Economic evaluations of a pharmacogenomics test for Statin-induced myopathy in secondary cardiovascular prevention

Statins are the mainstay of treatment for dyslipidemia. Statin-induced myopathies are thought to be a major cause of patients discontinuing statin treatment. Myopathy diagnoses are based on creatine kinase (CK) elevation, which is compared to age-gender specific CK upper limit of normal values. Studies have shown, however, reference CK values are not representative of all population subgroups. Thus, CK tests have limited diagnostic capacity due to poor internal validity and limited external validity. A pharmacogenomics (PGx) test for statin-induced myopathies is in development for patients who have initiated statin therapy and who have mild to moderate CK elevation. We conducted economic evaluations of this hypothetical PGx test using two modelling techniques: a Markov health state model and a discrete event simulation (DES) model. We evaluated the economic models with a lifetime horizon from the Canadian payer perspective for high cardiovascular (CV) risk patients initiating a statin in secondary prevention. We found that even more important than the choice of modelling technique when evaluating the economic value of diagnostic tools, was the assessment of the diagnostic test false-positive and false-negative results. In this thesis, we have proposed an approach for interpreting diagnostic test results broadly such that physician and patient behaviours are akin to test errors. This definition addresses the clinical utility of the test in influencing physician prescribing recommendations and, importantly, patient decisions to adhere to therapy. This point is especially true for preventive medications, such as statins where the long-term benefits of therapy depend on patient adherence. Articles I and II present the model results from the Markov health state model and the DES model. We found that, although the Markov and DES model results differed slightly, the qualitative model results were in agreement. A PGx test for statin-induced myopathy was cost-effective at a relatively low willingness-to-pay (WTP). In the probabilistic sensitivity analyses, the Markov and DES strategies were favoured in at least 90% of the model simulations with a payer WTP as low as $6,150 and $12,000 per quality-adjusted life year, respectively. Article III was a reflection on the implications of model results presented in Articles I and II. Articles I and II highlighted that a totally inaccurate PGx test (i.e., false-positive rate [FPR] = false-negative rate [FNR] = 100%) would yield a positive incremental net monetary benefit for the payers. This result is explained by the risk imbalance between the benefit in reduction of CV events for patients suffering from mild to moderate myopathy compared to the extremely low risk of rhabdomyolysis. Although the totally inaccurate test result helped us understand the consequences of test errors, we recognize that a PGx test that is completely inaccurate, is not a plausible solution. The PGx test must be clinically valid and account for long-term physician and patient behavioural responses to the test results. As we have argued, the economic value of the PGx test for statin-induced myopathy in high CV risk patients depends on its ability to influence lifetime adherence to statin therapy.  Overall, this thesis highlights the importance of assessing the economic consequences of test errors. The assessment of test errors should not be limited to an a priori supposition of test performance parameters. The complete range of FPR and FNR test values should be investigated to fully understand the economic consequences of diagnostic tests. This is even more important when the diagnostic test is used to prescribe a long-term preventive medication.

Keyphrases: Markov, Myopathie, Pharmacoeconomics, Pharmacogenomics test, Discrete event simulation, Secondary cardiovascular prevention, Dyslipidemia, Statins, Myopathy