He was mad.
He thought he’d been sold a bill of goods.
You see he’s a cardiologist who reads and pays attention to all things new in an attempt to offer leading-edge innovations to his patients. He attended this meeting to inquire about little known safety data about the drug ranolazine (Ranexa).
In January 2006, the FDA approved ranolazine, a piperazine derivative, as a new drug for patients with angina (chest pain) refractory to conventional medical therapy. It was hailed as the first new drug to help patients with angina in the past 10 years. One of its mechanisms of actions is to inactivate slowly inactivating component of the late inward sodium channel which may reduce the deleterious effects of calcium overload and intracellular sodium that accompany cells of the heart when they lack oxygen. But the drug also prolongs QT interval, an important determinant of potential lethal arrhythmias in patients with diseased hearts from coronary blockages.
To serve as a bit of background, QT prolongation came to light as a cause of mortality in a much earlier drug trial called the Coronary Artery Arrhythmia Suppression (CAST) trial. This trial tested the safety of drugs that suppressed premature ventricular beats well but also prolonged the QT interval – and was shown to have an increased mortality of patients in the drug treatment arm as compared to placebo. Many, many other drugs have never made it to market (or have been pulled from the market, witness the withdrawl of terfanidine (Seldane)) because of QT prolongation effects and pro-arrhythmia.
The company had a "hired gun" expert speaker to present their data from the trials presented to the FDA called the MARISA, CARISA, and ERICA trials. The data from the clinical trials looked great. Ranexa was clearly the one and only QT-prolonging drug out there that was safe for patients with chronic refractory chest pain. At least so it seemed. But there were troubling issues about these trials.
First, there was the usual conflict-of-interest issues. Most of the "investigators" of the MARISA and CARISA trials were either paid grant recipients, consultant/speakers, or on CV Therapeutics' payroll and owned stock in the company. Worse still, the longest follow-up period of any of these trials was 12 weeks.
Concerns about QT prolongation were not lost on the US Food and Drug Administration, even in 2004. In the report from the 100th Cardiovascular and Renal Drugs Advisory Committee Meeting, ranolazine was reviewed and “the principle safety issue with the drug was related to QT prolongation.” The committee tabled approval but wanted long-term efficacy data in females, elderly patients, and African Americans.
So the presenting "doctor expert" was asked a question. He was asked how any drug could have been approved with only 12 weeks of clinical data upon which to base safety concerns – especially in a drug known to prolong the QT interval of such sick patients. My colleague was told by the respected physician speaker that night that "no data" exists to suggest the drug is anything but safe in this patient population.
But some data do exist on the FDA's website. In their slides, CV Therapeutics claimed that the efficacy and safety of ranolizine demonstrated “No evidence for an adverse effect of ranolazine on survival.” (See slide 27 of the FDA’s Powerpoint presentation by Dr. Thomas Wolff). But then we look at Slide 26 – the slide just before this that includes 4-month follow-up data of deaths found by “pharmacovigelence” after the study completion -- here’s what the slide says:
|Cause of Death||Therapy||Events||Follow-up,Pt yr||Incidence(%) (95% CI)|
|Sudden Death, death due to ventricular fibrillation/tachycardia or cardiac arrest||Placebo||2||169.3||1.17|
There it is: 4-month safety data that demonstrates an increased cardiovascular and all-cause mortality incidence in folks on ranolazine. Yet the drug was approved by the FDA in January 2006.
Can this be true? Was this slide not presented to the FDA reviewers? Did they not see this?
Well it seems they did. I called Michael Sweeney, MD, Vice President of Medical Affairs at CV Therapeutics, and he was kind enough to return my call. He acknowledged the event findings in the slide above, but because the numbers fell well within the 95% confidence intervals, they were not considered significant. Over a
Now the company has embarked on a large 6500-patient, randomized, double-blind, placebo-controlled multinational clinical trial to evaluate the drug as treatment for adjunctive treatment in acute coronary syndromes (Heart attack and unstable angina) called the MERLIN-TIMI 36 trial (MERLIN is a pneumonic for Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-elevation acute coronary syndromes) in an attempt to extend its clinical indications. This study results are to be released at 8:50 am Central Standard Time on March 27,2007 as a late-breaking trial at the American College of Cardiology Meeting in New Orleans, LA. The trial will evaluate safety and efficacy of ranolazine after 730 cardiovascular events and 310 deaths have occurred during the study period. It is important to realize that the study’s Data Safety Monitoring Board met when one half of the patients had their pre-determined adverse event and elected to continue the study (good news for CV Therapeutics). But given the company’s own follow-up data, it begs a question:
Given the former FDA data, has the MERLIN genie already been let out of the bottle regarding the safety of this drug in patients with chronic ischemic coronary disease?
There are long stock-holders who are painting a rosy picture of this drug’s chances, particularly since this individual notes that other large institutional investors are increasing their positions in CV Therapeutics.
So go ahead and take your chances. Make a guess how ranolazine will fair. But I'm waiting until the MERLIN TIMI-36 data are presented in March before any of my patients with chronic ischemic coronary disease are placed on this drug.
18:16PM Link fixed to FDA slides
Clarification: Several commentors to this post (see attached) have correctly pointed out the calculation for safety risk represents a 1.5:1 rather than 10:1 difference as I posted earlier. I regret the error.