Ranolazine for angina in the modern PCI/CABG era: Which patients, which therapies?

Shelley Wood

January 20, 2004

Chicago, IL - More than a month after ranolazine went before the FDA's cardiovascular and renal drugs advisory committee, primary results from the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial, showing it to increase exercise time in angina patients, have been published in the January 21, 2004 issue of the Journal of the American Medical Association[11]. The cart-before-the-horse timing of the paper's publication and FDA review is in keeping with the tortuous path this agent has traveled toward clinical approval.

Now, as Dr Peter Berger points out in an editorial accompanying the study[2], ranolazine may be poised to enter the marketplace at the same time that revascularization therapies—which may do away with angina altogether—are achieving better results, with less risk, than ever before.

CARISA results

The primary results from the CARISA trial were first presented by lead investigator Dr Bernard R Chaitman (St Louis University, MO) at the AHA Scientific Sessions 2001, as reported by heartwire . As Chaitman et al report in JAMA this week, CARISA was designed to evaluate whether ranolazine, a partial inhibitor of fatty-acid oxidation, could increase exercise time in patients with angina already taking atenolol, amlodipine, or diltiazem. CARISA patients (n=823) were randomized to 750 mg of ranolazine twice daily, 1000 mg ranolazine twice daily, or placebo. The patients then did treadmill tests at four hours and 12 hours after dosing after two, six, and 12 weeks on treatment.

The investigators report that improvements in exercise duration and mean time to angina occurred in all three groups but that the degree of improvement in the ranolazine-treated patients was significantly greater than that of the placebo-treated patients. Differences in mean time to ischemia on ECG also occurred, but they were not statistically significant among the three treatment groups.

Angina and exercise test results

Change from baseline

Placebo

750-mg ranolazine

1000-mg ranolazine

Mean exercise duration (s) +91.7 +115.4 (p=0.03)* +115.8 (p=0.03)*
Mean time to onset of angina (s) +114.3 +144.0 (p=0.01)* +140.3 (p=0.03)*
Mean time to ECG ischemia (s) +125.1 +145.1 (p=0.10)* +146.2 (p=0.09)*
*p compared with placebo  

Minor side effects, including dizziness, constipation, and nausea, occurred in roughly one third of all patients, including placebo-treated patients. Five patients in the 1000-mg ranolazine group reported syncope but recovered spontaneously.

-SW

In the FDA advisory panel review of ranolazinewhich did not go to a formal votepanel members said that they were pleasantly surprised by the depth of the safety analysis conducted by the sponsor, CV Therapeutics, to address the syncope issue. Most concluded that syncope and QT-interval prolongation were likely related to the higher dose and would not be a barrier to approving the drug. They did, however, identify other problems with the CARISA trial, including the homogeneity of the study population, the lack of participants who had undergone prior PCI, and the lack of a quality-of-life (QoL) end point.

In an interview with heartwire , Berger stated that he believed QoL measures were important to consider and "reasonable to ask for," not just for approving drugs but also for recommending them to patients. However, he added, "I would have said that the study provided indirect evidence about QoL in that side effects were relatively infrequent and frequency of angina and ability to exercise improved. So, indirectly, the trial did provide some QoL insights."

Antianginal therapies in the drug-eluting stent era

A more important issue to Berger is what he believes is the enduring relevance of medical therapies for angina in the era of rapid advancement of interventional therapies. He notes that, in recent years, both PCI and CABG have become much safer and produce more durable results. In particular, drug-eluting stents have taken PCI outcomes to unprecedented levels of success.

 
A concern of mine is that [drug-eluting stents] will then be applied to clinical situations where patients have only very mild angina that could easily respond to medical therapy.
 

"I think that drug-eluting stents will very quickly be found to be efficacious in a far wider variety of lesion types and clinical situations than have so far been studied, so their use will grow. A concern of mine is that they will then be applied to clinical situations where patients have only very mild angina that could easily respond to medical therapy," he commented. "I think that practice is completely unsupported by everything we know now and that there will continue to be a role for medical therapy."

Berger predicts that ranolazine will ultimately be approved by the FDA and that it could be used to treat patients with angina that is refractory to all other medications, but also patients with mild to moderate angina, both those who have already undergone revascularization and those who have not.

"Not everyone with angina will require revascularization, and even those patients who do require revascularization will often need medical therapy after their procedures, and not only antiplatelet agents and lipid-lowering drugs but also antianginals. Medical therapy will continue to have a role to play in patients with mild angina and not just those with unrevascularizable disease," he said.

A clear picture of ranolazine's future awaits a final decision on the drug by the FDA, which had previously signaled that it would likely approve the drug, then appeared to stall when it asked its advisory panel to comment, but not vote, on the available evidence.

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