The Age of Statins

It has been 17 years since the first publication of the Scandinavian Simvastatin Survival Study (Lancet 1994;344;1383-9) describing the benefit of coenzyme A reductase inhibitors (statins) on cardiovascular events in patients with coronary heart disease.

During this period, statins have become a major part of our strategy for the treatment and prevention of acute and chronic coronary heart disease. A number of statins have been introduced in a variety of clinical settings, and all have shown a consistent benefit. Although associated with some side effects, they have been relatively well tolerated by patients requiring either dose adjustment or switching to other drugs within the class.

Along the way, questions have been raised about the long-term safety of statins, and their potential oncogenic potential. The impact of statins directly on the cardiovascular intima has been elucidated using angiographic and intravascular imaging techniques. These studies have shown that statins mitigate to some degree the progression of localized intravascular abnormalities. Two recent studies provide important information both about the safety and long-term benefit of statins, and their remarkable effect on remodeling of the coronary arteries and regression of vascular lesions.

A recent intracoronary ultrasound study that compared high-dose rosuvastatin with atorvastatin in 1,039 patients with coronary disease provides striking evidence for the benefit of both of these drugs on regression of coronary plaque. In patients with residual lesions of 20%-50% by angiography, treatment with these drugs demonstrated a decrease in percent of atherosclerotic volume by 1.22% with rosuvastatin and by 0.99% with atorvastatin, and a decrease in total atheroma volume of 6.39 mm³ and 4.42 mm³, respectively. With doses of 40 mg atorvastatin and 80 mg rosuvastatin, low-density lipoprotein (LDL) cholesterol was decreased to 62.6 mg/dL and 70.2 mg/dL, respectively, and HDL cholesterol increased to 50.4 mg/dL and 48.6 mg/dL in the rosuvastatin and atorvastatin patients, respectively (N. Engl. J. Med. 2011;365;2078-87).

Regression of coronary lesions was observed in approximately two-thirds of the patients. Because of the short duration of the study, there were very few ischemic events and there was no difference between the two drug strategies. Since remodeling of the coronary artery is a surrogate indicator for clinical disease prevention, we cannot be certain that these ultrasound changes in plaques are directly related to the prevention of coronary events.

The second study of interest is the extended follow-up of the Heart Protection Study, which included more than 20,536 patients treated with 40 mg simvastatin or placebo for 5.3 years in-trial and a post-trial follow-up for a total 11 years (Lancet 2011:378;2013-20). There was an overall 23% decrease in major vascular events in the simvastatin-treated patients in the first year of the trial that continued to decrease annually during the trial phase. After study conclusion, when all patients were placed on therapy, there was a legacy benefit that persisted during the remaining 6 years of the study for the patients who were initially in the simvastatin arm of the study. The study confirms the long-term benefit of simvastatin and its safety without any evidence for an increase in cancer or other adverse events during the 11 years of follow-up.

The demonstration that statins can remodel the coronary artery provides pathologic support for their clinical benefit. Questions still remain in regard to mechanisms of action. The changes in the plaque volume theoretically could explain the therapeutic benefit of statins, but they must still be considered as surrogates for clinical benefit. Newer intravascular imaging technology using near-infrared spectroscopy is now able to characterize and measure the lipid core of the coronary plaque (JACC Cardiovasc. Imaging 2008;1:638-48), and may provide a better understanding of the mechanism by which statins modify plaque architecture.

Challenges still remain in regard to how the one-third of patients who did not experience any plaque regression should be approached. A treatment strategy for these presumably high-risk patients remains elusive.

Much has been learned from statin therapy, but many questions still remain in regard to the pathologic process by which the plaque progresses to cause an acute event, and how to prevent it.

This column, "Heart of the Matter," appears regularly in Cardiology News, a publication of Elsevier. Dr. Goldstein, medical editor of Cardiology News, is a professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

It has been 17 years since the first publication of the Scandinavian Simvastatin Survival Study (Lancet 1994;344;1383-9) describing the benefit of coenzyme A reductase inhibitors (statins) on cardiovascular events in patients with coronary heart disease.

During this period, statins have become a major part of our strategy for the treatment and prevention of acute and chronic coronary heart disease. A number of statins have been introduced in a variety of clinical settings, and all have shown a consistent benefit. Although associated with some side effects, they have been relatively well tolerated by patients requiring either dose adjustment or switching to other drugs within the class.

Along the way, questions have been raised about the long-term safety of statins, and their potential oncogenic potential. The impact of statins directly on the cardiovascular intima has been elucidated using angiographic and intravascular imaging techniques. These studies have shown that statins mitigate to some degree the progression of localized intravascular abnormalities. Two recent studies provide important information both about the safety and long-term benefit of statins, and their remarkable effect on remodeling of the coronary arteries and regression of vascular lesions.

A recent intracoronary ultrasound study that compared high-dose rosuvastatin with atorvastatin in 1,039 patients with coronary disease provides striking evidence for the benefit of both of these drugs on regression of coronary plaque. In patients with residual lesions of 20%-50% by angiography, treatment with these drugs demonstrated a decrease in percent of atherosclerotic volume by 1.22% with rosuvastatin and by 0.99% with atorvastatin, and a decrease in total atheroma volume of 6.39 mm³ and 4.42 mm³, respectively. With doses of 40 mg atorvastatin and 80 mg rosuvastatin, low-density lipoprotein (LDL) cholesterol was decreased to 62.6 mg/dL and 70.2 mg/dL, respectively, and HDL cholesterol increased to 50.4 mg/dL and 48.6 mg/dL in the rosuvastatin and atorvastatin patients, respectively (N. Engl. J. Med. 2011;365;2078-87).

Regression of coronary lesions was observed in approximately two-thirds of the patients. Because of the short duration of the study, there were very few ischemic events and there was no difference between the two drug strategies. Since remodeling of the coronary artery is a surrogate indicator for clinical disease prevention, we cannot be certain that these ultrasound changes in plaques are directly related to the prevention of coronary events.

The second study of interest is the extended follow-up of the Heart Protection Study, which included more than 20,536 patients treated with 40 mg simvastatin or placebo for 5.3 years in-trial and a post-trial follow-up for a total 11 years (Lancet 2011:378;2013-20). There was an overall 23% decrease in major vascular events in the simvastatin-treated patients in the first year of the trial that continued to decrease annually during the trial phase. After study conclusion, when all patients were placed on therapy, there was a legacy benefit that persisted during the remaining 6 years of the study for the patients who were initially in the simvastatin arm of the study. The study confirms the long-term benefit of simvastatin and its safety without any evidence for an increase in cancer or other adverse events during the 11 years of follow-up.

The demonstration that statins can remodel the coronary artery provides pathologic support for their clinical benefit. Questions still remain in regard to mechanisms of action. The changes in the plaque volume theoretically could explain the therapeutic benefit of statins, but they must still be considered as surrogates for clinical benefit. Newer intravascular imaging technology using near-infrared spectroscopy is now able to characterize and measure the lipid core of the coronary plaque (JACC Cardiovasc. Imaging 2008;1:638-48), and may provide a better understanding of the mechanism by which statins modify plaque architecture.

Challenges still remain in regard to how the one-third of patients who did not experience any plaque regression should be approached. A treatment strategy for these presumably high-risk patients remains elusive.

Much has been learned from statin therapy, but many questions still remain in regard to the pathologic process by which the plaque progresses to cause an acute event, and how to prevent it.

This column, "Heart of the Matter," appears regularly in Cardiology News, a publication of Elsevier. Dr. Goldstein, medical editor of Cardiology News, is a professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

It has been 17 years since the first publication of the Scandinavian Simvastatin Survival Study (Lancet 1994;344;1383-9) describing the benefit of coenzyme A reductase inhibitors (statins) on cardiovascular events in patients with coronary heart disease.

During this period, statins have become a major part of our strategy for the treatment and prevention of acute and chronic coronary heart disease. A number of statins have been introduced in a variety of clinical settings, and all have shown a consistent benefit. Although associated with some side effects, they have been relatively well tolerated by patients requiring either dose adjustment or switching to other drugs within the class.

Along the way, questions have been raised about the long-term safety of statins, and their potential oncogenic potential. The impact of statins directly on the cardiovascular intima has been elucidated using angiographic and intravascular imaging techniques. These studies have shown that statins mitigate to some degree the progression of localized intravascular abnormalities. Two recent studies provide important information both about the safety and long-term benefit of statins, and their remarkable effect on remodeling of the coronary arteries and regression of vascular lesions.

A recent intracoronary ultrasound study that compared high-dose rosuvastatin with atorvastatin in 1,039 patients with coronary disease provides striking evidence for the benefit of both of these drugs on regression of coronary plaque. In patients with residual lesions of 20%-50% by angiography, treatment with these drugs demonstrated a decrease in percent of atherosclerotic volume by 1.22% with rosuvastatin and by 0.99% with atorvastatin, and a decrease in total atheroma volume of 6.39 mm³ and 4.42 mm³, respectively. With doses of 40 mg atorvastatin and 80 mg rosuvastatin, low-density lipoprotein (LDL) cholesterol was decreased to 62.6 mg/dL and 70.2 mg/dL, respectively, and HDL cholesterol increased to 50.4 mg/dL and 48.6 mg/dL in the rosuvastatin and atorvastatin patients, respectively (N. Engl. J. Med. 2011;365;2078-87).

Regression of coronary lesions was observed in approximately two-thirds of the patients. Because of the short duration of the study, there were very few ischemic events and there was no difference between the two drug strategies. Since remodeling of the coronary artery is a surrogate indicator for clinical disease prevention, we cannot be certain that these ultrasound changes in plaques are directly related to the prevention of coronary events.

The second study of interest is the extended follow-up of the Heart Protection Study, which included more than 20,536 patients treated with 40 mg simvastatin or placebo for 5.3 years in-trial and a post-trial follow-up for a total 11 years (Lancet 2011:378;2013-20). There was an overall 23% decrease in major vascular events in the simvastatin-treated patients in the first year of the trial that continued to decrease annually during the trial phase. After study conclusion, when all patients were placed on therapy, there was a legacy benefit that persisted during the remaining 6 years of the study for the patients who were initially in the simvastatin arm of the study. The study confirms the long-term benefit of simvastatin and its safety without any evidence for an increase in cancer or other adverse events during the 11 years of follow-up.

The demonstration that statins can remodel the coronary artery provides pathologic support for their clinical benefit. Questions still remain in regard to mechanisms of action. The changes in the plaque volume theoretically could explain the therapeutic benefit of statins, but they must still be considered as surrogates for clinical benefit. Newer intravascular imaging technology using near-infrared spectroscopy is now able to characterize and measure the lipid core of the coronary plaque (JACC Cardiovasc. Imaging 2008;1:638-48), and may provide a better understanding of the mechanism by which statins modify plaque architecture.

Challenges still remain in regard to how the one-third of patients who did not experience any plaque regression should be approached. A treatment strategy for these presumably high-risk patients remains elusive.

Much has been learned from statin therapy, but many questions still remain in regard to the pathologic process by which the plaque progresses to cause an acute event, and how to prevent it.

This column, "Heart of the Matter," appears regularly in Cardiology News, a publication of Elsevier. Dr. Goldstein, medical editor of Cardiology News, is a professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.