No Ranolazine Benefit Against Angina in Small-Vessel Coronary Disease: RWISE

Marlene Busko

November 20, 2015

ORLANDO, FL — Ranolazine (Ranexa, Gilead Sciences) is effective for chronic angina in patients with obstructive CAD, but it did not significantly improve angina symptoms, angina frequency, or coronary flow in a 6-week crossover study of 128 patients (almost all women) with chronic angina due to coronary microvascular dysfunction (CMD)[1]. However, this late sodium-channel inhibitor improved coronary flow reserve in the patients with the worst initial coronary blood flow.

Dr Noel C Bairey-Merz (Cedars-Sinai Heart Institute, Los Angeles, CA), presented these findings from the Treatment With Ranolazine in Microvascular Coronary Dysfunction: Impact on Angina Myocardial Ischemia (RWISE) study at a press briefing prior a late-breaking clinical-trial session at the American Heart Association (AHA) 2015 Scientific Sessions.

The findings "[suggest] that subjects with more severe CMD may benefit [from ranolazine] . . . and should be included in future trials testing strategies to improve myocardial perfusion," she told heartwire from Medscape.

"It's a bit disappointing they didn't reach their primary outcome, and it really speaks to how complex this issue is and that we really need to learn more about the pathophysiology," said AHA spokesperson Dr Lori J Mosca (Columbia University, New York, NY). This is important, since this a fairly common condition, especially among women. Clinicians need to be able to better identify the subset of patients who are likely to benefit from this therapy, she said to heartwire .

Assigned discussant and session comoderator Dr Hiroaki Shimokawa (Tohoku University Graduate School of Medicine, Sendai, Japan) praised Bairey-Merz and colleagues for their seminal WISE study that showed that CMD is common in women and patients have a poor prognosis and said that clinicians should "pay more attention to this very complex disorder."

The current RWISE study "suggests that ranolazine may be effective for [patients with] reduced coronary flow reserve [especially below 2.5], but not others with normal coronary flow reserve," who may benefit from other drugs, he noted.

The findings need to be confirmed with in a larger, longer study, and more research is still needed to unravel the pathophysiology of CMD and determine how to better diagnose it, according to Shimokawa.

Promising Pilot Study

Dr Noelle Bairey-Merz

Little is known about the disease pathway for CMD and nonobstructive CAD, and there are no large outcome trials to guide treatment, Bairey-Merz said. They hypothesized that myocardial ischemia is part of the pathway for angina in CMD, and the late sodium-channel inhibitor ranolazine would improve symptoms.

Ranolazine was approved by the US Food and Drug Administration in 2006 as an add-on therapy to treat unresponsive chronic angina, and in 2008, as first-line therapy for this disease, but the approval studies were primarily done in patients with obstructive CAD.

In 2011, Bairey-Merz and colleagues published results from a pilot study in 20 women with angina, cardiac ischemia (on adenosine stress cardiac MRI), but no obstructive CAD, in which ranolazine appeared to improve angina symptoms[2].

Building on these findings, in 2011 RWISE began enrolling 142 men and women age 18 and older who had chronic angina, no obstructive CAD on a coronary angiogram, and objective evidence of ischemia by noninvasive methods (such as an exercise stress test), at two sites.

A total of 128 patients completed the study and were included in the analysis. Only 35 patients had invasive coronary reactivity testing to determine coronary flow reserve; 67 had less invasive cardiac MRI to determine myocardial perfusion reserve.

At baseline, the 123 women and five men had a mean age of 55. More than two-thirds (68.8%) had shortness of breath, and fewer had palpitations (41.4%) and nausea (31.3%). "You can see that the angina in this . . . population is often shortness of breath as opposed to typical [chest pain]," Bairey-Merz pointed out.

Based on diary entries, on average, patients reported that they had 4.9 angina episodes a week ("moderate" angina) and used nitroglycerin 2.6 times a week.

The patients were randomized to receive 2 weeks of ranolazine or placebo, followed by a 2-week washout period, then 2 weeks of the opposite therapy.

The ranolazine dose was 500 mg twice daily for 1 week, then 1000 mg twice daily for 1 week, if tolerated. About one in five patients returned to the lower dose due to side effects.

The patients were very compliant with therapy; 97% of pills were taken.

Overall, there were no significant changes in the primary outcomes (angina stability and angina frequency determined from the Seattle Angina Questionnaire [SAQ] and the SAQ-7 summary score) or in quality-of-life measures (other than depression symptoms), or in the replies to the Duke Activity Status Inventory questionnaire (a surrogate for physical activity).

Changes in SAQ scores were directly related to changes in myocardial perfusion index. Adverse effects were similar in both groups.

This was a short study, and SAQ may not capture atypical angina symptoms, Bairey-Merz acknowledged. Nevertheless, the study suggests that if a woman has chronic atypical chest pain, "clinicians should measure coronary blood flow invasively or noninvasively," she said.

"Disappointing" RWISE Study

To manage patients with CMD, the current strategy is to start with traditional anti-ischemic drugs, including beta-blockers, calcium-channel antagonists, and nitrates, and continue them, Shimokawa said. If symptoms persist, other anti-ischemic drugs including ACE inhibitors, statins, estrogen, and ranolazine can be added. If those drugs are still ineffective, alternative therapies such as rehabilitation, spinal-cord stimulation, and shock-wave therapy are recommended.

The RWISE study had somewhat vague inclusion criteria and a very short treatment period and used SAQ scores, which were developed in men with obstructive CAD, he noted.

Although the study was negative, since the primary end point was neutral, it suggests that ranolazine may benefit certain sicker patients and provides information to guide further research.

Speaking to heartwire , other observers agreed.

"The WISE study shows that microvascular disease is very prevalent in women, and I would have hoped to see a greater benefit from ranolazine," AHA spokesperson Dr Sidney C Smith, Jr (University of North Carolina at Chapel Hill) echoed.

Press briefing moderator Dr Raymond J Gibbons (Mayo Clinic, Rochester, MN) said, "From my standpoint, it's great that somebody tested [ranolazine], because as the discussant showed, it's very frequently used in the belief that 'maybe this'll help,' but there's no evidence to show it'll help, and certainly from this study, it doesn't help."

"Does giving this to a patient make them feel better? The answer is 'no,' " Smith agreed. This is not a "trivial" issue, because microvascular disease is so common in women, he stressed, like the others.

The study has been accepted for publication in the European Heart Journal, Bairey-Merz announced.

WISE is an NHLBI-sponsored study partly funded by Gilead Sciences. Bairey-Merz receives research grants from Gilead; is on the speakers' bureau of Practice Point Communications, Pri-Med, and Vox Media; and receives honoraria from the American Association of Clinical Endocrinologists; American College of Cardiology AZ Chapter; Florida Hospital; Mayo Scottsdale; Mayo Cancun; NAMS; Vascular Biology Working Group; University of California, Los Angeles; University of Chicago; Northwestern; Radcliffe Institute; and University of California, San Francisco. She is a consultant for or on the advisory boards of Amgen, Gilead, Medscape, Pfizer, and Scripps. Disclosures for the coauthors are listed in the abstract. Gibbons is a consultant for Lantheus Medical Imaging, Astellas Pharmaceuticals, Stealth Peptides, and Mobility (Lenovo).


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