Week 28 – Symptom-Triggered Benzodiazepines in Alcohol Withdrawal

“Symptom-Triggered vs Fixed-Schedule Doses of Benzodiazepine for Alcohol Withdrawal”

Arch Intern Med. 2002 May 27;162(10):1117-21. [free full text]

Treatment of alcohol withdrawal with benzodiazepines has been the standard of care for decades. However, in the 1990s, benzodiazepine therapy for alcohol withdrawal was generally given via fixed doses. In 1994, a double-blind RCT by Saitz et al. demonstrated that symptom-triggered therapy based on responses to the CIWA-Ar scale reduced treatment duration and the amount of benzodiazepine used relative to a fixed-schedule regimen. This trial had little immediate impact in the treatment of alcohol withdrawal. The authors of the 2002 double-blind RCT sought to confirm the findings from 1994 in a larger population that did not exclude patients with a history of seizures or severe alcohol withdrawal.

The trial enrolled consecutive patients admitted to the inpatient alcohol treatment units at two European universities (excluding those with “major cognitive, psychiatric, or medical comorbidity”) and randomized them to treatment with either scheduled placebo (30mg q6hrs x4, followed by 15mg q6hrs x8) with additional PRN oxazepam 15mg for CIWA score 8-15 and 30mg for CIWA score > 15 or to treatment with scheduled oxazepam (30mg q6hrs x4, followed by 15mg q6hrs x8) with additional PRN oxazepam 15mg for CIWA score 8-15 and 30mg for CIWA score > 15.

The primary outcomes were cumulative oxazepam dose at 72 hours and duration of treatment with oxazepam. Subgroup analysis included the exclusion of symptomatic patients who did not require any oxazepam. Secondary outcomes included incidence of seizures, hallucinations, and delirium tremens at 72 hours.

117 patients completed the trial. 56 had been randomized to the symptom-triggered group, and 61 had been randomized to the fixed-schedule group. The groups were similar in all baseline characteristics except that the fixed-schedule group had on average a 5-hour longer interval since last drink prior to admission. While only 39% of the symptom-triggered group actually received oxazepam, 100% of the fixed-schedule group did (p < 0.001). Patients in the symptom-triggered group received a mean cumulative dose of 37.5mg versus 231.4mg in the fixed-schedule group (p < 0.001). The mean duration of oxazepam treatment was 20.0 hours in the symptom-triggered group versus 62.7 hours in the fixed-schedule group. The group difference in total oxazepam dose persisted even when patients who did not receive any oxazepam were excluded. Among patients who did receive oxazepam, patients in the symptom-triggered group received 95.4 ± 107.7mg versus 231.4 ± 29.4mg in the fixed-dose group (p < 0.001). Only one patient in the symptom-triggered group sustained a seizure. There were no seizures, hallucinations, or episodes of delirium tremens in any of the other 116 patients. The two treatment groups had similar quality-of-life and symptom scores aside from slightly higher physical functioning in the symptom-triggered group (p < 0.01). See Table 2.

Symptom-triggered administration of benzodiazepines in alcohol withdrawal led to a six-fold reduction in cumulative benzodiazepine use and a much shorter duration of pharmacotherapy than fixed-schedule administration. This more restrictive and responsive strategy did not increase the risk of major adverse outcomes such as seizure or DTs and also did not result in increased patient discomfort.

Overall, this study confirmed the findings of the landmark study by Saitz et al. from eight years prior. Additionally, this trial was larger and did not exclude patients with a prior history of withdrawal seizures or severe withdrawal. The fact that both studies took place in inpatient specialty psychiatry units limits their generalizability to our inpatient general medicine populations.

Why the initial 1994 study did not gain clinical traction remains unclear. Both studies have been well-cited over the ensuing decades, and the paradigm has shifted firmly toward symptom-triggered benzodiazepine regimens using the CIWA scale. While a 2010 Cochrane review cites only the 1994 study, Wiki Journal Club and 2 Minute Medicine have entries on this 2002 study but not on the equally impressive 1994 study.

Further Reading/References:
1. “Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial.” JAMA. 1994.
2. Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar)
3. Wiki Journal Club
4. 2 Minute Medicine
5. “Benzodiazepines for alcohol withdrawal.” Cochrane Database Syst Rev. 2010

Summary by Duncan F. Moore, MD

Image Credit: VisualBeo, CC BY-SA 3.0, via Wikimedia Commons

Week 27 – Mortality in Patients on Dialysis and Transplant Recipients

“Comparison of Mortality in All Patients on Dialysis, Patients on Dialysis Awaiting Transplantation, and Recipients of a First Cadaveric Transplant”

N Engl J Med. 1999 Dec 2;341(23):1725-30. [free full text]

Renal transplant is the treatment of choice in patients with ESRD. Since the advent of renal transplant, it has been known that transplant improves both quality of life and survival relative to dialysis. However, these findings were derived from retrospective data and reflected inherent selection bias (patients who received transplants were healthier, younger, and of higher socioeconomic status than patients who remained on dialysis). While some smaller studies (i.e. single center or statewide database) published in the early to mid 1990s attempted to account for this selection bias by comparing outcomes among patients who received a transplant versus patients who were listed for transplant but had not yet received one, this 1999 study by Wolfe et al. was a notable step forward in that it used the large, nationwide US Renal Data System dataset and a robust multivariate hazards model to control for baseline covariates. To this day, Wolfe et al. remains a defining testament to the sustained, life-prolonging benefit of renal transplantation itself.

Using the comprehensive US Renal Data System database, the authors evaluated patients who began treatment for ESRD between 1991 and 1996. Notable exclusion criteria were age ≥ 70 and transplant prior to initiating dialysis. Of the 228,552 patients evaluated, 46,164 were placed on the transplant waitlist, and 23,275 received a transplant by the end of the study period (12/31/1997). The primary outcome was survival reported in unadjusted death rates per 100 patient-years, standardized mortality ratios (adjusted for age, race, sex, and diabetes as the cause of ESRD), and adjusted relative risk of death in transplant patients relative to waitlisted patients. Subgroup analyses were performed.

Regarding baseline characteristics, listed or transplanted patients were younger, more likely to be white or Asian, and less likely to have diabetes as the cause of their ESRD (see Table 1). Unadjusted death rates per 100 patient-years at risk: dialysis 16.1, waitlist 6.3, and transplant recipients 3.8 (no p value given, see Table 2). The standardized mortality ratio (adjusted for age, race, sex, and diabetes as the cause of ESRD) was 49% lower (RR 0.51, 95% CI 0.49–0.53, p<0.001) among patients on the waitlist and 69% lower among transplant recipients (p value not reported). The lower standardized mortality ratio of waitlisted patients relative to dialysis patients was sustained in all subgroup analyses (see Figure 1). The relative risk of death (adjusted for age, sex, race, cause of ESRD, year placed on waitlist, and time from first treatment of ESRD to placement on waitlist) is visually depicted in Figure 2. Importantly, relative to waitlisted patients, transplant recipients had a 2.8x higher risk of death during the first two weeks post-transplant. Thereafter, risk declined until the likelihood of survival equalized at 106 days post-transplant. Long term (3-4 years of follow-up in this study), mortality risk was 68% lower among transplanted patients than among waitlisted patients (RR 0.32, 95% CI 0.30–0.35, p< 0.001). The magnitude of this survival benefit varied by subgroup but was strong and statistically significant in all subgroups (ranging from 3 to 17 additional projected years of life, see Table 3).

Retrospective analysis of this nationwide ESRD database has clearly demonstrated the marked mortality benefit of renal transplantation over waitlisted status. This finding is present to varying degrees in all subgroups and leads to a projected additional 3 to 17 years of lifespan post-transplant. (There is an expected, mild increase in mortality risk immediately following transplantation. This increase reflects operative risk and immediate complications but is present for only 2 weeks post-transplantation.) As expected and as previously described in other datasets, this study also demonstrated that substantially healthier ESRD patients are selected for transplantation listing in the US in comparison to patients who remain on dialysis not on the waitlist.

Relative strengths of this study include its comprehensive national dataset and intention-to-treat analysis. Its multivariate analyses robustly controlled for factors, such as time on the waitlist, that may have influenced mortality. However, this study is limited in that its retrospective comparison of listed to transplanted does not entirely eliminate selection bias. (For example, listed patients may have developed illnesses that ultimately prevented transplant and lead to death.) Additionally, the mortality benefits demonstrated in this study from the first half of the 1990s may not reflect those of current practice, given that prevention and treatment of ASCVD (a primary driver of mortality in ESRD) has improved markedly in the ensuing decades and may favor one group disproportionately.

As suggested by the authors at UpToDate, improved survival post-transplant may be due to the following factors: increased clearance of uremic toxins, reduction in inflammation and/or oxidative stress, reduced microvascular disease in diabetes mellitus, and improvement of LVH.

As a final note: in this modern era, it is surprising to see both a retrospective cohort study published in NEJM as well as the lack of preregistration of its analysis protocol prior to the study being conducted. Preregistration, even of interventional trials, did not become routine until the years following the announcement of the International Committee of Medical Journal Editors (ICMJE) trial registration policy in 2004 (Zarin et al.). Although, even today, retrospective cohort studies are not routinely preregistered, high profile journals increasingly require it because it helps differentiate between confirmatory versus exploratory research and reduce the appearance of post-hoc data dredging (i.e. p-hacking). Please see the Center for Open Science – Preregistration for further information. Here is another helpful discussion in PowerPoint form by Deborah A. Zarin, MD, Director of ClinicalTrials.gov.

Further Reading/References:
1. UpToDate, “Patient Survival After Renal Transplantation”
2. Zarin et al. “Update on Trial Registration 11 Years after the ICMJE Policy Was Established.” NEJM 2017

Summary by Duncan F. Moore, MD

Image Credit: Anna Frodesiak, CC0 1.0, via Wikimedia Commons