A Study of the Effects of Ranolazine Using Automated Quantitative Analysis of Serial Myocardial Perfusion Images
Rajesh Venkataraman, MD, MPH*,*,
Luiz Belardinelli, MD ,
Brent Blackburn, PhD,
Jaekyeong Heo, MD*,
Ami E. Iskandrian, MD*
* Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama
Gilead Sciences Inc., Foster City, California
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Abstract
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Objectives: This study examined the hypothesis that the improvement in myocardial blood flow (MBF) with ranolazine therapy could be detected by serial automated quantitative myocardial perfusion imaging (MPI) in patients with coronary artery disease (CAD) and myocardial ischemia.
Background: Myocardial ischemia enhances late sodium current, which then causes cellular calcium overload leading to mechanical left ventricular dysfunction and arrhythmias. Ranolazine inhibits late sodium current and improves diastolic tension and MBF in the animal model.
Methods: In this open-label, nonrandomized pilot study, we recruited 20 patients with known or a high probability of CAD and who had reversible perfusion defects on exercise treadmill gated single-photon emission computed tomography MPI while receiving conventional antianginal therapy. Ranolazine (up to 1,000 mg twice daily) was added to baseline therapy and a repeat treadmill MPI was obtained after 4 weeks. The extent and severity of total and reversible left ventricular perfusion abnormality (based on polar maps and a 17-segment model) were determined quantitatively using automated methods.
Results: We screened 100 patients for 27 potential candidates; 5 declined and 2 did not complete the follow-up study. The mean age of the remaining 20 patients was 64 ± 9 years; 30% were women and 50% had diabetes mellitus. The exercise time increased (425 ± 105 s vs. 393 ± 116 s, p = 0.017), and angina improved in 15 (75%) patients after ranolazine treatment. In the entire cohort, summed stress scores (10 ± 7 vs. 13 ± 8, p = 0.04) and summed difference scores (4.7 ± 4 vs. 7.4 ± 5, p = 0.0037) decreased at follow-up. An improvement in perfusion pattern and severity was noted in 14 (70%) patients. In these patients, the polar maps showed a decrease in total abnormality from 26 ± 17% to 19 ± 15% and a decrease in the reversible abnormality from 16 ± 10% to 8 ± 6% (all p values <0.05).
Conclusions: In this preliminary hypothesis-driven study, short-term ranolazine therapy was shown to improve myocardial perfusion and decrease the ischemic burden in patients with CAD.
Key Words: ranolazine • myocardial perfusion imaging • coronary artery disease • single-photon emission computed tomography • ischemia • exercise testing
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Abbreviations and Acronyms
| | CAD = coronary artery disease | | LV = left ventricular | | MBF = myocardial blood flow | | MPI = myocardial perfusion imaging | | SDS = summed difference score | | SPECT = single-photon emission computed tomography |
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Coronary artery disease (CAD) is a leading cause of death and disability in the U.S., and despite many advances, chronic stable angina is present in >9.0 million Americans ( 3% of the entire population) (1). Many of the conventional medications such as beta-adrenergic blocking agents, calcium channel blockers, nitrates, and lipid-lowering drugs have been shown to improve symptoms and ameliorate myocardial ischemia (2). Ranolazine, a prototype of a late sodium current inhibitor, has recently been approved as first-line treatment in patients with angina based on studies showing that it increases time to angina and total treadmill exercise time and reduces the frequency of angina (3–10).
In an animal model, ranolazine increases myocardial blood flow (MBF), possibly because inhibition of late sodium current results in a decrease in left ventricular (LV) stiffness, which in turn decreases extravascular compressive forces on coronary microcirculation and thereby improves MBF (11–14). Such an improvement in MBF is likely to contribute to the antianginal effects of ranolazine. However, there are no data on the effect of ranolazine on myocardial perfusion or MBF in patients with CAD. Thus, the objective of this pilot study was to determine whether ranolazine improves myocardial perfusion during exercise in patients with CAD as assessed by serial automated quantitative myocardial perfusion imaging (MPI).
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Methods
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This was an open-label study conducted at the University of Alabama at Birmingham Medical Center and approved by its institutional review board, and all participants signed an informed consent form. The study design and data collection, interpretation, and reporting were the responsibility of the University of Alabama at Birmingham faculty.
Patients older than the age of 18 years with angina or angina equivalent (chest pain or shortness of breath) on optimal tolerated medical therapy who met the inclusion/exclusion criteria (Table 1) and had reversible perfusion defects on baseline MPI (either clinically indicated or as a part of the study protocol) were entered into the study. It should be noted that these patients did not have disabling angina, and the study was not designed to study the effects of ranolazine treatment on angina frequency but rather on myocardial perfusion.
Patients were given ranolazine as an add-on to their baseline medications in doses of 500 mg twice daily for 1 week and then 1,000 mg twice daily for 3 weeks. The doses of other medications were not altered during the 4 weeks of ranolazine therapy. After 4 weeks, a second exercise treadmill MPI was performed. The duration of therapy in previous placebo-controlled studies with ranolazine ranged from 1 to 12 weeks (5,9). We chose to use 4 weeks of therapy to ensure adequate compliance and up-titration to 2 g/day dosing and any unexpected changes in clinical status of the patient. Patients were closely followed by weekly telephone calls to assess for any adverse effects and compliance.
Demographic, clinical, and pertinent laboratory data were recorded at enrollment. Angina or angina equivalent severity, according to the Canadian Cardiovascular Society anginal class, was assessed at baseline and after treatment with ranolazine. At the time of the second exercise MPI, the patients were also asked, "how do you feel since your first imaging study: the same, better, or worse?"
Treadmill exercise testing.
The treadmill exercise was performed using a standard Bruce protocol (15). Patients were allowed to exercise until an exercise end-point was reached (moderate to severe angina, shortness of breath, fatigue or leg weakness,  2 mm ST-segment depression, hypotension, or severe arrhythmias). Technetium-99m sestamibi was injected at near-peak exercise, and the patients were asked to continue exercise for an additional minute. Electrocardiographic tracings were recorded at 30-s intervals and continued into recovery, until the heart rate returned to baseline. Heart rate, blood pressure, and QT measurements were performed at rest and peak exercise.
The second treadmill exercise test was done in a similar fashion, and the same radiotracer was injected at the same exercise time as the initial test, although the patient was allowed to exercise longer to achieve 1 of the previously cited end points if he or she could do so. This feature of the study design allowed comparison of the perfusion images at similar exercise levels, but it also allowed determination of improvement in exercise capacity if such existed.
Single-photon emission computed tomography (SPECT).
All images were acquired and processed according to the American Society of Nuclear Cardiology guidelines using either single-day or 2-day (depending on body weight) stress/rest–technetium-99m sestamibi (15). Imaging was started 60 min after the tracer injection at rest or exercise. Identical doses of the tracer were used for the baseline and follow-up studies. All raw data of gated SPECT images (2 sets per patient) were reconstructed using standard back-projection and identical filtering (Butterworth filter with a critical frequency of 0.4 cycles/s, order 5). Motion correction was applied before image reconstruction if >1 pixel of x or y axis deviation was observed over the 180° acquisition. No attenuation correction was used.
Quantitative SPECT was performed using a previously validated automated program that determines the extent and severity of LV perfusion defect size and the extent of reversible (ischemia) or fixed (scar) perfusion defects (16). LV defect severity within abnormally perfused regions was defined on a pixel-by-pixel basis as mild, moderate, or severe based on its relationship to expected normal pixel count activity (>50%, 26% to 50%, and 0% to 25%, respectively). Severity of ischemia was calculated as the percentage of count improvement toward normal values within ischemic pixels and defined as minimal (0% to 25% improvement), moderate (2% to 50% improvement), or marked (>50% improvement).
In addition, the automated program was used to derive the summed stress score, summed rest score, and summed difference score (SDS) based on conventional 17-segment model. The program assigned a score of 0 to 4 to each segment based on activity level: 0 = normal and 4 = absent. All data reported here are based on automated analysis of the data. In addition to perfusion data, the LV ejection fraction, end-diastolic volume, and end-systolic volume were measured from the gated SPECT as previously described (16).
At the conclusion of the protocol, the images were again interpreted side by side in a blinded fashion by 1 reader to qualitatively grade the perfusion pattern as improved, worsened, or no change.
Statistical analysis.
Data are expressed as percentages for discrete variables and mean ± SD for continuous variables. Descriptive statistics were computed for MPI and treadmill exercise variables and were compared between baseline and follow-up tests using paired t tests. All statistical analyses were performed by 1 of the authors (R.V.) using SAS version 9.1 (SAS Inc., Cary, North Carolina). All tests were 2-tailed, and a p value <0.05 was used as the level of significance.
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Results
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We screened 100 patients for 27 potential candidates; 5 declined because of long travel time, and 2 did not have a follow-up study, 1 because of dizziness and the other patient was hospitalized for acute cholecystitis in the interim. The remaining 20 patients completed the protocol, and 17 (85%) patients received ranolazine 1,000 mg twice daily. Mild dizziness was reported by 6 (30%) patients, 3 of whom only received 500 mg twice daily for the duration of 4 weeks. No other significant side effects were reported.
Baseline clinical and laboratory variables are shown in Table 2. Most patients were receiving aspirin, beta-blockers, and statins at baseline. At enrollment, 18 (95%) patients were in Canadian Cardiovascular Society anginal class II for angina pectoris. Finally, in response to the question of "how do you feel since your first imaging study," 15 (75%) patients responded by saying they feel better and used several adjectives to describe their well-being as having more energy or feeling less fatigued, which are difficult to quantify but clearly important from the patients' perspective.
Treadmill exercise testing results.
The end points of exercise in the baseline study were as follows: fatigue in 14 patients, shortness of breath in 2 patients, and chest pain in 4 patients. In the follow-up study, the end points were as follows: fatigue in 14 patients, shortness of breath in 5 patients, and chest pain in 1 patient. The exercise time increased from 393 ± 116 s to 425 ± 105 s after ranolazine treatment (p = 0.017, Fig. 1). There were ST shifts consistent with ischemia in 6 (30%) patients at baseline that persisted at follow-up. There were no significant changes in heart rate, but the systolic blood pressure was slightly lower on ranolazine therapy; the corrected QT intervals did not change (Table 3).
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Figure 1 Change in Exercise Treadmill Times
Change in exercise treadmill times (in seconds) before and after ranolazine therapy. The mean and SD values before and after treatment are shown.
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Quantitative MPI.
These results are shown in Table 4
and Figure 2. The resting perfusion pattern did not change, and hence the changes in perfusion reflected the changes in reversible defects. There was a trend toward a decrease in total perfusion defect size and reversible defect size by polar maps (p > 0.05) and a decrease in summed stress score and SDS (p < 0.05) in the total group. The individual responses are shown in Figure 2, and a representative example is shown in Figure 3. Of note, 1 patient had no perfusion defect in the initial and follow-up studies by automated analysis even though on visual analysis, there was a suggestion of a mild inferior abnormality. He was nevertheless included in this analysis.
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Figure 2 Change in Quantitative Myocardial Perfusion Variables
Changes in summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) (top rows) and changes in total, fixed (scar), and reversible (ischemia) defect size by polar maps (bottom rows). The mean ± SD values are shown in each panel.
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Figure 3 Representative Example of Improvement in Myocardial Perfusion by Single-Photon Emission Computed Tomography
A representative example of exercise myocardial perfusion imaging before and after ranolazine treatment showing quantitative improvement in myocardial perfusion in polar maps. Radionuclide injection was performed at a peak heart rate of 142 beats/min in both tests. The raw images during stress before ranolazine (A, top panel), stress after ranolazine (B, middle panel), and at rest (C, bottom panel) are shown. Each panel shows serial slices from the apex to the base in the short-axis projection and 1 slice at mid left ventricular level in the vertical and horizontal long-axis projections. The perfusion defect size decreased from 25% to 11% of left ventricular myocardium (14% absolute reduction) by polar maps, and the improvement is also visible by visual analysis of the images.
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Based on side-by-side analysis, improvement in the extent and severity of ischemia was noted in 14 (70%) patients. The MPI results in these 14 patients are shown in Table 5. A significant decrease was noted in the extent and severity of the total and ischemic perfusion defect size (all p values <0.025).
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Table 5 Comparison of Myocardial Perfusion Variables Between Baseline and Follow-Up Stress Tests Among Those Who Had Improved Perfusion
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There was no correlation between the change in reversible perfusion defect size and change in exercise time (r = 0.17). However, of the 15 patients who had improvement in angina, 11 also had an improvement in perfusion pattern. There were no interval changes in ejection fraction and LV volume after ranolazine therapy (Table 4).
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Discussion
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The main finding of this study is that an improvement in perfusion pattern during exercise could be demonstrated in most patients with CAD and exercise-induced ischemia after short-term ranolazine treatment at comparable work loads. Most patients who experienced clinical improvement also had improvement in MPI.
Mechanism of action of ranolazine.
Several acquired, congenital, and pharmacological interventions are known to enhance late sodium current (7). This current leads to an increase in intracellular sodium, which, via the sodium-calcium exchange, may cause cellular calcium overload. The calcium overload leads to electrical instability (afterdepolarization and arrhythmias) and mechanical dysfunction with an increase in diastolic tension. Demand-ischemia in patients with CAD such as that during exercise is one of the pathological conditions that presumably activates late sodium current. Hence, the ischemia begets a deleterious positive feedback cycle as the activation of the late sodium current leads to increases in wall tension and further decreases the MBF (17). Ranolazine, by improving diastolic tension, leads to improvement in MBF (3). In animal models of occlusion-reperfusion, ranolazine improved the MBF during reperfusion (11,12). It has also been shown that at therapeutic concentrations, ranolazine improves diastolic tension by shortening repolarization in patients with type 3 long QT syndrome (18).
In pivotal phase 3 trials in patients with stable angina, ranolazine reduced anginal frequency and prolonged the time to ST-segment depression during exercise stress testing (5,9). In patients with acute coronary syndromes (MERLIN–TIMI 36 [Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-elevation Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction 36] Randomized Controlled Trial), ranolazine showed only a modest, nonsignificant effect on ischemia as detected by continuous electrocardiographic monitoring during the initial 7 days after admission, although it had a more robust effect on clinical events that occurred several days after admission (19,20). Ranolazine significantly improved glycosylated hemoglobin (HbA1c) and recurrent ischemia in patients with diabetes mellitus and reduced the incidence of increased HbA1c in those without known hyperglycemia (19–21).
Based on the new labeling of ranolazine as a first-line treatment, many patients with stable angina, like those included in this study, may benefit from ranolazine therapy. Our preliminary findings of improved myocardial perfusion after ranolazine therapy suggest a noninvasive and objective method of follow-up in such patients.
We are unaware of data in humans with ranolazine on either measurements of absolute MBF or relative MBF (by means of MPI as was done in this study) to confirm the animal data. We believe that the improvement in myocardial perfusion reflects improvement in regional MBF and thus is consistent with the previously stated hypothesis. The use of MPI cannot answer the question of whether there was a concomitant improvement in MBF in remote normal zones.
Previous studies.
Multiple studies have shown that antiangina medications such as nitrates, beta-blockers, first-generation calcium channel blockers, and statins can decrease the extent and severity of reversible perfusion defects with serial MPI (2). Measurements of absolute MBF using positron emission tomography provide supportive evidence of the improved perfusion (rather than alternative mechanisms such as partial volume effect due to amelioration of ischemia and stunning). Most previous studies were based on the results of treadmill exercise testing, but there are data to indicate that improvement in myocardial perfusion and MBF could be demonstrated using vasodilator stress testing with adenosine or dipyridamole (2). Of note is that in almost all these studies, there is a considerable interindividual variability in the degree of improvement, and our current results are in agreement with these observations. Such variability was also noted in both arms of the nuclear substudy of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, the optimum medical therapy alone and the optimal medical therapy plus coronary revascularization (22).
Quantitative automated MPI analysis.
The Achilles heel of many imaging modalities is the mode of interpreting the results. Quantitative automated methods are superior to qualitative methods. These issues were recently discussed in detail elsewhere (23,24). For example, in a recent trial in >2,000 patients who had 2 sets of vasodilator imaging within a short period of time, the agreement rates of the presence and extent of perfusion abnormality were 60% by visual analysis and >90% by automated quantitative analysis (16). It is because of this reason that analysis in this study was based entirely on automated quantitative methods. The perfusion defect size is the extent of perfusion defect expressed as the percentage of the left ventricle. The SDS, however, is based on both the extent and severity of the perfusion defect. Thus, an improvement in severity will be reflected in the SDS but not in the perfusion defect size. The improvement in the severity of the ischemia was apparent on visual assessment in the side-by-side analysis and confirmed by the automated analysis.
Study limitations.
Our study has several limitations: these include the size, single-center study, and the lack of randomization or a control arm. The study design may have biased the observed improvement in exercise time with ranolazine, especially in the absence of a placebo arm. Regression to the mean in SPECT results or a training effect is plausible; however, our study should be considered hypothesis-generating, and more definitive studies with larger numbers of patients are needed. Our patients are likely to be representative of other patients with known CAD undergoing exercise testing in terms of total and reversible perfusion defect sizes.
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Conclusions
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In this preliminary hypothesis-driven study, short-term ranolazine therapy was shown to improve myocardial perfusion and decrease the ischemic burden in patients with CAD. These findings might have far-reaching ramifications as to how to define optimal medical therapy and how best to assess the effectiveness of such a therapy. Is it by clinical response, electrocardiographic response, or exercise time, or does it require imaging? The answers to these questions can only be obtained by future carefully designed larger studies.
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Acknowledgments
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The authors acknowledge the help of Misty Pruitt, RN, in data collection.
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Footnotes
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The study was funded by a grant from Gilead Sciences Inc., Foster City, California. Drs. Iskandrian and Blackburn are consultants to Gilead Sciences Inc. Dr. Belardinelli is an employee of Gilead Sciences Inc.
* Reprint requests and correspondence: Dr. Rajesh Venkataraman, University of Alabama at Birmingham, Division of Cardiovascular Disease, 314 LHRB, 1900 University Boulevard, Birmingham, Alabama 35294-0007 (Email: rajeshv{at}uab.edu).
Manuscript received June 24, 2009;
revised manuscript received September 10, 2009,
accepted September 16, 2009.
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Abstract
Methods