The novel PISA method reconstructs the time-dependent relationship between exposure and benefit from Kaplan-Meier curves to quantify event-free time gained and pharmaco-economic indices.
A novel method using event-free time gain derived from Kaplan-Meier curves provides a time-dependent assessment of clinical and economic benefits, facilitating objective comparisons among therapeutic options.
Abstract Background Major results of randomized clinical trials on cardiovascular prevention are currently provided in terms of relative or absolute risk reductions, including also the number needed to treat (NNT), incorrectly implying that a treatment might prevent the occurrence of the outcome/s under investigation. Provided that these results are based on survival analysis, the primary measure of which is time-to-the outcome and not the outcome itself, we sought an alternative method to describe, analyse and interpret clinical trial results consistent with this assumption, so as to better define qualitative and quantitative heterogeneity of various therapeutic strategies in terms of their effects and costs. Methods The original Kaplan-Meier graphs of three major positive cardiovascular prevention trials (PROVE-IT, LIFE and HOPE) were captured from the PDF images of the article and then digitalized. We calculated the difference between the placebo and active treatment curves and plotted it as a function of time to describe the event-free time gain ( Time-Gain ) produced by the active treatment. By calculating the exposure to the active treatment in terms of months (MoT) as a function of time and dividing it for the corresponding time-dependent number of event-free years gained (i.e. months/12), we described the kinetics of the pharmaco-economic index MoT/y + . The same procedure was repeated replacing MoT with the actual number of patients being treated at each time point as a function of time to obtain the NNT to gain 1 event-free year (NNT/y + ) curve. Results The Time-Gain curves depict the kinetics of the treatment-related effect over time and possess the peculiar feature of being smooth and accurately fitted by second-order polynomial functions ( a *time 2 + b *time); similarly, also the MoT/y + and NNT/y + curves can be accurately fitted by power functions ( a *time b ). These curves and indices allow to fully appreciate the quantitative and qualitative heterogeneity, both in terms of effects and costs, of the different therapeutic strategies adopted in the three trials. Conclusions With our novel method, by exploiting original Kaplan-Meier curves from three major clinical trials on cardiovascular prevention, we generate new information on the actual consequences of choosing a therapeutic strategy vs another, thus ultimately providing the clinical gain in terms of time-dependent functions. Accurately assessing clinically and economic meaningful results from any intervention trial reporting positive results through this approach, facilitates objective comparisons and increases reliability in predicting survival among the various therapeutic options provided. Trial registration PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy (TIMI22), Clinical trial registration number: NCT00382460 , date of registration: September 29, 2006, study start date: November 2000). LIFE (Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study, Clinical trial registration number: NCT00338260 , date of registration: June 20, 2006, study start date: June 1995). HOPE (Heart Outcomes Prevention Evaluation; we could not find Clinical trial registration number and date of registration).
Mengozzi et al. (Fri,) conducted a other in Cardiovascular prevention. PISA (Pragmatic Interpretation of Survival Analysis) method vs. Standard hazard ratio and NNT presentation was evaluated on Event-free time gain (Time-Gain). The novel PISA method reconstructs the time-dependent relationship between exposure and benefit from Kaplan-Meier curves to quantify event-free time gained and pharmaco-economic indices.