Improvement of Subjective Well-Being by Ranolazine in Patients with Chronic Angina and Known Myocardial Ischemia (IMWELL Study)

Introduction We aimed to assess if ranolazine would improve angina symptoms among patients with documented myocardial ischemia. Methods Eligible subjects had chronic stable angina and at least one coronary stenosis with fractional flow reserve (FFR) ≤0.80 or at least one chronic total occlusion (CTO) without attempted revascularization. Subjects were randomized to oral ranolazine 500 mg twice daily for 1 week, then ranolazine 1000 mg twice daily for 15 weeks versus matching placebo. The primary end point was change in angina at 16 weeks as assessed by the Seattle Angina Questionnaire (SAQ). Results Between September 2014 and January 2016, 25 subjects were randomized to ranolazine versus 25 to placebo. The most common reason for eligibility was CTO (72%), while the remainder had myocardial ischemia documented by low FFR. The mean FFR was 0.57 ± 0.12. Sixty-eight percent of subjects were on two or more anti-angina medications at baseline. Study medication was discontinued in 32% (eight of 25) of the ranolazine group versus 36% (nine of 25) of the placebo group. By intention-to-treat, 46 subjects had baseline and follow-up SAQ data completed. Ranolazine was not associated with an improvement in angina compared with placebo at 16 weeks. The results were similar among 33 subjects that completed study medication. The incidence of ischemia-driven hospitalization or catheterization was 12% (three of 25) of the ranolazine group versus 20% (five of 25) in the placebo group (p > 0.05). Conclusions In subjects with chronic stable angina and documented myocardial ischemia, ranolazine did not improve angina symptoms at 16 weeks. Funding Gilead. Clinical trial registration The study was registered at ClinicalTrials.gov (NCT02265796).

ranolazine versus 25 to placebo. The most common reason for eligibility was CTO (72%), while the remainder had myocardial ischemia documented by low FFR. The mean FFR was 0.57 ± 0.12. Sixty-eight percent of subjects were on two or more anti-angina medications at baseline. Study medication was discontinued in 32% (eight of 25) of the ranolazine group versus 36% (nine of 25) of the placebo group. By intention-to-treat, 46 subjects had baseline and follow-up SAQ data completed. Ranolazine was not associated with an improvement in angina compared with placebo at 16 weeks. The results were similar among 33 subjects that completed study medication.  [1,2]. Ranolazine is an anti-ischemia/ anti-angina medication that inhibits the late sodium current but does not affect the heart rate or blood pressure [3]. Ranolazine was associated with a reduction in recurrent ischemia among patients with acute coronary syndrome and history of angina [4]. In the Ranolazine for Incomplete Vessel Revascularization Post-Percutaneous Coronary

Intervention
(RIVER-PCI) multicenter randomized trial, ranolazine failed to reduce ischemia-driven hospitalization or ischemia-driven revascularization in chronic angina patients with incomplete revascularization [5]. However, incomplete revascularization was assessed angiographically, which is known to only modestly correlate with underlying myocardial ischemia [6,7].
Therefore, we aimed to assess whether ranolazine would improve angina symptoms and subjective well-being among patients with documented myocardial ischemia, defined by either low fractional flow reserve (FFR) or presence of a chronic total occlusion (CTO), and who did not undergo revascularization.

Study Design and Selection Criteria
This was a randomized single-center trial that enrolled subjects at least 18 years of age who were referred for catheterization for evaluation of angina, fatigue, or shortness of breath. This investigator initiated study was sponsored by Gilead Sciences. In addition to symptoms compatible with chronic stable angina, we required the following: (1) at least one borderline coronary stenosis with documented myocardial ischemia by FFR (B0.8) or at least one CTO, and (2) no attempted revascularization of the ischemic artery. CTO was defined as an occlusion in a C2 mm epicardial coronary artery in which distal flow was provided by antegrade or retrograde collaterals. An occlusion which was supplied by a patent bypass graft was not considered a CTO. The assumed FFR value of a CTO was 0.5 [8]. The decision not to revascularize an ischemic lesion was left to individual operator discretion, but included the following reasons: patient preference for initial medical therapy, lesion characteristics that increased the risk for restenosis (diffuse disease in a small vessel), or characteristics that increased the risk for procedural complication (severe calcification, excessive angulation/tortuosity, or inability to protect a bifurcation lesion). The following patients were excluded; coronary revascularization within the index procedure or planned in the next month, acute coronary syndrome or cardiogenic shock, use of strong inhibitors of CYP3A, use of inducers of CYP3A, liver cirrhosis, severe renal insufficiency (creatinine clearance \30 ml/min/1.73 m 2 ), or baseline corrected QT interval [500 ms.

Randomization
Eligible subjects were randomly assigned to receive either oral ranolazine 500 mg twice daily for 1 week, then ranolazine 1000 mg twice daily for 15 weeks vs. matching placebo (one tablet twice daily for 1 week, then two tablets twice daily for 15 weeks). Randomization was performed with Excel 2010 utilizing the RAND function. A sample size of 50 was randomized using a simple schema with two levels representing treatment assignments without stratification. Block size was set at 10.
Study investigator, patient, and research team were blinded to treatment assignment. The treatment assignment code was kept by research pharmacy.

Endpoints and Statistics
The primary end point was change in angina from baseline to 16 weeks as assessed by the Seattle Angina Questionnaire (SAQ) [9].
Secondary endpoints included subjective well-being, in which subjects were asked, ''in the last month, how would you rate your overall feeling of well-being (poor, fair, good, or excellent) [10].'' Lastly, the incidence of

RESULTS
Between September 2014 and January 2016, 25 subjects were randomized to ranolazine versus 25 to placebo. Follow-up SAQ was not obtained in four subjects. This was due to one death, and two study withdrawals in the ranolazine group and one study withdrawal in the placebo group.
The most common reason for anatomic eligibility was chronic total occlusion that was present in 72%, while the remainder had myocardial ischemia documented by FFR (mean FFR value was 0.57 ± 0.12). The mean age was 67 years ± 9 years, mean left ventricular ejection fraction was 53 ± 11%, and mean left ventricular end diastolic pressure was 12 ± 5 mmHg. Sixty-eight percent of subjects were on two or more anti-angina therapies at baseline (80% on a beta-blocker, 60% on a long-acting nitrate, and 35% on a calcium channel antagonist). Additional baseline characteristics are provided in Table 1.
Discontinuation of study medication occurred in 32% (eight of 25) of the ranolazine group at a mean of 55 ± 46 days By intention-to-treat, 46 subjects had baseline and follow-up SAQ data completed at 16 weeks. Three out of five SAQ domains improved from baseline to follow-up in both groups (Angina Stability, Angina Frequency, and Quality of Life); however, there was no difference between the treatment and placebo groups ( Table 2). There was no within-group change in Physical Limitation, or Treatment Satisfaction ( Table 2). There was also no change in subjective well-being over the follow-up period (

DISCUSSION
Among patients with documented myocardial ischemia (mean FFR = 0.57) and no attempted revascularization, ranolazine failed to improve angina symptoms or subjective well-being compared with placebo. Findings were the same by intention-to-treat analysis and also among the cohort that completed their treatment assignment. As a secondary outcome, incidence of ischemia-driven hospitalization or catheterization was similar between treatment groups. Discontinuation of study medication was high, but similar between groups and there was no appreciable difference in adverse events between treatment groups.
Lack of benefit could be due to good background medical therapy (68% on two or more anti-angina therapies at baseline) versus relative ineffectiveness of ranolazine as an anti-angina agent [12]. There was also a strong placebo effect. For example, subjects randomized to placebo experienced a six-unit improvement in angina stability, a 15-unit improvement in angina frequency, and an 18-unit improvement in quality of life.
Inadequate power also remains a possible explanation for the lack of association between ranolazine and angina measures.
While anti-angina therapy is an important treatment strategy among patients with ischemic heart disease [13], PCI has been shown to provide greater angina relief compared with optimal medical therapy [14].  [5]. This group is most similar to the characteristics of our study participants. There was also no improvement in angina burden from ranolazine versus placebo in the overall RIVER-PCI trial [15].
This study was intended to be a pilot study to investigate for any potential benefit in this patient population, and in so doing to estimate the sample size needed for a definitive study. However, given the lack of benefit in the present study, a larger study is not planned.
This study has some limitations. The primary outcome was relatively subjective; however, SAQ has been previously validated and is widely used in ischemic heart disease studies.
In addition, a large proportion of patients discontinued the study medication; however, the rate of discontinuation was the same between study drug and placebo. The small sample size might have decreased to study power to detect statistically significant differences between both groups. Additionally, there was no difference in the intention-to-treat analysis versus the on-treatment analysis.

CONCLUSIONS
In conclusion, among subjects with chronic stable angina and documented myocardial ischemia, ranolazine did not improve the frequency of angina or subjective well-being at 16 weeks.