugs in the UK, 53% of serious adverse events were reported by family doctors.8 Serious events were five times more likely to be reported than non-serious events. Similarly, among cardio pulmonary bypass patients at a single USA hospital, 43% of severe protamine-related adverse events were reported to the institutional adverse drug reaction programme, compared with 19% of all protamine-related adverse events.15 As cardiac surgery is the most common setting for albumin administration,16 and protamine, like albumin, has been in widespread clinical use for a protracted time period,17 this 57% rate of under-reporting for severe protamine-related adverse events may be similar to that for albumin, at least before 1998. However, this estimate of under-reporting for albumin is subject to substantial uncertainty, in part because albumin and protamine differ in their indications for clinical usage. Also, albumin adverse event reports in our study were collected worldwide while the protamine data were derived from an American investigation, and marked country-to-country variability in under-reporting rates has been documented.18 19

The problem of under-reporting notwithstanding, spontaneous reporting systems are a mainstay of pharmaco vigilance worldwide, providing sensitive signals of therapeutic agent safety problems.2 12 20 21 Spontaneous adverse event reports arise primarily from healthcare professionals and are directed to therapeutic product suppliers and regulatory agencies. Serious adverse events reported to suppliers must by law be relayed to regulatory authorities, typically within 15 days.2 12 21 22 Indeed, in the USA and certain other countries such as Canada, Germany and Italy, suppliers account for the largest proportion of adverse event reports received by regulatory authorities.2 20 23 Recognized advantages of spontaneous adverse event reporting include high sensitivity in detecting novel or rare adverse events, cost-effectiveness, simplicity, continuous coverage of all therapeutic agents after introduction into clinical practice as well as of the entire population of patients receiving such agents, lack of interference with clinical practice patterns, and suitability for follow-up studies of patients with serious adverse events for the purpose of investigating causal mechanisms.2 20

Available empirical evidence indicates that spontaneous reporting systems are more sensitive in detecting adverse events than prospective studies employing active surveillance, primarily because of practical limitations in the numbers of patients who can be actively followed. Investigators at the US Food and Drug Administration compared the ability to detect new adverse events between spontaneous reporting and phase IV clinical studies involving active prospective surveillance in approximately 4 x 104 patients.24 New adverse events were established for two of the three tested drugs by spontaneous reports; no new adverse events were identified by the phase IV studies. Furthermore, a programme of intensive, prospective surveillance to detect adverse events in a large teaching hospital was found not to be cost-effective compared with a hospital-wide spontaneous reporting programme.25

The safety of human albumin has been investigated for over 60 yr. Even at the time of its introduction in 1942, human albumin safety was a subject of intense interest, in part because attempts to adapt bovine albumin for clinical use had to be abandoned because of serious and sometimes fatal cases of serum sickness.26 The first evidence on human albumin safety was furnished by the report published in 1942 of a multicentre clinical trial in 200 patients requiring fluid resuscitation for hypovolaemic shock after trauma, surgery or other causes of haemorrhage.27 No adverse events were encountered in the trial. A subsequent 600 patient multicentre safety trial was reported in 1944, indicating the absence of adverse reactions to albumin, and pathological studies of necropsy material from albumin recipients failed to reveal significant changes attributable to administered albumin such as pathological tissue accumulation of albumin, renal glomerular damage or periarteritis nodosa.28

Through numerous further investigations in the 1940s and thereafter human albumin gained the reputation of a very safe fluid.29 Summarizing the first 35 yr of clinical experience in the report of a US National Institutes of Health consensus conference, Tullis characterized albumin safety as ‘so high that it rarely warrants discussion’.30 This conclusion received support from subsequent large-scale pharmacovigilance studies. In addition to the earlier report on serious adverse events in the 1990–1997 period,1 two additional investigations have focused on all adverse events among albumin recipients without regard to seriousness.31 32 One encompassing 7.4 x 106 albumin doses in patients with hypoalbuminaemia or hypovolaemia indicated incidence rates for all adverse events of 6.12 per 105 doses of 5% albumin and 8.56 per 105 doses of 20% albumin.31 The other involved clinical reactions reported to the Commonwealth Serum Laboratories of Australia during 1976–1985 in a population receiving 1.5 x 106 albumin doses.32 The respective adverse event incidence rates after administration of 25% normal serum albumin and 5% stable plasma protein solution were 3.1 per 105 doses and 6.8 per 105 doses, and hypotension syndrome accounted for the majority of adverse events. In a prospective study of approximately 8 x 104 hospitalized patients in whom serious adverse events were identified by a computerized surveillance programme, no albumin-associated adverse events of any kind were reported.33 We have recently described meta-analytic evidence indicating that administered albumin reduces complications in a dose-dependent manner among patients with hypoalbuminaemia.34

The observed incidence of all non-fatal and fatal adverse events during 1998–2000 was approximately five times that for 1990–1997. It appears likely that this large increase is primarily attributable to reduced under-reporting rather than a true increase in the frequency of adverse events. A true increase might ensue from substantial changes in the populations of patients receiving albumin and/or clinical practice patterns in the use of albumin. Little evidence exists for such changes between the 1990–1997 and the 1998–2000 periods. On the other hand, the 1998 meta-analysis4 focused intense attention on possible albumin-mediated harm, and the widespread awareness of the meta-analytic results likely prompted an increase in albumin adverse event data reporting that would explain the higher observed adverse event data incidence in 1998–2000. It should be recognized that, even with the apparent increase in reporting, the overall observed incidence of adverse events remained very low among patients receiving albumin.

Our fatal serious adverse event data invite comparison with the mortality results from the 1998 meta-analysis;4 however, important distinctions need to be drawn between the two study designs. Ours was an observational study in which deaths were reported based upon clinical suspicion of a relationship to albumin in the routine acute care setting. The 1998 meta-analysis addressed all-cause mortality among albumin recipients compared with a control group receiving crystalloid, no albumin or lower-dose albumin in the exclusive context of randomized trials. While our study estimated the incidence of death among patients exposed to albumin, the meta-analysis examined the relative risk of death for albumin recipients in comparison with a control group.

The 6% excess mortality rate in the 1998 meta-analysis indicated that for every 17 patients treated with albumin there would be one additional death, and the investigators suggested that albumin might be increasing mortality by exerting an anticoagulant effect or promoting oedema. This implies that albumin might contribute to death on a frequent basis but, in view of the rarity of fatal adverse event reports we demonstrated, this harmful effect has in the vast majority of cases eluded clinical suspicion despite widespread long-term usage of albumin. In any case, the reliability of the 1998 meta-analysis has been questioned.35 As detailed elsewhere,36 the 2001 meta-analysis7 encompassed 2.5-fold the number of patients and 3-fold the statistical weight of evidence considered in the 1998 meta-analysis, but could not replicate the finding of significant excess mortality. That finding appears to have rested upon a small biased subset of the available evidence.36

Serious non-fatal and fatal adverse events after administration of albumin appear to be rare. No death was judged to be probably related to albumin. The present study adds to a large body of existing evidence indicating human albumin to be remarkably safe, despite having been conducted during a period of heightened awareness regarding albumin-related adverse events, likely resulting in increased adverse event reporting.


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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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