ENHANCE trial calls cardiovascular imaging into question
Although the ENHANCE trial has highlighted limitations of imaging-based surrogate endpoints for atherosclerosis, they will keep their central place in the transition from early Phase II to Phase III, because strong indications of a beneficial therapeutic profile are needed before developers commit to the very large Phase III programs, according to a commentary published in the May issue of Nature.
The ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial aroused a media storm at the end of March when the trial was presented at ACC08 in Chicago, according to author Bethan Hughes.
In the trial, involving 720 patients with heterozygous familial hypercholesterolemia (FH), 10 mg of ezetimibe combined with 80 mg of simvastatin did not further improve atherosclerosis regression versus simvastatin alone.
Merck and Schering-Plough manufacture and distribute the combination drug under the brand name Vytorin.
Hughes noted that the assessment was based on changes in carotid intima–media thickness (IMT), observed with an ultrasound-based imaging technique. Previous similar studies with the LDL-lowering statins had demonstrated that progression of IMT can be slowed or even regressed with higher doses. The researchers anticipated that adding ezetimibe, which lowers LDL cholesterol by a different mechanism, to a statin would have a greater effect than the statin alone, Hughes wrote.
One possibility for the lack of beneficial effect of adding ezetimibe on IMT progression is that people with FH are no longer a good patient population for such studies, according to John Kastelein, the primary investigator of the ENHANCE trial, and professor of medicine at the Academic Medical Centre at the University of Amsterdam in The Netherlands.
“We underestimated how well we have been treating FH. If you look at the baseline characteristics of patients in the ENHANCE trial, their blood pressure was lower than the general population in Holland, they had less diabetes and less hypertension. Their only risk factor for atherosclerosis is high LDL. They almost cured their other risk-factor profile themselves and we cured the high LDL,” Kastelein noted.
“Baseline IMT in this study was on the low end of the spectrum. These patients had been treated previously with lipid-lowering drugs and then received high-dose (80 mg) simvastatin, with quite robust cholesterol lowering, even without the additional ezetimibe. Under such conditions, the potential to effect [further] changes in IMT may have been blunted,” concurred Robin Choudhury, MD, at the University of Oxford, England, according to Nature.
If companies still want to conduct IMT trials with FH patients to test the efficacy of drugs to treat atherosclerosis, Kastelein recommends ensuring that the patients have a thick IMT at baseline and have not received previous aggressive LDL-lowering treatment, Hughes reported.
However, Kastelein said that it could be more appropriate in the future to study people with conditions more prevalent in society: “I think we will move to a situation where there will be multiple risk factors driving IMT, which makes a lot of biological sense because the more risk factors, the more progression there will be…conditions with the most risk factors such as diabetes, metabolic syndrome or mixed dyslipidemia will be the populations of the future where imaging trials are concerned.”
Another possibility for the lack of IMT benefit observed with ezetimibe is that the trial was not long enough, Valentin Fuster, director of the Henry R. Kravis Center for cardiovascular health at the Mount Sinai Medical Center in New York City, said. “Carotid IMT studies can answer if a drug works or not in preventing progression of the thickening of the arteries, but these studies took longer than ENHANCE…two years is a limitation.”
While imaging studies can show whether a drug has beneficial effects on IMT, their ability to inform on safety issues is more limited, Hughes wrote. "All atherosclerotic risk factors in the end have their effect on the arterial wall, and therefore imaging is quite powerful to see whether your drug translates to risk-factor modification," Kastelein said.
With regard to providing more information on potential mechanisms of action, Hughes wrote that imaging technology is evolving very rapidly. “I'm sure that MRI of the carotids will replace ultrasound in time because it is more precise and sample sizes are smaller,” Kastelein said.
There are also functional techniques being validated, according to Choudhury. “The most accessible of those is PET techniques to look at plaque inflammation," he said. “That’s very much in its early days but it is emerging."
Kastelein also said he expects endothelial function studies such as flow-mediated dilatation to gain in importance over the coming years, particularly with the new generation of cholesteryl ester transfer protein inhibitors being developed.
“It's all about mitigating risk,” Choudhury concluded. “It’s about adding (and interpreting) biomarkers in an intelligent way to the overall body of scientific evaluation to help design clinical outcome trials.”
The ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial aroused a media storm at the end of March when the trial was presented at ACC08 in Chicago, according to author Bethan Hughes.
In the trial, involving 720 patients with heterozygous familial hypercholesterolemia (FH), 10 mg of ezetimibe combined with 80 mg of simvastatin did not further improve atherosclerosis regression versus simvastatin alone.
Merck and Schering-Plough manufacture and distribute the combination drug under the brand name Vytorin.
Hughes noted that the assessment was based on changes in carotid intima–media thickness (IMT), observed with an ultrasound-based imaging technique. Previous similar studies with the LDL-lowering statins had demonstrated that progression of IMT can be slowed or even regressed with higher doses. The researchers anticipated that adding ezetimibe, which lowers LDL cholesterol by a different mechanism, to a statin would have a greater effect than the statin alone, Hughes wrote.
One possibility for the lack of beneficial effect of adding ezetimibe on IMT progression is that people with FH are no longer a good patient population for such studies, according to John Kastelein, the primary investigator of the ENHANCE trial, and professor of medicine at the Academic Medical Centre at the University of Amsterdam in The Netherlands.
“We underestimated how well we have been treating FH. If you look at the baseline characteristics of patients in the ENHANCE trial, their blood pressure was lower than the general population in Holland, they had less diabetes and less hypertension. Their only risk factor for atherosclerosis is high LDL. They almost cured their other risk-factor profile themselves and we cured the high LDL,” Kastelein noted.
“Baseline IMT in this study was on the low end of the spectrum. These patients had been treated previously with lipid-lowering drugs and then received high-dose (80 mg) simvastatin, with quite robust cholesterol lowering, even without the additional ezetimibe. Under such conditions, the potential to effect [further] changes in IMT may have been blunted,” concurred Robin Choudhury, MD, at the University of Oxford, England, according to Nature.
If companies still want to conduct IMT trials with FH patients to test the efficacy of drugs to treat atherosclerosis, Kastelein recommends ensuring that the patients have a thick IMT at baseline and have not received previous aggressive LDL-lowering treatment, Hughes reported.
However, Kastelein said that it could be more appropriate in the future to study people with conditions more prevalent in society: “I think we will move to a situation where there will be multiple risk factors driving IMT, which makes a lot of biological sense because the more risk factors, the more progression there will be…conditions with the most risk factors such as diabetes, metabolic syndrome or mixed dyslipidemia will be the populations of the future where imaging trials are concerned.”
Another possibility for the lack of IMT benefit observed with ezetimibe is that the trial was not long enough, Valentin Fuster, director of the Henry R. Kravis Center for cardiovascular health at the Mount Sinai Medical Center in New York City, said. “Carotid IMT studies can answer if a drug works or not in preventing progression of the thickening of the arteries, but these studies took longer than ENHANCE…two years is a limitation.”
While imaging studies can show whether a drug has beneficial effects on IMT, their ability to inform on safety issues is more limited, Hughes wrote. "All atherosclerotic risk factors in the end have their effect on the arterial wall, and therefore imaging is quite powerful to see whether your drug translates to risk-factor modification," Kastelein said.
With regard to providing more information on potential mechanisms of action, Hughes wrote that imaging technology is evolving very rapidly. “I'm sure that MRI of the carotids will replace ultrasound in time because it is more precise and sample sizes are smaller,” Kastelein said.
There are also functional techniques being validated, according to Choudhury. “The most accessible of those is PET techniques to look at plaque inflammation," he said. “That’s very much in its early days but it is emerging."
Kastelein also said he expects endothelial function studies such as flow-mediated dilatation to gain in importance over the coming years, particularly with the new generation of cholesteryl ester transfer protein inhibitors being developed.
“It's all about mitigating risk,” Choudhury concluded. “It’s about adding (and interpreting) biomarkers in an intelligent way to the overall body of scientific evaluation to help design clinical outcome trials.”