CLINICAL RESEARCH: PHARMACOLOGIC STUDY
Long-Term Safety of a Novel Antianginal Agent in Patients With Severe Chronic Stable Angina
The Ranolazine Open Label Experience (ROLE)
Michael J. Koren, MD, FACC*,*,
Michael R. Crager, PhD
and
Michael Sweeney, MD
* Jacksonville Center for Clinical Research, Jacksonville, Florida
CV Therapeutics, Inc., Palo Alto, California.
Manuscript received August 14, 2006;
revised manuscript received October 26, 2006,
accepted October 30, 2006.
* Reprint requests and correspondence: Dr. Michael J. Koren, Jacksonville Center for Clinical Research, 4085 University Boulevard South, Suite 1, Jacksonville, Florida 32216. (Email: MichaelKoren{at}jaxresearch.com).
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Abstract
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Objectives: This report describes safety and tolerability data from 746 chronic angina patients treated in the ROLE (Ranolazine Open Label Experience) program.
Background: Ranolazine treats angina without depressing hemodynamic status. The long-term safety and tolerability of ranolazine have not been previously reported.
Methods: Patients with severe functional impairment from angina (mean Duke Treadmill Score [DTS] of –14.4) who completed 1 of 2 randomized treadmill trials entered the ROLE program. Ranolazine was titrated to optimal dosages between 500 and 1,000 mg twice daily. Physical examination, laboratory tests, and adverse event reporting were performed periodically. We conducted analyses to evaluate possible predictors of ranolazine intolerance, such as advanced age, diabetes, poor exercise tolerance, or history of myocardial infarctions or congestive heart failure (CHF). The ROLE program’s mortality was compared against the DTS predictive model and other contemporary cohorts of high-risk CHD patients.
Results: Mean follow-up was 2.82 years. Two years after initial dosing, 571 patients (76.7%) remained on therapy and 72 patients (9.7%) discontinued ranolazine due to adverse events. Among 6 factors evaluated, only age 
64 years predicted for higher withdrawal rates. Patients with a history of CHF had lower withdrawal rates. Mean QTc interval was prolonged by 2.4 ms. No treatment discontinuations occurred due to QTc prolongation, and no Torsades de Pointes was reported. Sixty-four deaths occurred during a total of 2,102 patient-years (3.0% annually) during the ROLE program. When extending observations to all patients exposed to ranolazine during the double-blind trials (n = 972) preceding the ROLE program, annual mortality was 2.8% compared with >5% as predicted by DTS.
Conclusions: Long-term therapy with ranolazine seems well tolerated in high-risk CHD patients. Survival analyses suggest that symptomatic improvements attributable to ranolazine are not offset by increased mortality.
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Abbreviations and Acronyms
| | AE = adverse event | | CHD = coronary heart disease | | CHF = congestive heart failure | | DTS = Duke Treadmill Score | | ECG = electrocardiogram/electrocardiographic | | EECP = enhanced external counterpulsation | | MI = myocardial infarction | | SR = extended-release |
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Ranolazine is a novel antianginal agent. Although its mechanism of action has not been fully elucidated, ranolazine seems to inhibit the late sodium current in the cardiac myocyte, reducing calcium and sodium overload and thereby increasing the efficiency of oxygen use. Its therapeutic effects do not depend on reductions in heart rate, blood pressure, or vascular resistance (1–4) Three multicenter placebo-controlled trials of extended-release (SR) ranolazine have demonstrated angina symptom improvements as assessed either by treadmill performance or patient diaries (1,2,5).
The MARISA (Monotherapy Assessment of Ranolazine In Stable Angina) trial (1) was a 4-group crossover study in which 191 patients received ranolazine SR at dosages of 500, 1,000, and 1,500 mg twice daily (b.i.d.) and placebo in randomly ordered 1-week phases. All active treatment dosages were associated with improvements in total and angina-free treadmill exercise duration. The CARISA (Combination Assessment of Ranolazine in Stable Angina) trial (2) was a 12-week, 3-group parallel study of 823 patients (receiving background therapy with once-daily diltiazem 180 mg, atenolol 50 mg, or amlodipine 5 mg) randomly assigned to receive ranolazine SR 750 or 1,000 mg b.i.d. or placebo. Both ranolazine dosages improved total and angina-free treadmill exercise duration and reduced angina frequency and nitroglycerin consumption.
The ROLE (Ranolazine Open Label Experience) program involved patients who completed the MARISA or CARISA trial and were willing to participate in an open-label extension program. Because of the entry requirements of the treadmill studies, all ROLE program participants were well characterized as having severe functional limitations due to angina and were assigned a Duke Treadmill Score (DTS). The DTS (6), a widely accepted prognostic scoring system, provides a measurement by which outcomes for the ROLE program participants can be compared with expected survival rates. Although the open-label methodology of the ROLE program is unsuitable for strictly attributing safety and efficacy outcomes to ranolazine, our analysis is intended to help clinicians identify factors more or less likely related to drug intolerance. In addition, the ROLE cohort is large enough to benchmark outcomes against other similar groups of patients reported in published medical reports.
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Methods
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Study design.
Institutional review board approval and informed consent were obtained for all patients. Upon successful completion of the MARISA or CARISA trials, ROLE program subjects were enrolled at 123 outpatient investigative sites in 12 nations: Australia (<1%), Canada (16%), Czech Republic (22%), Georgia (3%), Greece (<1%), Israel (4%), New Zealand (2%), Poland (11%), Russia (21%), Spain (2%), United Kingdom (<1%), and the U.S. (17%). Investigators could titrate to optimal ranolazine dosages between 500 and 1,000 mg b.i.d. on the basis of clinical responses at up to 6 initial weekly visits. Maintenance-phase visits were scheduled 1 month after completion of titration and every 3 months thereafter. Patients who experienced recurrent angina or adverse events (AEs) during the maintenance phase could be titrated to higher or lower drug doses.
For MARISA patients, ranolazine was initiated at 750 mg b.i.d. and increased to a maximum dose of 1,000 mg b.i.d. as guided by clinical effects. The optional addition of other antianginal agents was permitted. For CARISA patients, ranolazine titration was initiated at 500 mg b.i.d. and could be increased to 1,000 mg b.i.d. Background antianginal therapy was maintained through the period of ranolazine titration, with the options of increasing or decreasing the dose, substituting another background antianginal agent, or discontinuing background antianginal therapy left to investigators. Open-label ranolazine was not immediately available for some of the patients who entered the ROLE program from the CARISA trial. Among 406 patients who entered the ROLE program after receiving ranolazine in the CARISA trial, the resulting interruption in ranolazine dosing averaged 4 months.
Outcome measures.
Safety and tolerability assessments included vital signs, electrocardiograms (ECGs), and AE evaluations. Physical examination and laboratory analyses (hematology, chemistry, and plasma ranolazine concentrations) were conducted at baseline and all maintenance-phase visits. Urinalysis and serum lipids were assessed at baseline and every 6 months during maintenance. Reasons for study drug discontinuation were recorded.
Statistical analyses.
Adverse events, study drug discontinuations, and ECG intervals were summarized, beginning with first exposure to open-label ranolazine and continuing through April 1, 2005. Exploratory analyses were conducted with Cox proportional hazards regression to assess whether age, gender, history of myocardial infarction (MI), history of congestive heart failure (CHF), diabetes mellitus, or baseline exercise tolerance predicted discontinuation of therapy due to AEs. The ECG intervals were averaged within patients over the follow-up period and compared with pretreatment baseline with the paired Student t test.
To avoid selection biases, analyses of survival incorporated all available follow-up of patients who were exposed to ranolazine in the MARISA or CARISA trials or the ROLE program, including patients who participated only in the randomized studies. Survival time was assessed, beginning with first exposure to ranolazine. The ROLE program did not require ongoing follow-up for survival beyond 14 days after treatment discontinuation. When patient deaths more than 14 days after discontinuation were nonetheless reported, they were included in the analysis. Mortality per patient-year was estimated assuming a constant hazard rate, and expected survival rates at 1 and 2 years were computed. Survival over the entire follow-up period was described with Kaplan-Meier methods.
Comparator studies.
We searched the PubMed database with the following combination of medical subject heading terms: "coronary disease" OR "myocardial ischemia" OR "angina pectoris" AND "prospective studies" OR "survival analysis" OR "treatment outcome." PubMed search limits were "middle aged: 45 to 64 years," "aged: 65+ years," "English," "publication date from 1996 to 2005," "clinical trial," and "core clinical journals." We limited comparator studies to those of at least 2 years’ duration and 500 patients except for one that represented the largest published experience with surgical transmyocardial laser revascularization.
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Results
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A total of 746 patients entered the ROLE program (143 of the 168 patients who completed the MARISA trial plus 603 of the 731 patients who completed the CARISA trial). Patient characteristics are summarized in Table 1, and the flow of patients through the studies is presented in Figure 1. The population was largely male and white. Average exposure time to ranolazine was 2.82 years (range 6 days to 6.5 years). Twenty-three percent of the population was diabetic, and 58% had a previous MI. Four hundred thirty-two (58%) subjects were titrated at some point to the highest ranolazine dose of 1,000 mg b.i.d., 209 subjects (28%) received a maximum dose of 750 mg b.i.d., and 14% received 500 mg b.i.d.
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Figure 1 The ROLE Program Schematic
Disposition of subjects in preceding double-blind trials leading to the ROLE (Ranolazine Open Label Experience) program. AE = adverse event; CARISA = Assessment of Ranolazine in Stable Angina trial; MARISA = Monotherapy Assessment of Ranolazine In Stable Angina trial; pts = patients.
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Discontinuations.
Patient disposition over time is shown in Table 2. Of the original 746 patients enrolled, all but 2 have follow-up data through 2 years or discontinued prior to that point owing to adverse effects, death, or choice. Five hundred seventy-one patients (76.7%) completed 2 years of open-label ranolazine therapy, and 173 patients (23.3%) had discontinued therapy. Adverse events were the most common reason for discontinuation in the first 2 years of open-label treatment, accounting for slightly less than one-half of all discontinuations (n = 72 [9.7% of total cohort]). The next most common reasons for discontinuation were elective withdrawal at the discretion of patients and/or investigators (n = 46 [6.0%]) and death (n = 34 [4.6%]). Adverse events are summarized by preferred term in the MedDRA dictionary (Version 8) in Table 3. Aside from angina, the symptom under study, the most common AEs recorded were dizziness (11.8%) and constipation (10.9%). These complaints, solely or in combination with other AEs, led to discontinuation in 7 (0.9%) and 5 (0.6%) patients, respectively. Adverse event profiles did not differ between the 197 subjects who received ranolazine for the first time in the ROLE program (randomized to placebo in MARISA or CARISA trials) and 549 patients who had previously received ranolazine.
Table 4
shows the results of predictive modeling to analyze possible correlations between baseline demographic and clinical variables and the likelihood of AE-related discontinuation. Older age (64 years) was the only factor that showed a statistically significant correlation with increased AE-related discontinuation (relative risk 2.32, p < 0.001). History of CHF was the only factor that showed a significant correlation with reduced AE-related discontinuation (relative risk 0.55, p = 0.030). There was a trend toward decreased risk of AE-related discontinuations among patients with a history of MI (relative risk 0.74, p = 0.14) and those with baseline exercise duration shorter than the median (relative risk 0.75, p = 0.16).
ECG findings.
Durations of the PR, QRS, and QTc (Fridericia correction) intervals at baseline and the within-patient average values during open-label ranolazine treatment are presented in Table 5. There were no significant changes from baseline in either the PR or QRS interval. The QTc interval showed a mean prolongation of approximately 2.4 ms compared with baseline (p < 0.001). Sixteen ECG tracings showed QTc interval prolongation exceeding 500 ms occurring in 10 patients (1.2%). Ten occurrences of QTc intervals >500 ms were recorded while patients received the 1,000 mg b.i.d. dosage, and 6 occurrences were recorded at the 750 mg b.i.d. dosage. No subject was withdrawn from the ROLE program for QTc interval prolongation. Serum electrolyte levels obtained proximate to the time of QTc interval prolongation did not indicate any significant abnormalities. No case of Torsades de Pointes was reported.
Mortality.
Data were available and analyzed from a total of 2,372 patient-years of follow-up of the 942 patients exposed to ranolazine through randomization in the MARISA or CARISA trials or in the ROLE program, incorporating 2,233 patient-years of ranolazine treatment exposure. The difference between the patient-years of follow-up and patient-years of treatment is due primarily to the delay in availability of the ROLE program for some CARISA trial patients. There were 4 deaths during ranolazine treatment in the MARISA and CARISA trials (vs. 3 deaths during placebo treatment) and 64 deaths during 2,102 patient-years in the ROLE program (3.0% annual incidence). In all, there were 68 deaths during the 2,372 patient-years of follow-up (2.8% annual incidence). The estimated 1- and 2-year survival from this incidence is 97.2% and 94.4%, respectively. A Kaplan-Meier survival plot is shown in Figure 2. Among the 68 deaths reported, the most common causes—not unexpected in this population—were cardiovascular including MI and ventricular tachyarrhythmia. The most common noncardiac causes of death were cancer and pulmonary embolism (Table 6).
Table 7
compares the ROLE program mortality rates with those predicted by the DTS model and contemporary treatment trials (6–12). Comparison cohorts were selected in which patients had either refractory chronic angina or coronary heart disease (CHD) with increased risk. With the exception of the younger population reflected in the DTS model, comparative cohorts were of similar age as ROLE program participants.
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Discussion
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The market availability of novel pharmaceutical products inevitably generates both excitement and concern among clinicians. Although physicians might welcome ranolazine as an agent that addresses the unmet need of treating CHD symptoms without altering hemodynamic status, safety concerns are understandable. These concerns are particularly germane to cardiovascular therapeutics, recently including drugs such as flosequinone, mibefradil, and nesiritide—all agents that received regulatory approval on the basis of symptom relief only to be subsequently withdrawn or highly scrutinized after the release of safety data that were unavailable at the time of initial approvals.
Ranolazine was well tolerated during long-term treatment, which is consistent with the findings of randomized, double-blind studies (1,2,5). The most common side effects were dizziness and constipation, but these symptoms were usually not severe enough to cause treatment discontinuation. Overall, 76.7% of patients completed 2 years of open-label therapy. Of the 23.3% of patients who did not complete 2 years of therapy, less than one-half (9.7%) stopped study participation owing to AEs. Predictive modeling showed a significantly increased likelihood of AE-related discontinuation associated with only 1 categorical variable, age 64 years. Increased susceptibility to untoward effects with advancing age is common for many therapeutic interventions and is not an unexpected finding (13–15). Curiously, there was a decreased probability of AE-related discontinuation in patients with a history of CHF. Although this finding should be interpreted with caution, it is intriguing that improvements in ventricular function related to ranolazine were observed in animal models (15,16).
The open-label methodology of the ROLE program does not allow for a rigorous analysis of mortality. Because of the absence of a comparator group, it is difficult to fully characterize implications of the 68 deaths reported. However, the mortality rate of 5.6% over 2 years can be placed into context by comparing this result with predictions based on DTS and cohorts treated with other antianginal modalities.
High-risk DTS (<–10) has been associated with a 4-year survival rate of <79%, intermediate-risk scores (–10 to +4) with a 4-year survival risk of 75% to 95%, and low-risk scores (+5) with a 4-year survival rate of 99% (6,12). The mean baseline DTS for ROLE patients, –14.4, implies a poor prognosis and a yearly mortality estimate above 5%. The finding of an actual 2-year mortality of 5.6% and a yearly mortality of approximately one-half the DTS predicted rate is reassuring prognostic information about ranolazine. Although prognosis on the basis of the DTS might not reflect recent invasive and noninvasive advances in cardiovascular care (e.g., stents and statin use) and might overestimate contemporary CHD mortality, the DTS cohort was significantly younger than ROLE program participants—an offsetting factor that could lead to underestimation of DTS-predicted mortality for the ROLE program patients.
Benchmarking outcomes in patients exposed to ranolazine with the prognosis reported in recent high-risk CHD treatment trials is another useful comparison. In 1998, a registry was set up to assess treatment with enhanced external counterpulsation (EECP) in patients with refractory angina (17). In 2001, Michaels et al. (7) described the experience of 978 patients at 43 centers, of whom 81% had previously undergone revascularization and 69% were considered unsuited for either percutaneous coronary intervention or coronary artery bypass graft surgery at the start of treatment with EECP. Although EECP registry patients might have had more severe CHD, on average, in that they could be angina treatment failures despite multiple drugs, these patients might not be dissimilar prognostically to ROLE program participants who were required to have angina limiting exercise at low work levels (
end of Bruce protocol stage 1). Cumulative mortality among EECP registry patients was 8.5% at 2 years (7) versus 5.6% in ROLE program participants. Data from cohorts undergoing other treatments for medically refractory angina such as high-risk coronary revascularization or surgical laser transmyocardial revascularization also show mortality rates greater than the ROLE program cohort (8,9). By contrast, studies of lower-risk CHD populations have shown similar (10) or lower mortality risk (11).
The finding of mortality rates in the ROLE program at or below expectations should help address concerns about whether or not the QTc interval prolongation previously reported in association with ranolazine use is of clinical significance. Previous work with ranolazine demonstrated a prolongation of the Bazett’s corrected QTc interval by <10 ms (2). Although prolongation of QTc interval is associated with Torsades de Pointes, investigators (18) have shown that QTc interval prolongation alone is not sufficient to cause Torsades de Pointes. Induction of early after depolarizations (EADs) and an increase in transmural dispersion are also required. Electrophysiologically, ranolazine does not induce EADs in animal models and reduces transmural dispersion (19). In the ROLE program, there were no investigator-ordered discontinuations related to QTc interval prolongation or cases of Torsades de Pointes.
Although the safety results of the ROLE experience are encouraging, clinicians should maintain their vigilance for untoward effects. While the relatively large ROLE cohort safety dataset should be predictive of patient experiences as ranolazine makes it way into routine clinical use, limitations of the present study should be acknowledged. Some patients in the original randomized studies terminated early from the randomized studies because of AEs (7.9% of ranolazine patients vs. 4.8% of placebo patients in the CARISA trial, and 1.1%, 0.6%, 0.6%, and 5.9% of patients treated with placebo, ranolazine 500 mg b.i.d., ranolazine 1,000 mg b.i.d., and ranolazine 1,500 mg b.i.d., respectively, in the MARISA trial). Because completion of a blinded study was required to participate in the ROLE program we might have eliminated patients who were more intolerant of ranolazine and reduced the incidence of AEs in the ROLE program. There was also no requirement for long-term systematic follow-up after patients discontinued medication in the ROLE program. Although these discontinued patients are not expected to have any untoward long-term complications attributable to their use of the drug, this possibility cannot be entirely excluded.
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Conclusions
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Long-term safety and tolerability of ranolazine in patients with chronic stable angina seems favorable without indication of increased long-term cardiac mortality compared with reference populations. Electrophysiological complications were not a major determinant of study drug discontinuation. Ranolazine discontinuation due to adverse experiences was more common in older patients. Because participation in the ROLE program was voluntary, it is reasonable to conclude that the high rate of patients continuing ranolazine open-label treatment reflects a perception of net benefit for a symptomatic condition by study participants and their physicians.
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Footnotes
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This work was supported by CV Therapeutics, Inc.
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References
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