Cost-utility of Ranolazine for Chronic Stable Angina Pectoris: Systematic Review and Meta-analysis.

PURPOSE: Ranolazine is used to treat stable angina pectoris, the most common symptom of ischemic heart disease. Appropriate management of chronic stable angina pectoris is essential from both a clinical and an economic view point. METHODS: This systematic review and meta-analysis adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included cost-utility analyses, which compared ranolazine with other standard treatments for treating stable angina pectoris. The search was conducted in PubMed, EMBASE, and Scopus databases. A random-effects model based on the DerSimonian and Laird method was used to pool the incremental net benefit reported in purchasing power parity adjusted US dollars. The modified economic evaluation checklist was used to assess the risk of bias. FINDINGS: The pooled results from 7 selected studies with a time horizon of 1 year show that add-on ranolazine was significantly cost-effective compared with standard treatment, with a pooled incremental net benefit of US$1335 (95% CI, 500 to 2169) but with substantial heterogeneity (I2 = 79.46%). On subgroup analysis, ranolazine was cost-effective from the payers' perspective (US$1975; 95% CI, 1042 to 2908; I2 = 69.23) but not from a societal perspective (US$297; 95% CI, -241 to 715; I2 = 0%)]. There was limited evidence from lower economies. IMPLICATIONS: Pooled evidence suggests that add-on ranolazine therapy is cost-effective for chronic stable angina pectoris up to a 1-year time horizon. There is a lacuna of evidence from low- and middle-income countries and on long-term cost-effectiveness. The current evidence synthesis may provide a macroeconomic point of view for policy makers regarding the direction of ranolazine's cost-effectiveness for evidence-informed policy-making. PROSPERO identifier: CRD42022332454.

Proarrhythmia Risk Assessment Using Electro-Mechanical Window in Human iPS Cell-Derived Cardiomyocytes.

Evaluation of drug-induced cardiotoxicity is still challenging to avoid adverse effects, such as torsade de pointes (TdP), in non-clinical and clinical studies. Numerous studies have suggested that human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a useful platform for detecting drug-induced TdP risks. Comprehensive in vitro Proarrhythmia Assay (CiPA) validation study suggested that hiPSC-CMs can assess clinical TdP risk more accurately than the human ether-a-go-go-related assay and QT interval prolongation. However, there were still some outliers, such as bepridil, mexiletine, and ranolazine, among the CiPA 28 compounds in the CiPA international multi-site study using hiPSC-CMs. In this study, we assessed the effects of the positive compound dofetilide, the negative compound aspirin, and several CiPA compounds (bepridil, mexiletine, and ranolazine) on the electromechanical window (E-M window), which were evaluated using multi-electrode array assay and motion analysis, in hiPSC-CMs. Similar to previous in vivo studies, dofetilide, which has a high TdP risk, decreased the E-M window in hiPSC-CMs, whereas aspirin, which has a low TdP risk, had little effect. Bepridil, classified in the high TdP-risk group in CiPA, decreased the E-M window in hiPSC-CMs, whereas ranolazine and mexiletine, which are classified in the low TdP-risk group in CiPA, slightly decreased or had little effect on the E-M window of hiPSC-CMs. Thus, the E-M window in hiPSC-CMs can be used to classify drugs into high and low TdP risk.

Microvascular Assessment of Ranolazine in Non-Obstructive Atherosclerosis: The MARINA Randomized, Double-Blinded, Controlled Pilot Trial.

BACKGROUND: Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease. METHODS: In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (<50% stenosis by angiography and fractional flow reserve >0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed. RESULTS: No significant differences in ΔSAQ angina frequency scores (P=0.53) or Duke Activity Status Index (P=0.76) were observed between ranolazine versus placebo, although patients on ranolazine had lesser improvement in SAQ physical limitation scores (P=0.02) compared with placebo at 3 months. There were no significant differences in ΔCFR or Δhyperemic myocardial resistance between ranolazine and placebo groups. Patients treated with ranolazine, compared with placebo, had no significant improvement in maximum rate of oxygen consumption measured during incremental exercise (VO2 max) and peak metabolic equivalents of task. Interestingly, in the ranolazine group, patients with baseline CFR<2.0 demonstrated greater gain in CFR compared with those with baseline CFR≥2.0 (P=0.02). CONCLUSIONS: Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02147067.

Long-Term (3 Years) Outcomes of Ranolazine Therapy for Refractory Angina Pectoris (from the Ranolazine Refractory Registry).

Ranolazine is approved for patients with chronic stable angina but has not been formally studied in patients with refractory angina pectoris (RAP). Patients with RAP have limited therapeutic options and significant limitations in their quality of life. The Ranolazine Refractory Angina Registry was designed to evaluate the safety, tolerability, and effectiveness of ranolazine in RAP patients in order to expand treatment options for this challenging patient population. Using an extensive prospective database, we enrolled 158 consecutive patients evaluated in a dedicated RAP clinic. Angina class, medications, major adverse cardiac events including death, myocardial infarction, and revascularization were obtained at 12, 24, and 36 months. At 3 years, 95 (60%) patients remained on ranolazine. A ≥2 class improvement in angina was seen in 48% (38 of 80 patients with known Canadian Cardiovascular Society class) of those who remained on ranolazine. Discontinuation due to side effects, ineffectiveness, cost, and progression of disease were the principle reasons for discontinuation, but primarily occurred within the first year. In conclusion, ranolazine is an effective antianginal therapy at 3-year follow-up in patients with RAP and may reduce cardiac readmission.

Revascularization Rates and Associated Costs in Patients With Stable Ischemic Heart Disease Initiating Ranolazine Versus Traditional Antianginals as Add-on Therapy.

To assess the frequency and costs of revascularization procedures in patients with stable ischemic heart disease (SIHD) initiating ranolazine versus traditional antianginals. Adults (≥18 years) with a diagnosis of SIHD who initiated ranolazine or a traditional antianginal (beta-blocker [BB], calcium channel blocker [CCB], or long-acting nitrate [LAN]) as second or third line therapy between 2008 and 2016, were selected from the IBM MarketScan Databases. Inverse probability weighting based on propensity score was employed to balance the ranolazine and traditional antianginals cohorts on patient clinical characteristics. Outcomes assessed were frequency and total cost of revascularization procedures over a 12-month follow-up. A total of 108,741 patients with SIHD were included. Of these, 18% initiated treatment with ranolazine, 21% received BBs, 24% received CCBs, and 37% were treated with LANs. Revascularization rates were significantly lower in ranolazine patients (11%) than in BB (16%) and LAN (14%) patients (both p <0.001), and more comparable to CCB patients (10%; p = 0.007). Compared with BB and LAN, those in the ranolazine cohort were less likely to have a revascularization procedure during hospitalization and had a shorter length of stay if hospitalized (all p <0.001). The mean healthcare costs associated with revascularization were lower in ranolazine patients ($2,933) than in BB ($4,465) and LAN ($3,609) patients (p <0.001), but similar to CCB patients ($2,753; p = 0.29). In conclusion, ranolazine treatment in patients with SIHD was associated with fewer revascularization procedures and lower associated healthcare costs compared with patients initiating BB or LAN, and comparable to patients initiating CCBs.

Clinical and Economic Outcomes of Ranolazine Versus Conventional Antianginals Users Among Veterans With Chronic Stable Angina Pectoris.

Real-world outcomes in patients with chronic stable angina treated with ranolazine and other antianginal medications as second- or third-line therapy are limited. In a historical cohort study of veterans with chronic stable angina, we compared time with coronary revascularization procedures, hospitalizations, and 1-year healthcare costs between new-users of ranolazine versus conventional antianginals (i.e., calcium channel blockers, ß blockers, or long-acting nitrates) as second- or third-line. Weighted regression models calculated adjusted hazard ratios (HR) at up to 8-year follow-up, and adjusted incremental costs in the first year. Weighted groups comprised 4,699 ranolazine users and 31,815 conventional antianginal users. Percutaneous coronary intervention (PCI) occurred more often in ranolazine users compared with conventional antianginal users (HR 1.16; 95% confidence intervals [CI] 1.08 to 1.25, p <0.001), and coronary artery bypass grafting occurred less often (HR 0.82; 95% CI 0.68 to 1.00, p <0.046). All-cause and atrial fibrillation (AF) hospitalizations were less common with ranolazine users compared with conventional users (all-cause: HR 0.94; 95% CI 0.90 to 0.99, p <0.010; AF:HR 0.74; 95% CI 0.67 to 0.82, p <0.001), and acute coronary syndrome was more common (HR 1.13; 95% CI 1.00 to 1.27, p <0.042). Adjusted 1-year costs were $24,517 in ranolazine users and $24,798 in conventional users (difference, $-280; 95% CI $-1,742 to $1,181, p = 0.71). In conclusion, ranolazine users had lower rates of coronary artery bypass grafting and all-cause and AF hospitalizations, but higher rates of percutaneous coronary intervention and hospitalizations due to acute coronary syndrome compared with conventional antianginal users. Healthcare costs were similar between ranolazine and conventional antianginal users.

Ranolazine in patients with type 2 diabetes and chronic angina: A cost-effectiveness analysis and assessment of health-related quality-of-life.

BACKGROUND: Type 2 diabetes (T2D) is associated with a high burden of angina. Ranolazine has been shown to reduce angina frequency versus placebo in patients with T2D and stable angina. We sought to estimate the cost-effectiveness of ranolazine when added to standard-of-care (SoC) versus SoC alone in patients with T2D and stable, but symptomatic coronary disease despite treatment with 1-2 antianginals. METHODS: A Markov model was developed and evaluated using cohort simulation. The model utilized a US societal perspective, 1-month cycle length and 1-year time horizon and was developed to estimate the cost-effectiveness of ranolazine versus SoC. Patients entered the model in 1 of 4 angina frequency health states based on baseline Seattle Angina Questionnaire Angina Frequency scores (100 = no; 61-99 = monthly; 31-60 = weekly; 0-30 = daily) and could transition between health states (first cycle only) or to death (any cycle) based on probabilities derived from the Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina trial. RESULTS: Our model estimated patients treated with ranolazine lived a mean of 0.728 quality adjusted life years (QALYs) at a cost of $16,654. Those not receiving ranolazine lived a mean of 0.702 QALYs and incurred costs of $15,476. The incremental cost-effectiveness ratio for the addition of ranolazine to SoC was $45,308/QALY. Short Form-36 data suggest improvements in patients' bodily pain drove the gain in QALYs associated with ranolazine (2.73 versus 3.96, p = 0.01). CONCLUSION: Our model suggests the addition of ranolazine to SoC is likely cost-effective from a US societal perspective for the treatment of patients with T2D and stable, symptomatic coronary disease despite treatment with 1-2 antianginals.

The J to T-peak interval as a biomarker in drug safety studies: A method of accuracy assessment applied to two algorithms.

OBJECTIVES: To evaluate performance of J-to-T-peak (JTP) measurements of 12-lead ECGs, in a five-arm study using drugs with various levels of electrolyte channel block. METHODS: The novel evaluation method distinguishes between different aspects of measurement. "Random noise" is the variability among repeated measurements made without changing the conditions. "Context noise" is the variability of changes in context of the measurement, e.g. T-wave morphology, autonomic nervous system state. RESULTS: The average random noise of our RR-corrected JTPc measurements in standard deviations was 3.0 ms and not dependent on the drug. The average context noise was 4.0 ms for ranolazine, verapamil, and placebo, and 8.8 ms for dofetilide and quinidine. Measurement consistency is corroborated by linear fit confidence intervals of baseline- and placebo-corrected JTPc versus drug concentration. CONCLUSIONS: Systematic differences were found in JTPc drug response between the Mortara method and published data. Residual signal component in the context noise may influence future study design.

Use of Antiarrhythmic Medications in Medicare Part D Patients With an Implantable Cardioverter-Defibrillator and Ventricular Tachycardia.

Ventricular tachycardia (VT) is common in cardiomyopathy patients with an implantable cardioverter-defibrillator. This analysis evaluated antiarrhythmic medication use and change in use over time in patients with VT and structural heart disease. Query of Medicare claims identified patients with an implantable cardioverter-defibrillator and VT. Patients with atrial fibrillation or supraventricular tachycardia were excluded. Two cohorts were created of patients enrolled in Medicare Part D for the 12 months before 2007 and 2012. Patients were identified through a search for antiarrhythmic medication fills with a supply covering January 1 of the cohort year. Adjusted logistic regression modeling evaluated the association between patient characteristics and antiarrhythmic medication use. The 2007 (n = 2,334) and 2012 (n = 3,892) Medicare Part D cohorts had similar demographics: median age 76 years, 64%-67% male, and 87%-89% white. Of the 2007 cohort, 1,380 (59%) patients were on a beta blocker, and 484 (20.7%) were on an antiarrhythmic medication (70% amiodarone and 20% sotalol). Between 2007 and 2012, there was a statistically significant higher use of any antiarrhythmic medication (p = 0.014), beta blockers (p <0.0001), mexiletine (p = 0.005), and ranolazine (p <0.0001), while amiodarone use remained unchanged (p = 0.53). After multivariable adjustment, male gender and renal disease were associated with higher antiarrhythmic medication use. In conclusion, although antiarrhythmic medication and beta blocker use in patients with VT increased over time, <1 in 4 patients were on an antiarrhythmic medication and only 65% of the patients were on a beta blocker.

A literature review to evaluate the economic value of ranolazine for the symptomatic treatment of chronic angina pectoris.

To conduct a systematic review of the evidence regarding the economic value of ranolazine relative to standard-of-care (SOC) for the treatment of symptomatic chronic stable angina (CSA). Electronic databases were searched using relevant keywords. The identified studies were independently reviewed by two investigators against pre-determined inclusion and exclusion criteria. Their data were extracted using a relevant form and consequently were synthesized. Studies were also evaluated using the Quality of Health Economic Studies scale. The main outcomes considered were the cost and effectiveness for each comparator and the incremental cost per quality-adjusted-life year (QALY) gained. Six studies were included in the review. Five of these assessed the cost-utility of ranolazine added to SOC, compared to SOC alone, using decision trees or Markov models whereas one was a retrospective cost evaluation study. The analysis was conducted from a payer perspective in five studies and from a societal perspective in one study with the time horizon varying between six months and a year. The incremental cost-effectiveness ratio (ICER), ranged from €4000 to €15,000 per QALY gained. Ranolazine appears to be dominant or cost-effective, mainly due to its ability to decrease angina-related hospitalizations and also due to a marginal improvement in quality of life. The acquisition cost of ranolazine was the variable with the greatest impact upon the ICER. The existing evidence, although limited, indicates that ranolazine may be a dominant or cost-effective therapy option, for the treatment of patients with symptomatic CSA. Further research is required to evaluate the cost-effectiveness of ranolazine.

Ranolazine for the symptomatic treatment of patients with chronic angina pectoris in Greece: a cost-utility study.

BACKGROUND: To conduct an economic evaluation comparing ranolazine as add-on therapy to standard-of-care (SoC) with SoC alone in patients with stable angina who did not respond adequately to first line therapy, in Greece. METHODS: A decision tree model was locally adapted in the Greek setting to evaluate the cost-utility of ranolazine during a 6-month period. The analysis was conducted from a third-party payer perspective. The clinical inputs were extracted from the published literature. The cost inputs considered in the model reflect drug acquisition, hospitalizations, vascular interventions and monitoring of patients. The resource utilization data were obtained from 3 local experts. All costs refer to the year 2014. Cost-effectiveness was assessed by means of the incremental cost per quality adjusted life year (QALY) gained with the ranolazine as add-on therapy relative to SoC alone (ICER). Probabilistic sensitivity analysis (PSA) was performed. RESULTS: Ranolazine as add-on therapy was more costly compared to SoC alone, as the 6-month total cost per patient was €1170 and € 984, respectively. Patients received ranolazine plus SoC and SoC alone gained 0.3155 QALYs and 0.2752 QALYs, respectively. Ranolazine plus SoC resulted in an ICER equal to €4620 per QALY gained, well below the threshold of €34,000 per QALY gained. The PSA showed that the likelihood of ranolazine plus SoC being cost-effective at the threshold of €34,000 per QALY gained was 100 %. CONCLUSIONS: Τhe results suggest that ranolazine as add-on treatment may be a cost-effective alternative for the symptomatic treatment of patients with chronic stable angina in Greece.

Ranolazine for the treatment of chronic stable angina: a cost-effectiveness analysis from the UK perspective.

OBJECTIVES: To estimate the cost-effectiveness of ranolazine when added to standard-of-care (SoC) antianginals compared with SoC alone in patients with stable coronary disease experiencing ≥3 attacks/week. SETTING: An economic model utilising a UK health system perspective, a 1-month cycle-length and a 1-year time horizon. PARTICIPANTS: Patients with stable coronary disease experiencing ≥3 attacks/week starting in 1 of 4 angina frequency health states based on Seattle Angina Questionnaire Angina Frequency (SAQAF) scores (100=no; 61-99=monthly; 31-60=weekly; 0-30=daily angina). INTERVENTION: Ranolazine added to SoC or SoC alone. Patients were allowed to transition between SAQAF states (first cycle only) or death (any cycle) based on probabilities derived from the randomised, controlled Efficacy of Ranolazine in Chronic Angina trial and other studies. Patients not responding to ranolazine in month 1 (not improving ≥1 SAQAF health state) discontinued ranolazine and were assumed to behave like SoC patients. PRIMARY AND SECONDARY OUTCOMES MEASURES: Costs (£2014) and quality-adjusted life-years (QALYs) for patients receiving and not receiving ranolazine. RESULTS: Ranolazine patients lived a mean of 0.701 QALYs at a cost of £5208. Those not receiving ranolazine lived 0.662 QALYs at a cost of £5318. The addition of ranolazine to SoC was therefore a dominant economic strategy. The incremental cost-effectiveness ratio was sensitive to ranolazine cost; exceeding £20,000/QALY when ranolazine's cost was >£203/month. Ranolazine remained a dominant strategy when indirect costs were included and mortality rates were assumed to increase with worsening severity of SAQAF health states. Monte Carlo simulation found ranolazine to be a dominant strategy in ∼71% of 10,000 iterations. CONCLUSIONS: Although UK-specific data on ranolazine's efficacy and safety are lacking, our analysis suggest ranolazine added to SoC in patients with weekly or daily angina is likely cost-effective from a UK health system perspective.

Comparative Effectiveness of Ranolazine Versus Traditional Therapies in Chronic Stable Angina Pectoris and Concomitant Diabetes Mellitus and Impact on Health Care Resource Utilization and Cardiac Interventions.

Comparative studies evaluating traditional versus newer antianginal (AA) medications in chronic stable angina pectoris (CSA) on cardiovascular (CV) outcomes and utilization are limited, particularly in patients with diabetes mellitus (DM). Claims data (2008 to 2012) were analyzed using a commercial database. Patients with CSA receiving a ß blocker (BB), calcium channel blocker (CCB), long-acting nitrate (LAN), or ranolazine were identified and followed for 12 months after a change in AA therapy. Patients on traditional AA medications were required to have concurrent sublingual nitroglycerin. Therapy change was defined as adding or switching to another traditional AA medication or ranolazine to identify patients whose angina was inadequately controlled with previous therapy. Four groups were identified (BB, CCB, LAN, or ranolazine users) and matched on relevant characteristics. A DM subset was identified. Logistic regression compared revascularization at 30, 60, 90, 180, and 360 days. Negative binomial regression compared all-cause, CV-, and DM-related (in the DM cohort) health care utilization. A total of 8,008 patients were identified with 2,002 patients in each matched group. Majority were men (mean age 66 years). A subset of 3,724 patients with DM (BB, n = 933; CCB, n = 940; LAN, n = 937; and ranolazine, n = 914) resulted from this cohort. Compared to ranolazine in the overall cohort, traditional AA medication exhibited greater odds for revascularization and higher rates in all-cause outpatient, emergency room visits, inpatient length of stay, and CV-related emergency room visits. In the DM cohort, ranolazine demonstrated similar benefits over traditional AA medication. In conclusion, ranolazine use in patients with inadequately controlled chronic angina is associated with less revascularization and all-cause and CV-related health care utilization compared to traditional AA medication.

Comprehensive T wave morphology assessment in a randomized clinical study of dofetilide, quinidine, ranolazine, and verapamil.

BACKGROUND: Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology. METHODS AND RESULTS: Twenty-two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. At pre-dose and 15 time-points post-dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L-type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide). CONCLUSIONS: T wave morphology changes are directly related to amount of hERG block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with ECG intervals and T wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/ Unique identifier: NCT01873950.

Update on ranolazine in the management of angina.

Mortality rates attributable to coronary heart disease have declined in recent years, possibly related to changes in clinical presentation patterns and use of proven secondary prevention strategies. Chronic stable angina (CSA) remains prevalent, and the goal of treatment is control of symptoms and reduction in cardiovascular events. Ranolazine is a selective inhibitor of the late sodium current in myocytes with anti-ischemic and metabolic properties. It was approved by the US Food and Drug Administration in 2006 for use in patients with CSA. Multiple, randomized, placebo-controlled trials have shown that ranolazine improves functional capacity and decreases anginal episodes in CSA patients, despite a lack of a significant hemodynamic effect. Ranolazine did not improve cardiovascular mortality or affect incidence of myocardial infarction in the MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome)-TIMI (Thrombolysis In Myocardial Infarction) 36 trial, but significantly decreased the incidence of recurrent angina. More recently, ranolazine has been shown to have beneficial and potent antiarrhythmic effects, both on supraventricular and ventricular tachyarrhythmias, largely due to its inhibition of the late sodium current. Randomized controlled trials testing these effects are underway. Lastly, ranolazine appears to be cost-effective due to its ability to decrease angina-related hospitalizations and improve quality of life.

Impact of angina frequency on health utility values of patients with chronic stable angina.

BACKGROUND: Chronic angina is a profoundly symptomatic disease. We evaluated the relationship between angina frequency and health utility. METHODS: We used data from stable angina patients reporting ≥3 attacks/week enrolled in the Efficacy of Ranolazine in Chronic Angina (ERICA) trial. Angina frequency was classified using the Seattle Angina Questionnaire angina frequency (SAQAF) domain into no (100); monthly (61-99); weekly (31-60); and daily (0-30) angina. EuroQol (EQ)-5D health utility scores were derived from SAQ data using two mapping equations. Median EQ-5D utility scores for each SAQAF classification after the 6-week trial period were calculated (reported as: Equation 1/Equation 2). Changes in EQ-5D utility scores from baseline to end-of-trial for patients achieving and not achieving a ≥20-point improvement in SAQAF score and improving and not improving ≥1 SAQAF classification were compared. RESULTS: Median EQ-5D utility scores (n = 548) were 0.68/0.60. Compared to patients reporting no angina symptoms (n = 28; 0.89/0.87) patients reporting monthly (n = 188; 0.80/0.76), weekly (n = 283; 0.72/0.65) and daily (n = 49; 0.65/0.54) symptoms had poorer health utility (p < 0.001 for both equations). Patients improving ≥1SAQAF classification (n = 254/541, 47%) experienced a median 0.05/0.07 greater improvement in EQ-5D health utility compared to those not improving ≥1 classification (p < 0.001 for both equations). Patients improving ≥20-points on the SAQAF (n = 355/541, 66%) experienced a median 0.06/0.07 greater improvement in health utility compared to those not achieving a ≥20-point improvement (p < 0.001 for both). CONCLUSIONS: Chronic angina patient health utility decreases as angina frequency increases. Patients reporting clinically important improvement in angina frequency experience a tangible improvement in health utility. CLINICAL TRIAL REGISTRATION: NCT00091429.

Cost-effectiveness of ranolazine added to standard-of-care treatment in patients with chronic stable angina pectoris.

Ranolazine has been shown to decrease angina pectoris frequency and nitroglycerin consumption. We assessed the cost-effectiveness of ranolazine when added to standard-of-care (SoC) antianginals compared with SoC alone in patients with stable coronary disease experiencing ≥3 attacks/week. A Markov model utilizing a societal perspective, a 1-month cycle length, and a 1-year time horizon was developed to estimate costs (2013 US$) and quality-adjusted life years (QALYs) for patients receiving and not receiving ranolazine. Patients entered the model in 1 of the 4 angina frequency health states based upon Seattle Angina Questionnaire angina frequency (SAQAF) scores (100=no; 61 to 99=monthly; 31 to 60=weekly; and 0 to 30=daily angina) and were allowed to transition between states or to death based upon probabilities derived from the Efficacy of Ranolazine in Chronic Angina and other studies. Patients not responding to ranolazine in month 1 (not improving ≥1 SAQAF health state) were assumed to discontinue ranolazine and behave like SoC patients. Ranolazine patients lived a mean of 0.700 QALYs at a cost of $15,661. Those not receiving ranolazine lived 0.659 QALYs and at a cost of $14,321. The incremental cost-effectiveness ratio (ICER) for the addition of ranolazine was $32,682/QALY. The ICER was most sensitive to ranolazine cost but only exceeded $50,000/QALY when the cost of ranolazine increased >32% above base case. The ICER remained <$50,000/QALY when indirect costs were excluded, and mortality rates were assumed equivalent between SAQAF health states. Monte Carlo simulation found ranolazine cost-effective in 97% of 10,000 iterations at a $50,000/QALY willingness-to-pay threshold. In conclusion, ranolazine added to SoC is cost-effective in patients with weekly or daily angina.

Cost-utility of ranolazine for the symptomatic treatment of patients with chronic angina pectoris in Spain.

BACKGROUND: Ranolazine is an antianginal agent that was approved in the EU in 2008 as an add-on therapy for symptomatic chronic angina pectoris treatment in patients who are inadequately controlled by, or are intolerant to, first-line antianginal therapies. These patients' quality of life is significantly affected by more frequent angina events, which increase the risk of revascularization. OBJECTIVE: To assess the cost-utility of ranolazine versus placebo as an add-on therapy for the symptomatic treatment of patients with chronic angina pectoris in Spain. METHODS: A decision tree model with 1-year time horizon was designed. Transition probabilities and utility values for different angina frequencies were obtained from the literature. Costs were obtained from Spanish official DRGs for patients with chronic angina pectoris. We calculated the incremental cost-utility ratio of using ranolazine compared with a placebo. Sensitivity analyses, by means of Monte Carlo simulations, were performed. Acceptability curves and expected value of perfect information were calculated. RESULTS: The incremental cost-utility ratio was €8,455 per quality-adjusted life-year (QALY) per patient in Spain. Sensitivity analyses showed that if the decision makers' willingness to pay is €15,000 per QALY, the treatment with ranolazine will be cost effective at a 95 % level of confidence. The incremental cost-utility ratio is particularly sensitive to changes in utility values of those non-hospitalized patients with mild or moderate angina frequency. CONCLUSIONS: Ranolazine is a highly efficient add-on therapy for the symptomatic treatment of chronic angina pectoris in patients who are inadequately controlled by, or intolerant to, first-line antianginal therapies in Spain.

Ranolazine reduces neuronal excitability by interacting with inactivated states of brain sodium channels.

Ranolazine is an approved drug for chronic stable angina that acts by suppressing a noninactivating current conducted by the cardiac sodium channel [persistent sodium ion current (INa)]. Ranolazine has also been shown to inhibit the increased persistent INa carried by NaV1.1 channels encoding epilepsy- and migraine-associated mutations. Here, we investigate the antiepileptic properties of ranolazine exhibited through the reduction of hippocampal neuronal excitability. At therapeutically relevant concentrations, ranolazine reduced action potential firing frequency of hippocampal neurons in response to repetitive depolarizing current injections. Similarly, using a single current injection paradigm, ranolazine required a long depolarization (4 seconds) to produce significant inhibition of excitability, which was similar to that observed for the anticonvulsants phenytoin (slowly binds to the fast-inactivated state) and lacosamide (binds to the slow-inactivated state). Ranolazine enhanced the development of fast and slow inactivation assessed with conditioning prepulses of 100, 1000, or 10,000 milliseconds. Recovery of channels from inactivated states was also slowed in the presence of ranolazine. Interestingly, the use-dependent inhibition of hippocampal neurons was dependent on the duration of the voltage step, suggesting ranolazine does not selectively affect the open state and may also interact with inactivated states. NEURON (Yale University, New Haven, CT) computational simulations predict equal inhibition of action potential generation for binding to either fast-inactivated or slow-inactivated states. Binding of ranolazine to either preopen or open states did not affect the excitability of the simulation. Ranolazine was able to significantly reduce the epileptiform activity of the neuronal cultures, suggesting possible antiepileptic activity.