Outcomes3 The health outcomes upon which the comparative clinical performance of molecular testing for LQTS (in addition, or as a triage for the current diagnostic approaches for LQTS), versus the comparator of current LQTS diagnostic approaches alone, will be measured are: Effectiven ess Primary (patient relevant) • mortality/survival • incidence of life-threatening events, ie. cardiac arrest • quality of life Secondary • incidence of symptoms, including arrhythmia (eg tachycardia), length of the patient’s QTc in milliseconds, torsade de pointes (TdP), T-wave alternans, notched T wave in 3 leads, low heart rate for age, ventricular fibrillation and syncope • patient anxiety • age at diagnosis Safety • psychological and physical harms from testing Summary of PICO to be used for assessment of evidence (systematic review) 7 provides a summary of the PICO used to: (1) define the question for public funding, (2) select the evidence to assess the safety and effectiveness of molecular testing for LQTS, and (3) provide the evidence-based inputs for any decision-analytic modelling to determine the cost-effectiveness of molecular testing for LQTS. The methodology for undertaking this assessment of molecular testing in the diagnosis of LQTS is outlined in detail in the "Assessment methodology" section of the protocol. 3 These will be assessed in the event that there is direct evidence of the effect of molecular testing on health outcomes (eg randomised controlled trials or intervention studies). In the absence of this evidence, a linked evidence approach will be used – the PICO criteria that are relevant to this type of evidence are given in Appendix A.
Proposed structure of economic evaluation (decision-analytic) The extended PICO to be used for the economic evaluation are provided in Table 10. Table 10 Summary of extended PICO to define research questions that economic evaluation will investigate Patients Intervention Comparator Outcomes to be assessed Healthcare resources to be considered Patients suspected of having long QT syndrome, who are classified as intermediate or high risk (Schwartz score ≥3) ECG (Schwartz score) ± exercise stress test ± Holter monitoring plus molecular genetic testing for LQTS ECG (Schwartz score) ± exercise stress test ± Holter monitoring Effectiveness: Direct evidence Primary outcomes – Mortality/survival; quality of life; incidence of life- threatening events including cardiac arrest and ventricular fibrillation. Linked evidence see Table 9 Clinically unaffected relatives of a patient with a known long QT syndrome Molecular genetic testing for LQTS ± ECG (Schwartz ± exercise stress test ± Holter monitoring ECG (Schwartz score) ± exercise stress test ± Holter monitoring Effectiveness: Direct evidence Primary outcomes – Mortality/survival; quality of life; incidence of life- threatening events including cardiac arrest and ventricular fibrillation. Linked evidence see 9 Research Questions 1. Is molecular testing for the genetic mutations associated with LQTS cost-effective when used in addition to clinical diagnostic approaches in the diagnosis of patients presenting with symptoms suggestive of long QT syndrome? 2. Is molecular testing for the genetic mutations associated with LQTS cost- effective when used as a triage for clinical assessment, treatment and life-long monitoring of family members of patients who are known to have LQTS? Two main analyses will be performed, assessing: 1) the consequences of adding the genetic test into clinical practice for the proband (index case) alone (diagnostic setting; Figure 3); and 2) the consequences of using the genetic test for both the proband and their family members (predictive setting; Figure 4). A stepped analysis will be performed to determine whether the genetic test is cost-effective when restricted to index cases and first degree relatives alone, and subsequently, if it is cost-effective when broadened to the index case plus first and second degree relatives.
Table 21 Inclusion criteria for identification of studies relevant to assessment of a change in patient management as a result of molecular testing for long QT syndrome (family members) Characteristic Criteria design Randomised or non-randomised controlled trials or cohort studies, uncontrolled case series, or systematic reviews of these study designs Population Patients with a relative with a known LQTS mutation Intervention/test Molecular testing for clinical relevant mutations, ie KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1 or SCN5A mutations + ECG (Schwartz score) ± exercise stress test and Holter monitoring Comparator ECG (Schwartz score) ± exercise stress test and Holter monitoring Outcome of treatment, method of treatment, rates of referral, type of referral, rate of hospitalisation, rates of consultation Search period 1991 – May 2011 Language Non-English language articles will be excluded unless they appear to provide a higher of evidence than the English language articles identified Broad inclusion criteria for studies assessing the health impact of a change in patient management in family members is outlined in Table 22. Targeted treatment with potassium supplementation or sodium channel blockers would be assessed using the inclusion criteria outlined in Table 18 and Table 19. In the proposed pathway, some family members will be ruled out of having a pathogenic mutation. They therefore may avoid the need for prophylactic treatment and lifelong surveillance. Table 23 outlines the inclusion criteria for assessing the health impact of no treatment versus treatment within the population with no pathogenic mutation. However, it would be unethical to treat asymptomatic family members who are known to be free from a pathogenic mutation. Studies meeting the PICO criteria in Table 23 are therefore unlikely to exist, unless they provide retrospective data, ie evaluating treatment prior to knowledge of mutation status.