Thank you Bill. As Dr. Boden mentioned, the AIM-HIGH DSMB met regularly to go over the trial data. By the time of the group’s most recent meeting on April 25, AIM-HIGH had already achieved the enrollment goal for the study, there was an excellent level of adherence to study medication, and participants had achieved the intended targets of higher HDL Cholesterol, lower triglycerides and similar levels of LDL-Cholesterol. However, at that April 25th meeting, after a thorough review of all the data, the DSMB recommended stopping the study and, after careful review, the NHLBI accepted that recommendation and stopped AIM-HIGH.
The trial was stopped because the data showed that there was less than a 1 in 10,000 chance that the trial would ever show the expected benefit planned in the protocol on the primary outcome measure, that is, a reduction in the combined rates of coronary heart disease deaths, non-fatal heart attacks, stroke due to blockage of arteries leading to the brain, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization surgeries.
The DSMBs of well-designed trials such as AIM-HIGH establish boundaries at the beginning of the study to guide their recommendations as the independent group reviews the data. These boundaries improve guidance in the situation that the trial is showing unexpected early benefit or lack of benefit. In AIM-HIGH, the pre-established mark for showing a lack of efficacy, was reached before the planned end of the trial. The April 25th meeting was the second consecutive meeting at which this boundary was crossed.
Since the NHLBI’s decision to stop the trial, we have notified all participants and investigators and we are now notifying all of the primary care physicians of the participants.
The DSMB also observed that while the total number of strokes among study participants was low, there was an imbalance in the occurrence of strokes which reached a level of statistical significance. In AIM-HIGH there were 40 participants who had strokes due to blockage of arteries to the brain, known as ischemic stroke; 28 of those occurred in the Niaspan® group. We are performing further analyses to explore this unexpected finding. No similar finding has been observed in previous studies with any form or dose of niacin therapy given for any length of follow-up. And as Dr. Boden said, until AIM-HIGH, previous studies had shown a consistent reduction in stroke associated with niacin use. I would also like to note that one-third of the strokes in the niacin group occurred long after Niaspan was stopped by those participants in this study.
There were no signs of significant adverse side effects in the study beyond the expected increase in flushing and skin irritation frequently associated with niacin. Participants had a modest amount of flushing.
I want to re-emphasize that statin therapy has proven benefit from previous studies. As Dr. Boden described earlier, all participants in AIM-HIGH were treated with statin therapy. Statins are a well-established therapy for the treatment of fatty deposit-related cardiovascular disease and they have been shown in other studies to reduce all of the main cardiovascular events that we measured in AIM-HIGH. Further, as Dr. Boden said, the National Cholesterol Education Program (NCEP) has published guidelines on the use of statins and target LDL values for this patient population. AIM-HIGH offers no reason to change the recommended use of statins alone or in combination with ezetimide for lowering LDL Cholesterol.
It is important to know that the high-dose extended-release niacin used in AIM-HIGH produced the predicted effect on all lipids measured. As expected, Niaspan® raised HDL Cholesterol levels approximately 20 percent. This is consistent with previous studies of similar doses of niacin. Niaspan® also lowered triglycerides by approximately 25 percent, again in keeping with other studies of comparable doses of niacin.
The total and LDL cholesterol levels were lowered primarily by statin therapy. Because of our ability to adjust both the statin dose and add ezetimide for additional cholesterol lowering if desired, the reduction of LDL and total cholesterol was roughly comparable in the two treatment groups and only a small portion of this effect could be attributed to Niaspan®.
We accepted the DSMB’s recommendation that the NHLBI and investigators continue to follow the participants in AIM-HIGH for another 12 to18 months to determine whether we can learn anything additional regarding the imbalance in ischemic stroke observed between the two treatment groups.
We have presented today the preliminary results of the AIM-HIGH trial which led to the DSMB’s recommendation and the NHLBI’s decision to stop the trial before its expected conclusion. We have answered the question this study set out to answer and found that while high dose niacin raised the participants’ HDL cholesterol levels, it did not affect the rate of their cardiovascular events. We don’t know if the same outcome would have occurred in a different population or with a different drug. We are now exploring our data to determine if there are answers that explain the findings including the observed imbalance in ischemic stroke.
As Dr. Shurin said, a full report will be delivered at a future major scientific meeting and complete findings will be published in a peer-reviewed journal. We will continue to follow the participants to monitor their health through phone calls and clinic visits. We extend our thanks to all of the 3414 participants. Finally, if you are a patient who takes cholesterol lowering or other lipid-altering drugs and you have questions after learning of the early stopping of this study, please contact your physician before making any changes to your drug therapy for your blood fat disorder.