When a study reveals that a product can produce a 30% reduction in mortality as a result of sudden cardiac death (SCD), the particular subject of that trial probably has a bright future. That is the primary implication of the Multi-center Automatic Defibrillator Implantation Trial (MADIT II), according to Lehman Brothers (New York), medical technology analyst David Gruber, MD, and Joseph Smith, MD, PhD, director of the Arrhythmia Institute, in a conference call held in mid-December.
MADIT II was scheduled to run until 2003 but was stopped by the FDA before completion, due to the compelling evidence of lifesaving potential provided by the implantable cardioverter defibrillator (ICD) technology for those who had already had one myocardial infarction (MI). And what is good for Guidant (Indianapolis Indiana), whose ICD technology was used in the trial, ought to be good for the entire sector. Gruber said that the results "reveal that there is clearly a mortality benefit, that market expansion is likely and that earnings per share [EPS] impact from the results will vary by company, based on sales assumptions and the amount of shares outstanding."
MADIT II compared the mortality rates from SCD for those with the Guidant ICDs vs. patients receiving conventional pharmaceutical treatment. A randomized, multicenter study supported by a grant from Guidant, the trial followed more than 1,200 patients who had survived a heart attack and had moderate impairment of the left ventricle.
Smith said also that MADIT II is significant because it does not speak solely to heart failure doctors but had broader implications. "If this were really a heart failure trial [alone], the implications might not be as immediate," he said. He noted that the results are based on ejection fractions "and that's something that every cardiologist and many internists are very familiar with ... and the likely uptake from this is a lot more immediate than if it were just heart failure patients." Smith noted ejection fraction as a key indicator: "It's absolutely clear that if you base your decisions on this trial, that if your ejection fraction is less than 30[%] and you've had a heart attack, you will get a defibrillator." Smith also noted that just since the results of the trial, he has seen a marked increase in the number of referrals for ICDs. "I've already put in devices based on this trial. The uptake has been very quick."
However, Smith stopped short of saying that this trial makes ICD use the standard of care. "We've not even seen [the results] reviewed in a peer-reviewed format. But it certainly is something that people are willing to adopt once we give them the green light ..." He added that his practice alone could see a two- to three-fold increase in the number of implants done in the next six to 12 months. His practice now implants around 350 ICDs per month, he said. And of a total patient population of roughly 6.5 million post-MI patients, Smith estimated that about a quarter of those would have the defining ejection fraction of less than 30% to qualify for the device.
Smith said the trial was easy to understand and showed results that were consistent with similar trials, so there shouldn't be many criticisms. But he noted that the data presented in this study are not quite as compelling as the MADIT or MUSTT data in which the numbers were more like 50% relative reductions in mortality. However, "decreasing mortality by 30% is a number that people can get their arms around readily. That's not something you can walk away from," Smith said.
Smith also addressed the issue of obsolescence, suggesting that ICDs may be superseded by other technology before having a chance to take root. People waiting to put in a bi-ventricular pacing/defibrillator device, "when such a product is approved by the FDA," might slow down the effect of the positive MADIT II results. Looking at ICD sales, Gruber estimated an incremental $100 million increase in 2002 and $240 million in 2003.
Estrogen levels linked to chest pain
A host of indicators have been explored that correlate to heart problems, and a group of Japanese researchers have now produced researching linking fluctuations in estrogen levels in pre-menopausal women to chest pain called variant angina. The study, published in the Dec. 4, 2001, issue of the journal Annals of Internal Medicine, found that the chest pain occurred less frequently when levels of estrogen were highest. The conclusion is significant because women's risk for cardiovascular disease appears to increase sharply after menopause, striking on the average 10 years later than in men.
Dr. Hiroaki Kawano and colleagues at Kumamoto University followed 10 premenopausal women with variant angina, which tends to occur when a person is at rest and is caused by spasms that narrow heart arteries and impede blood flow to the heart. The researchers kept track of the women's estrogen levels and other hormones during their menstrual cycles and measured the response to increased blood flow in the brachial artery in the arm. They found that chest pain occurred least often around the time of ovulation, when estrogen levels and blood-vessel responsiveness peaked. Since estrogen is known to relax smooth muscle, it is possible that the hormone has a similar effect on the lining of blood vessels, making them more responsive to increased blood flow, according to the researchers.
One conclusion of the study was that premenopausal women do not always benefit from the cardioprotective effect of estrogen because of the fluctuation in their estrogen levels. And the researchers theorized that women with hardening of the arteries or other cardiovascular risk factors may have a greater risk of heart attack at the end of the luteal period of the menstrual cycle to the start of menstruation, when estrogen levels are low.