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.

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.

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.

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.

Design and assessment of a potent sodium channel blocking derivative of mexiletine for minimizing experimental neuropathic pain in several rat models.

Physical or chemical damage to peripheral nerves can result in neuropathic pain which is not easily alleviated by conventional analgesic drugs. Substantial evidence has demonstrated that voltage-gated Na+ channels in the membrane of damaged nerves play a key role in the establishment and maintenance of pathological neuronal excitability not only of these peripheral nerves but also in the second- and third-order neurons in the pain pathway to the cerebral cortex. Na+ channel blocking drugs have been used in treating neuropathic pain with limited success mainly because of a preponderance of side-effects. We have developed an analogue of mexiletine which is approximately 80 times more potent than mexiletine in competing with the radioligand, 3H-batrachotoxinin for binding to Na+ channels in rat brain membranes and also it is much more lipophilic than mexiletine which should enhance its uptake into the brain to block the increased expression of Na+ channels on second- and third-order neurons of the pain pathway. This analogue, HFI-1, has been tested in three different rat models of neuropathic pain (formalin paw model, ligated spinal nerve model and contusive spinal cord injury model) and found to be more effective in reducing pain behaviours than mexiletine.

Neuroprotection assessment by topographic electroencephalographic analysis: effects of a sodium channel blocker to reduce polymorphic delta activity following ischaemic brain injury in rats.

The spatiotemporal electroencephalogram (EEG) pathology associated with brain injury was studied using high-resolution, 10-electrode cortical EEG mapping in a rat model of middle cerebral artery occlusion (MCAo). Using this model we evaluated the ability of the novel sodium channel blocker and neuroprotective agent RS100642 to resolve injury-induced EEG abnormalities as a measure of neurophysiological recovery from brain injury. The middle cerebral artery (MCA) was occluded for 1 h during which a dramatic loss of EEG power was measured over the injured cortex with near complete recovery upon reperfusion of blood to the MCA region in all rats. The resultant progression of the MCAo/reperfusion injury (6-72 h) included the appearance of diffuse polymorphic delta activity (PDA), as visually indicated by the presence of high-amplitude slow-waves recorded from both brain hemispheres. PDA was associated with large increases in EEG power, particularly evident in outer 'peri-infarct' regions of the ipsilateral parietal cortex as visualized using topographic EEG mapping. Post-injury treatment with RS100642 (1.0 mg/kg, i.v.) significantly reduced the PDA activity and attenuated the increase in EEG power throughout the course of the injury. These effects were associated with a reduction in brain infarct volume and improved neurological function. These methods of EEG analysis may be helpful tools to evaluate the physiological recovery of the brain from injury in humans following treatment with an experimental neuroprotective compound.

BIII-890-CL. Boehringer Ingelheim.

BIII-890-CL is a non-orally active sodium channel blocker under development by Boehringer Ingelheim Corp for the potential treatment of thromboembolic stroke. By April 2001, the compound was in phase II clinical trials for this indication, with trials ongoing in June 2002. The compound is also under investigation for its potential use in the treatment of pain.