Clinical Trials and Surrogate End Points: Lessons From the ENHANCE TrialPosted 08/12/2008
John Alan Farmer, MDAuthor
The lipid hypothesis was originally proposed as a theory to explain the central role of dyslipidemia in the initiation and progression of atherosclerosis. The lipid hypothesis was supported by epidemiologic, pathologic and genetic observations. However, definitive proof of concept would require prospective clinical trial evidence that demonstrates that optimization of dyslipidemia would result in a reduction in risk from the complications of atherosclerosis. Epidemiologic studies that demonstrate a statistical correlation between dyslipidemia and atherosclerosis do not necessarily imply that pharmacologic modification of the lipid profile will alter the natural history of atherosclerosis. Early clinical trials that employed a variety of interventions did demonstrate that modification of dyslipidemia resulted in a modest decrease in the incidence of cardiovascular events. Clinical trials such as the Lipid Research Clinic Coronary Primary Prevention Trial, which utilized cholestyramine, and the Helsinki Heart Study, which analyzed gemfibrozil, demonstrated that these interventions did reduce cardiovascular event rates.[1,2] However, the interpretation and implication of these trials generated considerable controversy. The absolute degree of risk reduction was minimal and total mortality was not improved. The failure of pharmacologic therapy to reduce total mortality despite a decline in cardiovascular mortality implied a potential drug-mediated adverse effect of cholesterol lowering that would negate the vascular benefits. The early clinical trials were also hampered by problems in trial design and only a modest improvement in circulating lipid levels. The advent of pharmacologic agents that partially inhibit the key enzyme in cholesterol synthesis (3-hydroxy-3-methyl-glutaryl-CoA reductase) provided the ability to significantly reduce LDL levels. Statin therapy was originally approved by the US FDA solely with an indication to improve dyslipidemia since clinical trial evidence for event reduction was lacking at the time of approval. The role of statin therapy in cardiovascular risk reduction was subsequently studied in a variety of clinical trials that encompassed the spectrum of atherosclerosis. The role of cardiovascular risk factor modification in primary prevention (clinical absence of atherosclerosis) has been controversial owing to economic, efficacy and safety concerns. Primary prevention can be subdivided into high- and low-risk populations depending on the degree of dyslipidemia and extent of associated risk factors. Statin therapy was subsequently demonstrated to be efficacious in both high- and low-risk subgroups. The West of Scotland Coronary Primary Prevention Study analyzed the role of pravastatin therapy in a patient cohort characterized by significant dyslipidemia coupled with a high prevalence of other risk factors, such as tobacco usage.[3]
Pravastatin therapy demonstrated a clear reduction in the incidence of cardiovascular events. The Air Force/Texas Coronary Atherosclerosis Prevention Study evaluated the role of lovastatin therapy in a large cohort of both men and women with LDL-C levels that were considered to be within normal limits by contemporary guidelines.[4] The primary lipid abnormality was a reduced level of HDL. Lovastatin therapy significantly reduced the primary end point, which was a composite consisting of sudden death, fatal and nonfatal myocardial infarction and unstable angina. The role of statin therapy in secondary prevention (documented presence of atherosclerosis) was evaluated in patients who survived a myocardial infarction coupled with a significantly elevated LDL-C level in the Simvastatin Scandinavian Survival Study (4S).[5] Simvastatin therapy reduced not only cardiovascular but also total mortality. Additionally, pravastatin therapy was demonstrated to reduce cardiovascular events in survivors of a myocardial infarction whose total cholesterol levels were considered to be normal (<240 mg/dl) in the Cholesterol and Recurrent Events (CARE) study.[6] Analysis of secondary prevention studies demonstrated a linear reduction in cardiovascular event rates, which correlated with the degree of reduction in LDL-C levels (Figure 1). Additionally, multiple vascular imaging (angiography, intravascular ultrasound, B-mode ultrasound etc.) studies have analyzed the impact of modification of the lipid profile on the progression of coronary atherosclerosis. Intravascular ultrasound studies have been performed, which compared aggressive lipid-lowering strategies with a more conventional approach.[7] The intensive reduction of LDL-C has been correlated with reduced plaque volume. The controversy relative to the clinical benefits, which accrue from the reduction of LDL-C levels, appeared to have been resolved and the concept that ‘lower is better’ achieved widespread acceptance. Many experts felt that further clinical trials demonstrating the reduction of hard clinical end points following lipid-lowering therapy were no longer required owing to the extensive clinical trial experience involving thousands of patients. Clinical trials require large numbers of subjects followed for a period of years and are extremely expensive to perform. The problems associated with enrolment and funding of clinical trials has led to the concept of the substitution of surrogate markers a satisfactory means to demonstrate clinical benefit. However, the utilization of surrogate markers is problematic. The problems encountered by relying upon surrogate markers were emphasized in the recent clinical controversy surrounding the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study.
Secondary prevention trials and LDL reduction.
The ENHANCE trial was designed to study the potential benefits of the addition of the cholesterol absorption inhibitor ezetimibe to maximum statin dosing on the progression of atherosclerosis.[8] The ENHANCE trial is a randomized, double-blind active comparator study, which employed a surrogate marker (B-Mode ultrasound) in lieu of clinical end points such as myocardial infarction. The progression of atherosclerosis was assessed by the utilization of B-mode ultrasonography imaging to calculate the intimal medial thickness of the carotid and femoral arteries.
The modification of intimal medial thickness is not recognized by the US FDA as an end point qualifying for drug approval or a new drug indication. The rationale for combination therapy lies in the fact that the greatest reduction in LDL-C occurs with the initial statin dose. Subsequent doubling of the dose results in approximately a 5-7% additive reduction in LDL reduction and is associated with an increased incidence of side effects.[9] The therapeutic rationale for the addition of ezetimibe is to further reduce circulating LDL levels as a means of achieving goals established by the National Cholesterol Education Program (NCEP). Ezetimibe lowers LDL by reducing the absorption of cholesterol from the gastrointestinal tract by binding to the Niemann-Pick C1-like 1 protein, which is the key transport mediator.[10] The reduction in the delivery of cholesterol to the liver results in a decrease in intrahepatic cholesterol followed by an upregulation of the LDL receptor. The increase in LDL-receptor activity is associated with enhanced plasma clearance of lipoproteins that carry ApoB or ApoE on their surface. The gastrointestinal absorption of cholesterol is at least partially under genetic control and the average individual absorbs approximately 55% of the cholesterol presented to the gastrointestinal tract. The administration of ezetimibe monotherapy results in a 15-20% reduction in LDL-C in the individual with normal absorptive capacity. The use of ezetimibe is associated with minimal systemic toxicity owing to the limited absorption and enterohepatic circulation. The ENHANCE study compared simvastatin 80 mg plus ezetimibe 10 mg versus simvastatin 80 mg alone on carotid and femoral intimal thickness. The study population was composed of 720 subjects with heterozygous familial hypercholesterolemia who were evaluated over a 24-month trial period. The trial was well designed and conducted by a research group that is highly experienced in the analysis of carotid intimal thickness. The baseline characteristics of the patients were well matched, with the exception of a higher prevalence of increased BMI in the simvastatin plus ezetimibe group.
Combination therapy resulted in a significant reduction in circulating lipid levels compared with the group who received simvastatin alone. The circulating levels of LDL-C decreased from 317.8 to 192.7 mg/dl in the simvastatin alone group. Combination therapy reduced circulating LDL-C levels from 319.0 to 141.3 mg/dl and represented a between-group difference of 16.5%, which was statistically significant. Combination therapy also resulted in a significant reduction in high-sensitivity C-reactive protein (hs c-RP) protein of 49% compared with 23% in the simvastatin monotherapy group. The primary end point of the EHANCE study was the change from baseline in the mean intimal thickness of the carotid artery. Combination therapy did not result in a significant alteration of the primary end point for simvastatin monotherapy (0.0058 ± 0.0037 versus 0.0111 ± 0.0038; p = 0.29). Additionally, a variety of secondary end points were not beneficially altered by combination therapy. New plaque formation, which was defined as intimal medial thickness in excess of 1.3 mm, was demonstrable in 2.8% of the monotherapy group and 4.7% of subjects who received combination therapy (p = 0.20). The addition of combination therapy also did not beneficially alter intimal thickness in the femoral arteries. The ENHANCE study thus evaluated three surrogate markers that have been correlated with risk for atherosclerosis (LDL-C, c-RP and carotid intimal thickness). The hypothesis that reduction of LDL-C and inflammatory markers would result in a beneficial duration of carotid intimal thickness was not verified. How can these surprising results be explained?
The possibility of technical problems in the assessment of carotid intimal thickness is highly unlikely. Physicians involved in the analysis of the images are considered to be world experts. Additionally, the research group that designed and performed the ENHANCE trial previously performed the well-regarded Atorvastatin Versus Simvastatin on Atherosclerosis Progression (ASAP) study. The ASAP and EHANCE studies both analyzed subjects with heterozygous familial hypercholesterolemia. The ASAP trial was designed to compare the effects of atorvastatin 80 mg with simvastatin 40 mg on carotid intimal thickness in 320 subjects over a 2-year period.[11] The study populations in the ASAP and ENHANCE trials was similar in age, lipid profile and method employed to quantitate carotid intimal thickness. The ENHANCE and ASAP trials both utilized the same central core laboratory for image evaluation. However, carotid intimal thickness at baseline was not the same in the two groups. The ASAP cohort had carotid intimal thickness of 0.925 mm compared with 0.695 mm in the ENHANCE cohort. The normal value for carotid intimal thickness in subjects 40-49 years of age is 0.64 mm at the bifurcation of the common carotid. The values for carotid intimal thickness in the ENHANCE study were essentially normal at baseline implying prior significant risk factor modification (especially considering the high-risk patient population, which was composed of heterozygous familial hypercholesterolemic subjects in their fifth decade of life) prior to the onset of the study.
The ASAP trial was begun in 1997 when aggressive therapy with statins was less prevalent. The number of patients in the ASAP trial who previously were treated with statins and the duration of therapy is not available. By contrast, 80% of subjects in the EHANCE study had previously received statin therapy and only a short washout period was employed. The possibility of a lengthy period of pretreatment with statins resulting in delipidation of the vasculature in the EHANCE cohort may have blunted potential benefits from a further 24-month treatment period.
Assuming that there were no technical problems encountered in the accumulation and analysis of the data, a major question to be answered is the validity of the surrogate end points that were analyzed in the ENHANCE trial as a means of predicting risk from atherosclerosis. The clinical utility of a surrogate marker would require confirmation that the substitution of a laboratory measurement (LDL-C, carotid intimal thickness etc.) is a substitute for clinically meaningful end points, such as reduction of cardiovascular events.
Thus, definite proof should be present to demonstrate the changes induced by any therapeutic intervention on a surrogate end point accurately predict a clinically meaningful outcome alteration. The ENHANCE trial is basically an analysis of several biomarkers on the process of atherosclerosis with carotid intimal thickness designated as the primary end point. LDL-C, c-RP and other lipid subfractions were significantly reduced. A major question is which of the analyzed surrogates is the most valid in predicting risk from atherosclerosis? The major lipid alteration in the ENHANCE trial was a highly significant reduction in LDL-C by the combination of simvastatin and ezetimibe of 51 mg/dl, which was statistically significant with a p-value of less than 0.01. LDL reduction has consistently been correlated with a decrease in cardiovascular event rates in multiple trials. LDL-C and c-RP have extensive databases that support their use as surrogate end points.[12] The utility of employing the rate of change in carotid intimal thickness is conceptually attractive as it directly analyzes vascular structure but lacks the robust database of LDL-C modification and clinical end point reduction. Modest positive statistical correlations between the degree of carotid intimal thickness and event rates have been demonstrated in 30 of 34 clinical studies.[13] The role of lipid therapy in the modification of carotid intimal thickness has been analyzed in 15 clinical studies and has demonstrated that high-dose statin therapy has slowed or caused regression of atherosclerosis.[14] However, studies with less than 2 years of follow-up have not demonstrated event reduction, which raises the possibility that short-term studies such as the ENHANCE trial may not be valid in the utilization of intimal thickness as a surrogate marker. A major clinical question that was raised by the ENHANCE trial also relates to the efficacy of ezetimibe. The result of the trial has been interpreted by some as evidence that the addition of ezetimibe provides no benefit in reducing the risk of atherosclerosis either in combination or monotherapy. Ezetimibe has been demonstrated to reduce the degree of atherosclerosis in experimental animals, which may not be applicable to human subjects. However, ezetimibe has been demonstrated to exhibit several proatherogenic effects, including inhibition of the scavenger receptor B1 and decreasing the activity of the ATP-binding cassette A1, which modulates the efflux of cholesterol from the lipid-laden macrophage.[15] However, for these mechanisms to exhibit clinically relevant proatherogenic activity, ezetimibe would require significant systemic activity and the drug is only minimally absorbed from the gastrointestinal lumen.
Additionally, LDL-lowering interventions (fibric acid derivatives, nicotinic acid, bile acid sequestrants, diet and ileal bypass) have all been demonstrated to reduce clinical events.
The major exception is the cholesterol ester transfer protein inhibitors, such as torcetrapib, which improved the lipid profile but demonstrated adverse affects such as the induction of hypertension. Ezetimibe has not been correlated with the worsening of any metabolic effects due to the lack of systemic absorption.
The controversy surrounding the ENHANCE trial may have been avoided by the formation and presence of an external advisory board to independently analyze the design of the trial with modification of the aforementioned problems. The null results of the trial are difficult to translate into clinical practice guidelines. The NCEP guidelines remain valid and appropriate LDL goals should still be attempted to be achieved. Statin therapy should remain the primary therapeutic intervention. If combination therapy is required, utilization of agents with a proven clinical efficacy should be employed. Ezetimibe therapy may still be added to achieve LDL goals when statin monotherapy is inadequate or associated with side effects such as myopathy. The clinical benefits of combination therapy utilizing statins and ezetimibe will await the results of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial, which will analyze the affect of combination therapy on hard end points.[16] The IMPROVE-IT trial will provide insight into the role of absolute LDL reduction in addition to clarification of the role and efficacy of the therapies employed to achieve LDL goals.
References
Rifkind BM: The Lipid Research Clinics Coronary Primary Prevention Trial: results and implications. Monogr. Atheroscler. 13, 74-84 (1985).
Frick MH, Elo O, Haapa K et al.: Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 317(20), 1237-1245 (1987).
Shepherd J, Cobbe SM, Ford I et al.: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333(20), 1301-1307 (1995).
Downs JR, Clearfield M, Weis S et al.: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279(20), 1615-1622 (1998).
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344(8934), 1383-1389 (1994).
Sacks FM, Pfeffer MA, Moye LA et al.: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N. Engl. J. Med. 335(14), 1001-1009 (1996).
Nissen SE, Tuzcu EM, Schoenhagen P et al.: Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 291(9), 1071-1080 (2004).
Kastelein JJ, Akdim F, Stroes ES et al.: Simvastatin with or without ezetimibe in familial hypercholesterolemia. N. Engl. J. Med. 358(14), 1431-1443 (2008).
Roberts WC: The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am. J. Cardiol. 80(1), 106-107 (1997).
Altmann SW, Davis HR Jr, Zhu LJ et al.: Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science 303(5661), 1201-1204 (2004).
Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF: Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 357(9256), 577-581 (2001).
Ridker PM: C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J. Am. Coll. Cardiol. 49(21), 2129-2138 (2007).
Bots ML, Baldassarre D, Simon A et al.: Carotid intima-media thickness and coronary atherosclerosis: weak or strong relations? Eur. Heart J. 28(4), 398-406 (2007).
Zhao XQ, Yuan C, Hatsukami TS et al.: Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case-control study. Arterioscler. Thromb. Vasc. Biol. 21(10), 1623-1629 (2001).
During A, Dawson HD, Harrison EH: Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. J. Nutr. 135(10), 2305-2312 (2005).
Greenland P, Lloyd-Jones D: Critical lessons from the ENHANCE trial. JAMA 299(8), 953-955 (2008).
[
The ENHANCE trial was designed to study the potential benefits of the addition of the cholesterol absorption inhibitor ezetimibe to maximum statin dosing on the progression of atherosclerosis.[8] The ENHANCE trial is a randomized, double-blind active comparator study, which employed a surrogate marker (B-Mode ultrasound) in lieu of clinical end points such as myocardial infarction. The progression of atherosclerosis was assessed by the utilization of B-mode ultrasonography imaging to calculate the intimal medial thickness of the carotid and femoral arteries.
The modification of intimal medial thickness is not recognized by the US FDA as an end point qualifying for drug approval or a new drug indication. The rationale for combination therapy lies in the fact that the greatest reduction in LDL-C occurs with the initial statin dose. Subsequent doubling of the dose results in approximately a 5-7% additive reduction in LDL reduction and is associated with an increased incidence of side effects.[9] The therapeutic rationale for the addition of ezetimibe is to further reduce circulating LDL levels as a means of achieving goals established by the National Cholesterol Education Program (NCEP). Ezetimibe lowers LDL by reducing the absorption of cholesterol from the gastrointestinal tract by binding to the Niemann-Pick C1-like 1 protein, which is the key transport mediator.[10] The reduction in the delivery of cholesterol to the liver results in a decrease in intrahepatic cholesterol followed by an upregulation of the LDL receptor. The increase in LDL-receptor activity is associated with enhanced plasma clearance of lipoproteins that carry ApoB or ApoE on their surface. The gastrointestinal absorption of cholesterol is at least partially under genetic control and the average individual absorbs approximately 55% of the cholesterol presented to the gastrointestinal tract. The administration of ezetimibe monotherapy results in a 15-20% reduction in LDL-C in the individual with normal absorptive capacity. The use of ezetimibe is associated with minimal systemic toxicity owing to the limited absorption and enterohepatic circulation. The ENHANCE study compared simvastatin 80 mg plus ezetimibe 10 mg versus simvastatin 80 mg alone on carotid and femoral intimal thickness. The study population was composed of 720 subjects with heterozygous familial hypercholesterolemia who were evaluated over a 24-month trial period. The trial was well designed and conducted by a research group that is highly experienced in the analysis of carotid intimal thickness. The baseline characteristics of the patients were well matched, with the exception of a higher prevalence of increased BMI in the simvastatin plus ezetimibe group.
Combination therapy resulted in a significant reduction in circulating lipid levels compared with the group who received simvastatin alone. The circulating levels of LDL-C decreased from 317.8 to 192.7 mg/dl in the simvastatin alone group. Combination therapy reduced circulating LDL-C levels from 319.0 to 141.3 mg/dl and represented a between-group difference of 16.5%, which was statistically significant. Combination therapy also resulted in a significant reduction in high-sensitivity C-reactive protein (hs c-RP) protein of 49% compared with 23% in the simvastatin monotherapy group. The primary end point of the EHANCE study was the change from baseline in the mean intimal thickness of the carotid artery. Combination therapy did not result in a significant alteration of the primary end point for simvastatin monotherapy (0.0058 ± 0.0037 versus 0.0111 ± 0.0038; p = 0.29). Additionally, a variety of secondary end points were not beneficially altered by combination therapy. New plaque formation, which was defined as intimal medial thickness in excess of 1.3 mm, was demonstrable in 2.8% of the monotherapy group and 4.7% of subjects who received combination therapy (p = 0.20). The addition of combination therapy also did not beneficially alter intimal thickness in the femoral arteries. The ENHANCE study thus evaluated three surrogate markers that have been correlated with risk for atherosclerosis (LDL-C, c-RP and carotid intimal thickness). The hypothesis that reduction of LDL-C and inflammatory markers would result in a beneficial duration of carotid intimal thickness was not verified. How can these surprising results be explained?
The possibility of technical problems in the assessment of carotid intimal thickness is highly unlikely. Physicians involved in the analysis of the images are considered to be world experts. Additionally, the research group that designed and performed the ENHANCE trial previously performed the well-regarded Atorvastatin Versus Simvastatin on Atherosclerosis Progression (ASAP) study. The ASAP and EHANCE studies both analyzed subjects with heterozygous familial hypercholesterolemia. The ASAP trial was designed to compare the effects of atorvastatin 80 mg with simvastatin 40 mg on carotid intimal thickness in 320 subjects over a 2-year period.[11] The study populations in the ASAP and ENHANCE trials was similar in age, lipid profile and method employed to quantitate carotid intimal thickness. The ENHANCE and ASAP trials both utilized the same central core laboratory for image evaluation. However, carotid intimal thickness at baseline was not the same in the two groups. The ASAP cohort had carotid intimal thickness of 0.925 mm compared with 0.695 mm in the ENHANCE cohort. The normal value for carotid intimal thickness in subjects 40-49 years of age is 0.64 mm at the bifurcation of the common carotid. The values for carotid intimal thickness in the ENHANCE study were essentially normal at baseline implying prior significant risk factor modification (especially considering the high-risk patient population, which was composed of heterozygous familial hypercholesterolemic subjects in their fifth decade of life) prior to the onset of the study.
The ASAP trial was begun in 1997 when aggressive therapy with statins was less prevalent. The number of patients in the ASAP trial who previously were treated with statins and the duration of therapy is not available. By contrast, 80% of subjects in the EHANCE study had previously received statin therapy and only a short washout period was employed. The possibility of a lengthy period of pretreatment with statins resulting in delipidation of the vasculature in the EHANCE cohort may have blunted potential benefits from a further 24-month treatment period.
Assuming that there were no technical problems encountered in the accumulation and analysis of the data, a major question to be answered is the validity of the surrogate end points that were analyzed in the ENHANCE trial as a means of predicting risk from atherosclerosis. The clinical utility of a surrogate marker would require confirmation that the substitution of a laboratory measurement (LDL-C, carotid intimal thickness etc.) is a substitute for clinically meaningful end points, such as reduction of cardiovascular events.
Thus, definite proof should be present to demonstrate the changes induced by any therapeutic intervention on a surrogate end point accurately predict a clinically meaningful outcome alteration. The ENHANCE trial is basically an analysis of several biomarkers on the process of atherosclerosis with carotid intimal thickness designated as the primary end point. LDL-C, c-RP and other lipid subfractions were significantly reduced. A major question is which of the analyzed surrogates is the most valid in predicting risk from atherosclerosis? The major lipid alteration in the ENHANCE trial was a highly significant reduction in LDL-C by the combination of simvastatin and ezetimibe of 51 mg/dl, which was statistically significant with a p-value of less than 0.01. LDL reduction has consistently been correlated with a decrease in cardiovascular event rates in multiple trials. LDL-C and c-RP have extensive databases that support their use as surrogate end points.[12] The utility of employing the rate of change in carotid intimal thickness is conceptually attractive as it directly analyzes vascular structure but lacks the robust database of LDL-C modification and clinical end point reduction. Modest positive statistical correlations between the degree of carotid intimal thickness and event rates have been demonstrated in 30 of 34 clinical studies.[13] The role of lipid therapy in the modification of carotid intimal thickness has been analyzed in 15 clinical studies and has demonstrated that high-dose statin therapy has slowed or caused regression of atherosclerosis.[14] However, studies with less than 2 years of follow-up have not demonstrated event reduction, which raises the possibility that short-term studies such as the ENHANCE trial may not be valid in the utilization of intimal thickness as a surrogate marker. A major clinical question that was raised by the ENHANCE trial also relates to the efficacy of ezetimibe. The result of the trial has been interpreted by some as evidence that the addition of ezetimibe provides no benefit in reducing the risk of atherosclerosis either in combination or monotherapy. Ezetimibe has been demonstrated to reduce the degree of atherosclerosis in experimental animals, which may not be applicable to human subjects. However, ezetimibe has been demonstrated to exhibit several proatherogenic effects, including inhibition of the scavenger receptor B1 and decreasing the activity of the ATP-binding cassette A1, which modulates the efflux of cholesterol from the lipid-laden macrophage.[15] However, for these mechanisms to exhibit clinically relevant proatherogenic activity, ezetimibe would require significant systemic activity and the drug is only minimally absorbed from the gastrointestinal lumen.
Additionally, LDL-lowering interventions (fibric acid derivatives, nicotinic acid, bile acid sequestrants, diet and ileal bypass) have all been demonstrated to reduce clinical events.
The major exception is the cholesterol ester transfer protein inhibitors, such as torcetrapib, which improved the lipid profile but demonstrated adverse affects such as the induction of hypertension. Ezetimibe has not been correlated with the worsening of any metabolic effects due to the lack of systemic absorption.
The controversy surrounding the ENHANCE trial may have been avoided by the formation and presence of an external advisory board to independently analyze the design of the trial with modification of the aforementioned problems. The null results of the trial are difficult to translate into clinical practice guidelines. The NCEP guidelines remain valid and appropriate LDL goals should still be attempted to be achieved. Statin therapy should remain the primary therapeutic intervention. If combination therapy is required, utilization of agents with a proven clinical efficacy should be employed. Ezetimibe therapy may still be added to achieve LDL goals when statin monotherapy is inadequate or associated with side effects such as myopathy. The clinical benefits of combination therapy utilizing statins and ezetimibe will await the results of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial, which will analyze the affect of combination therapy on hard end points.[16] The IMPROVE-IT trial will provide insight into the role of absolute LDL reduction in addition to clarification of the role and efficacy of the therapies employed to achieve LDL goals.
References
Rifkind BM: The Lipid Research Clinics Coronary Primary Prevention Trial: results and implications. Monogr. Atheroscler. 13, 74-84 (1985).
Frick MH, Elo O, Haapa K et al.: Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 317(20), 1237-1245 (1987).
Shepherd J, Cobbe SM, Ford I et al.: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333(20), 1301-1307 (1995).
Downs JR, Clearfield M, Weis S et al.: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279(20), 1615-1622 (1998).
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344(8934), 1383-1389 (1994).
Sacks FM, Pfeffer MA, Moye LA et al.: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N. Engl. J. Med. 335(14), 1001-1009 (1996).
Nissen SE, Tuzcu EM, Schoenhagen P et al.: Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 291(9), 1071-1080 (2004).
Kastelein JJ, Akdim F, Stroes ES et al.: Simvastatin with or without ezetimibe in familial hypercholesterolemia. N. Engl. J. Med. 358(14), 1431-1443 (2008).
Roberts WC: The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am. J. Cardiol. 80(1), 106-107 (1997).
Altmann SW, Davis HR Jr, Zhu LJ et al.: Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science 303(5661), 1201-1204 (2004).
Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF: Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 357(9256), 577-581 (2001).
Ridker PM: C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J. Am. Coll. Cardiol. 49(21), 2129-2138 (2007).
Bots ML, Baldassarre D, Simon A et al.: Carotid intima-media thickness and coronary atherosclerosis: weak or strong relations? Eur. Heart J. 28(4), 398-406 (2007).
Zhao XQ, Yuan C, Hatsukami TS et al.: Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case-control study. Arterioscler. Thromb. Vasc. Biol. 21(10), 1623-1629 (2001).
During A, Dawson HD, Harrison EH: Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. J. Nutr. 135(10), 2305-2312 (2005).
Greenland P, Lloyd-Jones D: Critical lessons from the ENHANCE trial. JAMA 299(8), 953-955 (2008).
[
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