IT'S ABOUT TIME: WOULD A NEW ACUTE STROKE TREATMENT TRIAL FOR THOSE 4.5-6.0 HOURS FROM STROKE ONSET BE GOOD VALUE FOR SAMPLE INFORMATION?

Purpose:

Current clinical guidelines recommend thrombolysis with alteplase (tPA) within 4.5 hours of acute ischemic stroke onset. We quantified the potential value of new research in patients treated with tPA in the 4.5-6.0 hour window after stroke onset and determined the optimal size of a future trial using value of information analysis.

Method:

Expected value of partial perfect and sample information analyses (EVPPI and EVSI) were conducted using a previously developed probabilistic acute stroke Markov model. Stroke outcome was characterized using the modified Rankin Scale (mRS), which ranges from 0 (no stroke symptoms) to 6 (death); in the model, mRS outcomes determine discounted lifetime stroke costs and quality-adjusted life years (QALYs). Data for mRS distributions in patients 4.5-6.0 hours since stroke onset for tPA (n=576) and placebo (n=543) were obtained from eight pooled RCTs, with odds ratios for good outcome (mRS0-1) of 1.22 (95% CI: 0.92-1.61) and death (mRS6) of 1.49 (95% CI: 1.00-2.21). We parameterized mRS outcomes for tPA and placebo using dirichlet distributions. EVSI was quantified with net monetary benefit (assuming willingness-to-pay for health=$100,000/QALY). We calculated discounted population-level EVSI by multiplying per-person EVSI by the annual number of stroke patients in the U.S. eligible for tPA in the 4.5-6.0 hour treatment window (115,572) and assuming a 10-year timeframe of treatment use. Study costs were based on administrative costs (fixed costs=$500,000, per-person variable costs=$2,000) and the costs of tPA (per-person costs=$6,720, treatment group only).  

Result:

The base-case lifetime cost-effectiveness analysis showed that tPA was dominated (i.e., more costly and less effective) by placebo in this patient group. EVPPI for mRS distributions was $1,003 per person. Based on EVSI, the optimal sample size of a new trial collecting data on tPA efficacy (quantified by mRS distributions) in these patients would be 5,600 across study arms with expected population-level societal returns (EVSI minus study costs) of $68.7 million (Figure 1).

Conclusion:

Expanding research attention to the 4.5-6.0 hour time window for tPA treatment of acute ischemic stroke patients is justified as the expected returns are substantial. Even a relatively large trial in which more information on treatment efficacy based on mRS scores is collected would represent good value for information. Results were sensitive to willingness-to-pay for health, timeframe of treatment use, and variable study costs inputs.