Author + information
- Received October 9, 2012
- Revision received November 29, 2012
- Accepted December 5, 2012
- Published online April 1, 2013.
- Lars S. Maier, MD∗∗ (, )
- Beth Layug, MD†,
- Ewa Karwatowska-Prokopczuk, MD, PhD†,
- Luiz Belardinelli, MD†,
- Stella Lee, MS†,
- Julia Sander, MS∗,
- Christian Lang, MS∗,
- Rolf Wachter, MD∗,
- Frank Edelmann, MD∗,
- Gerd Hasenfuss, MD∗ and
- Claudius Jacobshagen, MD∗
- ↵∗Reprint requests and correspondence:
Dr. Lars S. Maier, Department of Cardiology and Pneumology, Heart Center/Georg-August-University Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Objectives This study investigated whether inhibiting late Na+ current by using ranolazine improved diastolic function in patients with heart failure with preserved ejection fraction (HFpEF).
Background HFpEF accounts for >50% of all HF patients, but no specific treatment exists.
Methods The RALI-DHF (RAnoLazIne for the Treatment of Diastolic Heart Failure) study was a prospective, randomized, double-blind, placebo-controlled small proof-of-concept study. Inclusion criteria were EF ≥45%, a mitral E-wave velocity/mitral annular velocity ratio (E/E′) >15 or N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration >220 pg/ml, a left ventricular end-diastolic pressure (LVEDP) ≥18 mm Hg, and time-constant of relaxation (tau) ≥50 ms. Patients were randomized to ranolazine (n = 12) or placebo (n = 8). Treatment consisted of intravenous infusion for 24 h, followed by oral treatment for 13 days.
Results After 30 min of infusion, LVEDP (p = 0.04) and pulmonary capillary wedge pressure (p = 0.04) decreased in the ranolazine group but not in the placebo group. Mean pulmonary artery pressure showed a trend toward a decrease in the ranolazine group that was significant under pacing conditions at 120 beats/min (p = 0.02), but not for the placebo group. These changes occurred without changes in left ventricular end-systolic pressure or systemic or pulmonary resistance but in the presence of a small but significant decrease in cardiac output (p = 0.04). Relaxation parameters (e.g., tau, rate of decline of left ventricular pressure per minute [dP/dtmin]) were unaltered. Echocardiographically, the E/E′ ratio did not significantly change after 22 h. After 14 days of treatment, no significant changes were observed in echocardiographic or cardiopulmonary exercise test parameters. There were no significant effects on NT-pro-BNP levels.
Conclusions Results of this proof-of-concept study revealed that ranolazine improved measures of hemodynamics but that there was no improvement in relaxation parameters. (Ranolazine in Diastolic Heart Failure [RALI-DHF]; NCT01163734)
Approximately half of the patients with heart failure (HF) have diastolic HF, often referred to as HF with preserved ejection fraction (HFpEF) (1–3). The prognosis of HFpEF is comparable to that of systolic heart failure (SHF) with a 5-year mortality rate of ∼50% (1,3–5). Whereas a variety of evidence-based therapies exist for the improvement of symptoms and prognosis for SHF patients, treatment options for HFpEF patients are limited (1,6–8). To date, there is no evidence-based treatment for HFpEF patients, and most clinical trials using pharmacological agents have failed (6,9–11). Recently, exercise training has been shown to improve left ventricular diastolic function, exercise capacity, and quality of life (12).
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In patients with end-stage HF, late Na+ current (INa) is increased in cardiac myocytes, leading to elevated intracellular Na+ levels and Ca2+ overload (13–15). This raises diastolic tone of the heart, contributing to diastolic dysfunction. By inhibiting late INa using ranolazine, Na+ accumulation can be decreased (15,16). Hence, ranolazine would be expected to promote Ca2+ extrusion through the Na+/Ca2+ exchanger and thereby improve diastolic tension and relaxation. Data from a HF dog model indicate that ranolazine improves diastolic function (e.g., in left ventricular end-diastolic pressure [LVEDP]) as a parameter for diastolic dysfunction (17). Furthermore, ranolazine has been shown to improve diastolic function in patients with coronary artery disease (18,19).
The objective of this proof-of-concept trial was to determine whether ranolazine improves diastolic function in HFpEF patients.
The RALI-DHF (RAnoLazIne for the Treatment of Diastolic Heart Failure) study was a prospective, single-center, randomized, double-blind, placebo-controlled proof-of-concept study (NCT01163734, EudraCT 2009-017168-17).
Patients with symptoms of HF (New York Heart Association [NYHA] class II to III) were screened for inclusion in the study. Inclusion criteria consisted of left ventricular ejection fraction (LVEF) ≥45%, a mitral E-wave velocity/mitral annular velocity ratio (E/E′) >15 or an N-terminal pro–B-type natriuretic peptide (NT-pro-BNP) concentration >220 pg/ml at screening, and as continued eligibility criteria, an average resting LVEDP ≥18 mm Hg, as well as resting time constant of relaxation (tau) ≥50 ms during cardiac catheterization (2,9).
Study conduct and procedures
The study consisted of an intravenous bolus injection and continuous infusion of ranolazine or placebo for 24 h. One hour prior to the end of the 24-h infusion, patients were started on an oral study drug regimen, 1,000 mg twice daily, which they continued for 13 days (Fig. 1A).
Invasive hemodynamic measurements were performed initially, before the first intravenous bolus of study drugs. Pacing was performed at 120 beats/min for better comparison among patients, and hemodynamic and pressure measurements were collected again (20). These measurements were repeated 30 min after the initial intravenous bolus administration under both resting and paced conditions for two reasons: first, the goal was to further impair diastolic filling, and second, we wanted to exclude differences in heart rate as a confounder.
Tissue Doppler echocardiography and 12-lead electrocardiography were performed before catheterization, repeated 60 min prior to administration of oral study drug, and at day 14. Cardiopulmonary exercise test (CPET) was performed at baseline and on day 14.
Exploratory endpoints were 1) changes from baseline to 30 min in hemodynamic parameters under resting and paced conditions, including LVEDP, rate of decline of left ventricular pressure per minute (dP/dtmin), and tau (20); and 2) changes from baseline to day 14 in echocardiographic parameters including E/E′, CPET parameters including oxygen consumption (Vo2max), and NT-pro-BNP.
Between-treatment comparisons of all exploratory efficacy endpoints were analyzed using the Wilcoxon rank sum test. Within-treatment comparisons were analyzed using the Wilcoxon signed rank test. Values are mean ± SEM. A detailed Methods section can be found in the Online Appendix.
Twenty patients received the study drug and completed the trial (Fig. 1B). Table 1 summarizes baseline patient characteristics, which were comparable among patients between the groups. Basal functional parameters (Table 2) showed severe diastolic dysfunction in the presence of unaltered systolic left ventricular function.
Table 3 shows hemodynamic data during resting conditions. After 30 min, LVEDP decreased significantly in the ranolazine group (from 21.3 ± 1.0 mm Hg to 19.1 ± 1.7 mm Hg, p = 0.04) but not in the placebo group (Fig. 2A). Most of the patients in the ranolazine group showed a decrease in LVEDP (Fig. 2B). A comparison of the two groups showed no significant differences. Pulmonary capillary wedge pressure (PCWP) significantly decreased in the ranolazine group (from 14.3 ± 1.9 mm Hg to 12.2 ± 1.9 mm Hg, p = 0.04) but with a modest difference compared to that in the placebo group (p = 0.05) (Fig. 3A). Individual results underline the average data (Fig. 3B). Mean pulmonary artery pressure (mPAP) showed a nonsignificant decrease in the ranolazine group (Fig. 4A) that was statistically significant under pacing conditions (from 26.5 ± 2.7 to 25.2 ± 2.5, p = 0.02), without changes for the placebo group (Fig. 4B, Online Table).
These changes occurred without decreases in left ventricular end-systolic pressure or systemic or pulmonary resistance in the ranolazine group. Interestingly, there were no changes with respect to relaxation kinetics (e.g., tau, dP/dtmin) (Table 3).
Cardiac output at rest decreased in the ranolazine group (from 4.3 ± 0.2 l/min to 4.0 ± 0.2 l/min; p = 0.04) but not in the placebo group. This effect was more pronounced under pacing conditions (p < 0.01) (Online Table). Similarly, dP/dtmax decreased from 2,024.1 ± 167.7 mm Hg/s to 1,706.2 ± 74.3 mm Hg/s (p = 0.01) and stroke volume from 42.4 ± 2.1 ml to 37.5 ± 2.3 ml (p < 0.01) (Online Table) without changes in the placebo group under pacing conditions.
Cardiopulmonary exercise test
Table 4 shows CPET parameters at baseline and after 14 days. There were no significant changes between placebo and ranolazine parameters.
Table 5 shows echocardiographic data at baseline, after 22 h, and after 14 days. There were no significant differences between any of the parameters in either group.
Pharmacokinetic parameters of ranolazine
Mean ranolazine plasma concentrations were 1,610 ng/ml at 10 min, 4,036 ng/ml at 20 min, 3,109 ng/ml at 30 min, and 5,370 ng/ml at 22 h. Based on concentration-time data, the mean minimum ranolazine plasma concentration was 1,610 ± 108 ng/ml, and the peak plasma concentration was 5,595 ± 490 ng/ml.
Laboratory test parameters
NT-pro-BNP values were elevated in both groups but did not change significantly during follow-up. No other laboratory test value showed a significant change during the course of the trial.
Safety parameters and side effects
There were no changes in systolic and diastolic blood pressure or heart rate (Table 6). There were nonsignificant increases in QT and QTc intervals in the ranolazine group but not in the placebo group. No other electrocardiography parameters showed any significant changes. No patient had arrhythmias (Table 7).
Adverse events were experienced by 87.5% of patients in the placebo group and by 83.3% of patients in the ranolazine group (constipation, vertigo, hematoma, nausea, back pain, hypotension, headache). The proportion of patients with constipation was higher in the ranolazine group (58% vs. 0% in the placebo group), whereas all other adverse events were comparable between groups. Three patients (ranolazine group) had serious adverse events: in 2 patients these events were considered related to the cardiac catheterization procedures. One patient experienced severe musculoskeletal pain attributed to a preexisting condition (a previous rib fracture).
Results of this proof-of-concept study showed that ranolazine given intravenously for 24 h in patients with HFpEF was safe and modestly improved some important measures of diastolic function with decreases in LVEDP and PCWP during resting conditions and decrease in mPAP during paced conditions. After 14 days of oral treatment, no significant changes in noninvasive measures for diastolic function were observed.
Preclinical and clinical evidence for altered handling of Ca2+ and Na+ in diastolic dysfunction
Ranolazine, a potent late INa inhibitor, may normalize altered intracellular Ca2+ concentration due to the close relationship between Na+ and Ca2+ handling by the Na+/Ca2+ exchanger. Until now, ranolazine has been clinically investigated only as an antianginal agent in patients with coronary artery disease (21–23).
In vivo experiments suggest that late INa inhibition may be a potential therapeutic approach to improving diastolic function, but no placebo-controlled study has been performed (17).
In the MERLIN–TIMI-36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes–Thrombolysis In Myocardial Infarction-36) trial, patients with acute coronary syndrome treated with ranolazine showed a significant improvement in the combined primary endpoint (cardiovascular death, myocardial infarction, recurrent ischemia) if BNP levels were elevated (24). Because BNP levels are known to be indicative of increased wall tension, the beneficial effects of ranolazine in this group of patients may suggest an improvement of wall stress and diastolic function.
Acute ranolazine effects
The present data with immediate, although modest, improvements in LVEDP, PCWP, and mPAP in the presence of ranolazine suggest the potential role of late INa inhibition in the treatment of diastolic dysfunction. Of interest, these findings occurred with unchanged pulmonary and systemic resistance, which makes pure vasodilation as the underlying mechanism for the decrease in filling pressures rather unlikely. However, whether the small changes in pressure of ∼2 mm Hg in the presence of ranolazine actually may have any clinical relevance remains to be determined in a larger trial.
Hemodynamic relaxation kinetics (e.g., dP/dtmin and tau) were not affected by ranolazine. This finding is consistent with a recent in vitro report showing a lack of an improvement by ranolazine in active relaxation, although diastolic dysfunction over time was improved (15). Mechanistically, in diastolic HF there seems to be a difference between passive (or late-phase) relaxation, which may well be related to diastolic tension, and hence, improved by ranolazine due to improvement in slow Na+-dependent Ca2+ overload, and active (or early) relaxation, which would be more related to sarcoplasmic reticulum reuptake of Ca2+ ions from beat to beat, and, hence would not be affected by ranolazine.
A report of 5 patients with LQT3 syndrome showed that ranolazine caused an improvement in relaxation (25). This discrepancy may be the result of differences in levels of late INa and its relative contribution to ventricular repolarization/relaxation in different diseases. Hence, the magnitude of the reduction in late INa (estimated by changes in QTc) by ranolazine was much larger with a mean QTc shortening of 26.3 ± 3.5 ms, whereas in the present study of HFpEF patients, no QT shortening was observed.
Pulmonary hypertension (PH) is highly prevalent and often severe in HFpEF and is associated with increased mortality (26). Although a precapillary component is frequent in PH and HFpEF, there are concerns regarding the use of pulmonary vasodilators because increasing right heart output may result in further increases in left atrial pressures (27). In this study, ranolazine decreased mPAP without effects on PVR. Baseline mPAP was 24.4 mm Hg in the ranolazine group and 28.7 mm Hg in the placebo group, indicating a mild PH. It might be speculated whether, in HFpEF and severe PH, the effect of ranolazine on mPAP would be more pronounced.
Cardiac output, dP/dtmax, and stroke volume decreased slightly in the presence of ranolazine, indicating an acute reduction of systolic function. This is in line with in vitro observations demonstrating a mild negative inotropic effect of ranolazine (15). One explanation may be that ranolazine reduces intracellular Na+ and Ca2+ levels and hence reduces actin/myofilament interaction. A recent finding suggests that ranolazine causes a small decrease in myofilament Ca2+ sensitivity in a mouse model of diastolic dysfunction (28). Whether the changes in dP/dtmax and stroke volume are clinically relevant is speculative, but it is possible that these effects may offset the positive effects on diastolic function. Nevertheless, systolic blood pressure and EF remained unaffected throughout the study. In this regard, it should be noted that even beta-blockers acutely exert negative inotropic effects but improve systolic function and prognosis over time in patients with SHF (29). Hence, a small negative acute reduction in inotropy does not preclude positive long-term results in HF.
Effects of ranolazine after 14 days
After 14 days of treatment, we did not see any significant changes in echocardiographic and CPET data. The number and severity of adverse events were similar in both groups. Therefore, within the range of the limited number of study participants in the RALI-DHF study, ranolazine can safely be applied in HFpEF.
An abnormal handling of Ca2+ and Na+ is only one of several factors contributing to diastolic HF. Increased interstitial deposition of collagen and modified matricellular proteins also contribute to increased myocardial stiffness and slowed LV relaxation (30). Tau and other parameters for relaxation (e.g., t relax [time of relaxation], t sys [time in systole], and t dias [time in diastole]) were unaltered in this study and were markedly higher than those in a previous study, indicating severe diastolic HF in patients of the current study (20). Thus, a short-term treatment of ranolazine (acutely and up to 14 days) is not sufficient to affect the structural pathophysiology, and therefore, may be too short to detect beneficial effects in noninvasive parameters.
Also, we are aware of discrepancies between previous invasive positive proof-of-concept reports and several subsequent negative clinical trials and thereby acknowledge that there is no evidence that changes induced acutely by ranolazine would be predictive of the long-term beneficial effects.
The RALI-DHF study is considered exploratory, and therefore, there is no statistical justification for the present sample size. Post hoc analysis with power calculations assuming a two-sided alpha of 0.05 and a 1:1 randomization suggested a 39% power for LVEDP, 75% for PCWP, and 70% for mPAP when including 40 patients instead of 20 patients (currently 21%, 44%, and 40%, respectively).
Finally, we have to acknowledge that some of the significant results of this study could have been the results of chance because of the small number of patients studied and the multiple hypotheses tested.
Results of this proof-of-concept study revealed that ranolazine improved measures of hemodynamics, but that there was no improvement in relaxation parameters.
This study was funded by Gilead Sciences, Inc. Dr. Maier was funded by Deutsche Forschungsgemeinschaft (DFG) (MA1982/4-2, TPA03 SFB 1002) and Fondation Leducq as well as by the DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung). Dr. Maier received research grants from Gilead, Inc.; and serves as consultant with Berlin-Chemie. Drs. Jacobshagen, Wachter, and Edelmann have received honoraria from Berlin-Chemie. Drs. Layug, Karwatowska-Prokopczuk, Belardinelli, and Lee are employees of Gilead, Inc.
- Abbreviations and Acronyms
- cardiopulmonary exercise test
- diastolic heart failure
- mitral E wave velocity/mitral annular velocity ratio
- ejection fraction
- heart failure
- late INa
- late Na+-current
- left ventricular end-diastolic pressure
- N-terminal pro-B-type natriuretic peptide
- New York Heart Association
- pulmonary artery pressure
- pulmonary capillary wedge pressure
- pulmonary hypertension
- pulmonary vascular resistance
- systolic heart failure
- systemic vascular resistance
- time constant for relaxation
- Received October 9, 2012.
- Revision received November 29, 2012.
- Accepted December 5, 2012.
- American College of Cardiology Foundation
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