Design and analysis strategies to assess the effectiveness of long-term drug therapies

2. Design and analysis strategies to assess the effectiveness of long-term drug therapies Mirko Di Martino Rome, October 15th - 16th, 2012

3. The randomized controlled trial design The randomized controlled trial (RCT) design is essential to evaluate the efficacy of medications and to obtain regulatory approval for their use in clinical practice. 1) Yet, it rarely provides information on their pragmatic benefit in routine care. 2) In some cases, very important RCTs have not allowed to fill certain gray areas. The TORCH study is an emblematic example. This RCT was one of the largest and longest trials of pharmacotherapy in patients with chronic obstructive pulmonary disease (COPD). However, no definitive conclusions can yet be drawn on whether inhaled corticosteroids (ICS) has an effect on mortality.

4. The explosion in observational studies A large number of observational studies have been conducted in an attempt to fill this gap by assessing long-term effects of medications on infrequent outcomes. However, observational studies can be misleading.

5. Are observational studies reliable? In 2008 Samy Suissa identified 20 observational studies on the effects of commonly prescribed drugs that were subject to immortal time bias. At the end of the nineties, findings from non randomized studies influenced millions of women to use hormone replacement therapy for the presumed cardiac benefits. Healthy drug user effect and chronology bias (prevalent users) have greatly contributed to this illusion.

6. Objectives Our goal is to critically explore the potential and limits of non-experimental research, comparing different design and analysis strategies. The methods will be developed within the framework of the OUTPUL study to assess the benefits of inhaled corticosteroids in reducing mortality among Chronic Obstructive Pulmonary Disease (COPD) patients.

7. The study population We enrolled more than 21,000 patients, aged 45 or more, resident in two Italian regions (Lazio and Emilia-Romagna; data of Lombardia will be available soon), discharged from hospital with diagnosis of COPD between January 1st 2006 and December 31st 2009 and prescribed with respiratory drugs no later than six months after discharge.

8. The study design: the “two step” enrollment Six months after discharge Time Index prescription for respiratory drugs. The beginning of follow-up. First COPD hospital discharge during the enrollment period We considered an equal follow-up time per subject of one year.

9. Drug exposure and outcome We dynamically evaluated prescriptions of long-acting beta-agonists (LABA), tiotropium, inhaled corticosteroids (ICS) and other respiratory drugs. Prescription patterns were classified as follows. • ICS monotherapy • Long acting bronchodilators without ICS (LABA and/or tiotropium) • Long acting bronchodilators plus ICS • Other respiratory drugs (No ICS, no LABA, no tiotropium) The outcome was mortality from all causes.

10. Patient characteristics Patients were characterized according to socio-demographic factors (age, gender, educational level and area of residence), COPD severity (hospitalizations for COPD, diagnosis of respiratory failure, invasive respiratory procedures, staying in intensive care unit during a COPD hospitalization, emergency visits for COPD and use of oxygen), concomitant respiratory diseases (asthma, chronic respiratory disease other than COPD, pulmonary infections and acute pulmonary symptoms), previous use of respiratory drugs, previous use of oral corticosteroids and antibacterials, previous use of non-respiratory drugs and comorbidities (more than 20 conditions such as diabetes, hypertension or heart failure).

11. Estimation of the treatment effectiveness • Patients may use drugs very irregularly, medication patterns may contain a plethora of different drugs, doses and switching between treatments. • Several solutions are under evaluation: • cohort study using the censoring at switching approach; • longitudinal study using time-varying determinants; • longitudinal study using marginal structural models; • incidence density nested case-control design; • self-controlled designs; • new-user designs.

12. The censoring at switching approach We censored patients at switching or discontinuation and kept the person-time follow-up until the time of censoring. Prescription coverages were estimated on the basis of the Defined Daily Doses. Grace Time (7 days) CENSORING AT SWITCHING Prescription Coverage ICS ICS LABA Grace Time (7 days) Prescription Coverage CENSORING AT DISCONTINUATION ICS ICS ICS

13. The trade-off between “power” and validity * The new user designrequires the exclusion of patients with any filled prescription of respiratory drugs in the six months prior to the index prescription. The use of respiratory drugs in clinical practice is characterized by frequent changes in therapy and discontinuation. Therefore, the censoring at switching approach largely reduces the amount of events and person-years. The new user design further reduces the study population.

14. Censoring at switching and new user design: preliminary results (1)

15. Censoring at switching and new user design: preliminary results (2)

16. Censoring at switching: key points If preceded by an appropriate washout period, the censoring at switching design is free from carryover effect, and should provide an “independent” estimate of the relationship between treatment and outcome. However, it is necessary a careful evaluation of the balance between the “validity” of the study and the loss in follow-up time. The length of the grace time plays a central role. Moreover, there is a concern whether an excessive amount of these censorings carries information for patients' prognosis (informative censoring). Multiple propensity score could improve the control of confounding.

17. Critical aspects of the other methods Longitudinal study using time-varying determinants. Such estimates may be biased in the presence of time-dependent confounders which are themselves affected by prior exposure. Longitudinal study using Marginal Structural Models. This method can adjust for time-varying confounders affected by prior exposure. However, will be necessary to verify a) the plausibility of the assumption of no unmeasured confounding and b) the applicability of such a complex model in patients whose medication patterns are characterized by such a high switching rate. Self-controlled design. These designs are generally used to study short transient exposures and acute effects. Therefore, there are concerns whether self-matched designs may be applied to study long-term effects of chronic treatments.

18. Future prospects We think that a critical comparison between these methods will contribute to identify optimal strategies to assess the effectiveness of long-term therapies and will provide important elements on the real potential of observational studies in clinical research. Be careful about reading health books. You may die of a misprint. Mark Twain

19. Mirko Di Martino Department of Epidemiology, Lazio Regional Health Service. Via di Santa Costanza, 53 00198 Roma, Italy. E-mail: m.dimartino@deplazio.it