Comparative Effectiveness Research (CER) Warning—Using Observational Studies to Draw Conclusions About Effectiveness May Give You The Wrong Answer
Case Study: Losartan

This past week we saw five CER studies—all observational. Can we trust the results of these studies? The following is a case study that helps answer that question:

Numerous clinical trials have reported decreased mortality in heart failure patients treated with ARBs, but no head-to-head randomized trials have compared individual ARBs. In 2007, an administrative database study comparing various ARBs concluded that, “elderly patients with heart failure who were prescribed losartan had worse survival rates compared with those prescribed other commonly used ARBs.”[1] This study used hospital discharge data and information from physician claims and pharmacy databases to construct an observational study. The information on prescriptions included type of drug, dose category, frequency and duration. The authors used several methods to estimate adherence.

Unadjusted mortality for users of each ARB was calculated by using Kaplan-Meier curves. To account for differences in follow-up and to control for differences among patient characteristics, a multivariable Cox proportional hazards model was used.

The main outcome was time to all-cause death in patients with heart failure who were prescribed losartan, valsartan, irbesartan, candesartan or telmisartan. Losartan was the most frequently prescribed ARB (61% of patients). Other ARBs included irbesartan (14%), valsartan (13%), candesartan (10%) and telmisartan (2%). In this scenario, losartan loses. Using losartan as the reference, adjusted hazard ratios (HRs) for mortality among the 6876 patients were 0.63 (95% confidence interval [CI] 0.51 to 0.79) for patients who filled a prescription for valsartan, 0.65 (95% CI 0.53 to 0.79) for irbesartan, and 0.71 (95% CI 0.57 to 0.90) for candesartan. Compared with losartan, adjusted HR for patients prescribed telmisartan was 0.92 (95% CI 0.55 to 1.54). Being at or above the target dose was a predictor of survival (adjusted HR 0.72, 95% CI 0.63 to 0.83).

The authors of this observational study point out that head-to-head comparisons are unlikely to be undertaken in trial settings because of the enormous size and expense that such comparative trials of survival would entail. They state that their results represent the best available evidence that some ARBs may be more effective in increasing the survival rate than others and that their results should be useful to guide clinicians in their choice of drugs to treat patients with heart failure.

In 2011, a retrospective analysis of the Swedish Heart Failure Registry reported a survival benefit of candesartan over losartan in patients with heart failure (HF) at 1 and 5 years.[2] Survival by ARB agent was analyzed by Kaplan-Meier estimates and predictors of survival were determined by univariate and multivariate proportional hazard regression models, with and without adjustment for propensity scores and interactions. Stratified analyses and quantification of residual confounding analyses were also performed. In this scenario, losartan loses again. One-year survival was 90% (95% confidence interval [CI] 89% to 91%) for patients receiving candesartan and 83% (95% CI 81% to 84%) for patients receiving losartan, and 5-year survival was 61% (95% CI 54% to 68%) and 44% (95% CI 41% to 48%), respectively (log-rank P<.001). In multivariate analysis with adjustment for propensity scores, the hazard ratio for mortality for losartan compared with candesartan was 1.43 (95% CI 1.23 to 1.65, P<.001). The results persisted in stratified analyses.

But wait!

In March 2012, a nationwide Danish registry–based cohort study, linking individual-level information on patients aged 45 years and older reported all-cause mortality in users of losartan and candesartan.[3] Cox proportional hazards regression were used to compare outcomes. In 4,397 users of losartan, 1,212 deaths occurred during 11,347 person years of follow-up (unadjusted incidence rate [IR]/100 person-years, 10.7; 95% CI 10.1 to 11.3) compared with 330 deaths during 3,675 person-years among 2,082 users of candesartan (unadjusted IR/100 person-years, 9.0; 95% CI 8.1 to 10.0). Compared with candesartan, losartan was not associated with increased all-cause mortality (adjusted hazard ratio [HR] 1.10; 95% CI 0.9 to 1.25) or cardiovascular mortality (adjusted HR 1.14; 95% CI 0.96-1.36). Compared with high doses of candesartan (16-32 mg), low-dose (12.5 mg) and medium-dose losartan (50 mg) were associated with increased mortality (HR 2.79; 95% CI 2.19 to 3.55 and HR 1.39; 95% CI 1.11 to 1.73, respectively) but use of high-dose losartan (100 mg) was similar in risk (HR 0.71; 95% CI 0.50 to 1.00).

Another small cohort study found no difference in all-cause mortality between 4 different ARBs, including candesartan and losartan.[4] Can we tell who is the winner and who is the loser? It is impossible to know. Different results are likely to be due to different populations (different co-morbidities/prognostic variables), dosages of ARBs, co-interventions, analytic methods, etc. Svanström et al point out that, unlike the study by Eklind-Cervenka, they were able to include a wide range of comorbidities (including noncardiovascular disease), co-medications and health status markers in order to better account for baseline treatment group differences with respect to frailty and general health. As an alternative explanation they state that, given that their findings stem from observational data, their results could be due to unmeasured confounding because of frailty (e.g., patients with frailty and advanced heart failure tolerating only low doses of losartan and because of the severity of heart failure being more likely to die than patients who tolerate high candesartan doses). The higher average relative dose among candesartan users may have led to an overestimation of the overall comparative effectiveness of candesartan.

Our position is that, without randomization, investigators cannot be sure that their adjustments (e.g., use of propensity scoring and modeling) will eliminate selection bias. Adjustments can only account for the factors that can be measured, that have been measured and only as well as the instruments can measure them. Other problems in observational studies include drug dosages and other care experiences which cannot be reliably adjusted (performance and assessment bias).

Get ready for more observational studies claiming to show comparative differences between interventions. But remember, even the best observational studies may have only about a 20% chance of telling you the truth.[5]

References

1. Hudson M, Humphries K, Tu JV, Behlouli H, Sheppard R, Pilote L. Angiotensin II receptor blockers for the treatment of heart failure: a class effect? Pharmacotherapy. 2007 Apr;27(4):526-34. PubMed PMID: 17381379.

2. Eklind-Cervenka M, Benson L, Dahlström U, Edner M, Rosenqvist M, Lund LH. Association of candesartan vs losartan with all-cause mortality in patients with heart failure. JAMA. 2011 Jan 12;305(2):175-82. PubMed PMID: 21224459.

3. Svanström H, Pasternak B, Hviid A. Association of treatment with losartan vs candesartan and mortality among patients with heart failure. JAMA. 2012 Apr 11;307(14):1506-12. PubMed PMID: 22496265.

4. Desai RJ, Ashton CM, Deswal A, et al. Comparative effectiveness of individual angiotensin receptor blockers on risk of mortality in patients with chronic heart failure [published online ahead of print July 22, 2011]. Pharmacoepidemiol Drug Saf. doi: 10.1002/pds.2175.

5. Ioannidis JPA. Why Most Published Research Findings are False. PLoS Med 2005; 2(8):696-701. PMID: 16060722