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Cardiology Drugs Of The Year: New, Old, And Not-So-Funny

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New Drug Of The Year

This was an easy choice. The new drug of the year is LCZ696, the upcoming heart failure drug from Novartis. At the beginning of the year only a few heart failure experts were aware of it, and no one in the heart failure community or on Wall Street had even suggested that it might be a blockbuster. Expectations, if any, were that the drug would join the long string of recent failures of novel cardiovascular drugs, especially since LCZ696 is a chemical cousin to omipatrilat, the Bristol Myers drug which certainly counts as one of the most spectacular drug failures of all time.

Then, on the last day of March, during the American College of Cardiology meeting, Novartis issued a press release disclosing that the pivotal phase 3 LCZ696 trial, PARADIGM HF, had been stopped early on the recommendation of the Data Monitoring Committee because of a significant reduction in the combined primary endpoint of cardiovascular death and heart failure hospitalization. The initial announcement garnered only modest interest, since by now many observers have learned to be skeptical when a trial is stopped early. Too often the results don't hold up or reflect a statistically significant difference that may not translate into clinical significance.

But that changed a day later when Milton Packer, the co-principal investigator of the trial, pulled me aside at another ACC session to let me know that, for once (and to its ever-lasting credit) the trial sponsor had actually downplayed the full importance of the result. Packer told me that “the press release implies that the trial was stopped for the primary endpoint but that was not the case, the trial was stopped for a persuasive effect on cardiovascular mortality alone, and my enthusiasm was based on that very persuasive effect.”

It was this bit of news that prompted initial speculation, by myself (here and here) and others, that LCZ696 might be a big deal. Over the next few months the excitement and anticipation grew. The presentation of the actual results, at the European Society of Cardiology meeting at the end of August, became a major event. Despite a certain amount of pushback from skeptics the general consensus so far is that the trial has held up under fire. It now appears that LCZ696 may be poised to replace ACE inhibitors and ARBs as the gold tandard of treatment for heart failure. That's a big deal.

It's hard to say just how big LCZ696 will be in the real world. Analysts have now routinely started referring to it as a blockbuster. I think they may well be right, but until PARADIGM HF undergoes thorough scrutiny from the FDA I won't be satisfied. And there's always the danger that some sort of problem could crop up that could kill or wound the drug. One possibility-- remote but not impossible, based on studies in animals-- is that the drug might increase the risk of dementia. You can be sure the FDA and others will be looking very hard for signs of problems like these. And remember, it could only take an early signal of a problem like that to derail or seriously delay drug approval or acceptance. Sales predictions range from $1 or $2 billion a year to as high as $6 billion a year. I try not to predict the future. The past is hard enough to understand.

Speaking of the past. If LCZ is the new drug of the year, then ezetimibe is without doubt the

Old Drug Of The Year

LCZ696 represents the future of cardiology. Ezetimibe, by contrast, represents the past, and, in particular, the last decade of controversy, scandal, and gigantic missteps. (Ezetimibe is marketed by Merck as Vytorin and Zetia.) With any luck the final presentation of IMPROVE-IT at the American Heart Association meeting in November heralded the end of this miserable era. I've written extensively about IMPROVE-IT (here and here) in the past so I won't repeat myself. Suffice it to say that after 12 years we know, finally, that ezetimibe works. Sort of. Here's Marilyn Mann's summary:

...the benefit was small, a 6.4% reduction in risk of the primary endpoint (composed of cardiovascular death, heart attack, unstable angina requiring hospitalization, coronary revascularization, and stroke). In the high-risk trial participants — all patients who had been hospitalized for acute coronary syndrome within the 10 days before randomization — this translated to a 2% absolute benefit over 7 years. Of note, there was no reduction in all-cause or cardiovascular mortality.... it is regrettable that we had to wait 12 years after the drug’s approval to find out whether it improves outcomes.

 Not-So-Funny Drug Of The Year

There's nothing really funny about ivabradine, the drug marketed in Europe by Servier under the brand names of Corlentor and Procoralan and where it is approved for use in heart failure and stable angina. In the US it is not available but is under development by Amgen for the heart failure indication. The drug slows the rate of the heart by inhibiting the so-called “funny” current within the heart’s natural pacemaker, the sinoatrial node, but the news this year about the drug has been anything but funny.

A very large trial, called SIGNIFY, turned up some surprising and troubling findings. The trial tested a high dose of ivabradine in more than 19,000 patients with stable angina. Although the overall results were neutral, serious problems emerged in the very large subgroup (more than 12,000 patients) with symptomatic angina. This prompted a review by the European Medicines Agency (EMA) which concluded that ivabradine, when compared with placebo, had a small but significant increase in the risk of CV death and nonfatal MI (3.4% vs 2.9% yearly incidence rates) and a substantially higher risk of bradycardia (17.9% vs. 2.1%). The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) concluded that ivabradine “should only be started if the patient’s resting heart rate is at least 70 beats per minute.” The drug should only be used for the symptomatic relief of angina because it “has not been shown to provide benefits such as reducing the risk of heart attack or cardiovascular death.”

There was some funny business from the SIGNIFY investigators at the European Society of Cardiology meeting in Barcelona. At the last moment they backed out of participating in a scheduled news conference to discuss the results of SIGNIFY. They told the ESC that the EMA had asked them to keep quiet until the EMA investigation had concluded. But the EMA denied this story and told me that "at no point did the EMA request the investigators of the SIGNIFY trial and colleagues not to discuss or comment on their trial.... researchers are free to publish and discuss their findings in public.”

Given our current knowledge about ivabradine, however, many cardiologists without connections to Servier or Amgen are wondering why on earth any doctor would actually prescribe the drug. They are not being funny.