HARPOON

In Review

Schrijver EJM. "Haloperidol versus placebo for delirium prevention in acutely hospitalised older at risk patients: a multi-centre double-blind randomised controlled clinical trial". Age Ageing. 2018. 47(1):48-55.
PubMed • ClinicalTrials.gov

Clinical Question

In older adults admitted to hospital, does the use of haloperidol 1mg twice daily as compared to placebo prevent the development of delirium.

Bottom Line

Routine use of haloperidol in at-risk older-adult inpatients does not prevent delirium.

Major Points

Delirium is a poorly understood condition, the pathoetiology is not clear and is a heterogeneous condition. When it does develop, it has been associated with increased mortality and morbidity, including increased cognitive decline, decreased independent living, and repeat admission) With the pathoetiology poorly understood, preventative measures and targets for prophylaxis and treatment have been challenging to identify.

The Haloperidol versus placebo for delirium prevention in acutely hospitalized older at risk patients: a multi-centre double-blind randomized controlled clinical trial (HARPOON) randomized patient 70 years and older who were admitted to acute care for either medicine or surgery in one of 6 centres in the Netherlands. The patients were randomized to receive haloperidol 1mg orally twice daily or matched placebo. The trial did not find any statistical difference between groups in the prevention of delirium at 7 days. The trial also did not find any difference in secondary outcomes including duration of delirium, new institutionalism, hospital length of stay, or any adverse events.

There were several limitations with this trial, the main issue is that they did not reach target population (n=390) only randomizing 292 patients. Being underpowered it is unclear if there true is no difference between the two arms. One of the challenges the investigators faced was the screening including only patients that were at risk of delirium and that the screening tool was subjective. Data collection may have also been skewed as assessments did not occur at the guideline recommended frequency.

Currently pharmacologic preventative strategies have not been supported by previous research. Multimodal interventions have been shown to decrease delirium, however, these approaches may not be robust and long lasting.

Guidelines

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) in Adult Patients in the ICU, 2018, Adapted :

Prevention of Delirium: Recommend against the use of pharmacological agents (haloperidol, dexmedetomidine, HMG-CoA reductase inhibitors, ketamine) to prevent delirium (conditional recommendation, very low to low quality of evidence)

Design

• multi-centre, double-blind, stratified, block randomised, placebo-controlled trial
• N=242
  • Haloperidol (n=118)
  • Placebo (n=)124
• Setting: The Netherlands, 1 university and 5 teaching hospitals
• Enrollment: November 2012 - March 2015
• Follow-up: 6 months
• Analysis: Intention-to-treat
• Primary Outcome: Delirium within 7 days of initiation of study intervention

Population

Inclusion Criteria

• ≥70 years
• acute hospitalization through the emergency department (ED) *medical (gastroenterology, geriatrics, internal medicine, nephrology, pulmonology) or surgical specialty (colorectal-, general / trauma / vascular surgery, orthopaedics and urology) *at risk for delirium, defined as Dutch Safety Management Programme (Veiligheidsmanagementsysteem, VMS) delirium risk tool score ≥3

Exclusion Criteria

• VMS 0
• patients not able to take study medication according to protocol
• specific heart conditions:
  • QTc interval > 500 ms, recent myocardial infarction, decompensated heart failure, second- or third-degree AV block, (history of) ventricular arrhythmias or Torsade de Pointes (TdP), uncorrected serum potassium level ≤3.0 mEq/L, clinical significant bradycardia
• concomitant pharmacodynamically interacting medication
• use of antipsychotic or dopaminergic drugs
• Parkinson’s Disease
• Vascular or Lewy Body Dementia
• Hypokinetic Movement Disorder, Neuroleptic Malignant Syndrome, Central Anticholinergic Syndrome
• substance abuse and dependence
• epilepsy
• not competent to provide informed consent

Baseline Characteristics

• Demographics: 55% female, mean 83 years old,
• Physiologic parameters:
• Anthropomorphics: BMI 25.7 kg/m^2
• Social: 44% independent, 37% home care, 17% institutional, 29% independent mobility, 32% hearing aids, 88% visual aids
• Labs: Albumin 35 g/L, creatinine 90 mol/L, CRP 35 mg/L, baseline QTc 438 ms
• Pre-admission medications: 72% anticholinergic, 12% antidepressants, 5% antihistamines, 25% benzodiazepines, 12% Opioids

Interventions

• Haloperidol 1mg PO BID at noon and 20h00 for 7 days
• Placebo

Outcomes

Comparisons are haloperidol vs. placebo.

Primary Outcomes

Delirium incidence within 7 days

19.5% vs. 14.5% (OR 1.43, 95% CI 0.72-2.78) P = 0.302

Secondary Outcomes

Delirium duration

4 days vs. 3 days, P = 0.366

Hospital length of stay

7 days vs. 7 days, P = 0.949

Mortality

30 days - 5% vs. 7% (OR 0.78, 95% CI 0.26-2.33) P = 0.649

3 months - 10% vs. 13% (OR 0.77, 95% CI 0.34-1.75) P = 0.534

6 Months - 17% vs. 18% (OR 0.98 95% CI 0.49-2.00) P = 0.963

Discharge disposition

As prior to admission - 44% vs. 43%

As prior with supports - 24% vs. 23%

Rehabilitation centre - 23% vs. 27%

Institution - 6% vs. 5%

Death - 4% vs. 3%

ICU Admission

2.5% vs. 3.2% (OR 0.78, 95% CI 0.17-3.57) P = 1.000

Adverse Events

All Adverse events

13% vs. 16% (OR 0.81, 95% CI 0.40-1.67) P = 0.574

QTc interval change

no statistical difference between groups after 2, 6, or 12 doses

Criticisms

• Underpowered - did not reach target sample size
• screening for VMS delirium risk score ≥1 may have led to selection bias since the tool uses subjective questions
• Patient assessment was not always conducted at the guideline recommended frequency
• cognitive impairment or dementia were excluded

Funding

• nil