Clinical Trials

[Gatekeeper]

Εδώ ας αναφέρουμε θέματα σχετικά με τις κλινικές μελέτες....

[Gatekeeper]

ACC Statement on ENHANCE Trial

January 15, 2008

The ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial results were released by Merck and Schering-Plough Pharmaceuticals on January 14, 2008. The results of the trial show no benefit from the combination of ezetimibe (Zetia) and simvastatin (sold together as Vytorin) over simvastatin alone in terms of affecting the rate of atherosclerosis progression.

The study involved 720 patients with heterozygous familial hypercholesterolemia and showed no significant difference in the primary endpoint between patients treated with ezetimibe and simvastatin versus patients treated with simvastatin alone over a two-year period. The study was designed to prove that Vytorin could slow the growth of plaque in carotid arteries supplying the brain more than simvastatin alone. Media reports indicate that the results of the trial show no benefit from the combination of ezetimibe (Zetia) and simvastatin (sold together as Vytorin) over simvastatin alone.

The American College of Cardiology recommends that major clinical decisions not be made on the basis of the ENHANCE study alone.

According to the American College of Cardiology (ACC), this study deserves serious thought and follow-up. The overall incidence rates of cardiac events were nearly identical between both treatment groups, and both medicines were generally well tolerated. There should no be reason for patients to panic. The difference in IMT changes between the simvastatin group and the Vytorin group was 0.006 mm vs. 0.011 mm.

Health care professionals should speak to their concerned patients using this drug. The ACC is also releasing a public statement explaining that this is not an urgent situation and patients should never stop taking any prescribed medications without first discussing the issue with their health care professional. Further research will be needed in this area to provide conclusive evidence about which lipid lowering strategy is preferred (statin alone vs. statin plus ezetimibe).

Furthermore, the ACC notes that this trial is an imaging study and not a clinical-outcome study. Conclusions should not be made until the three large clinical-outcome trials are presented within the next two to three years. The ACC recommends that Zetia remain a reasonable option for patients who are currently on a high dose statin but have not reached their goal. The ACC also notes that Zetia is a reasonable option for patients who cannot tolerate statins or can only tolerate a low dose statin.

Reports also indicate that the ENHANCE trial has been submitted as an abstract to be presented at the upcoming American College of Cardiology Scientific Session in March, 2008. The late-breaking clinical trial selections by the meeting co-chairs are scheduled to occur in late January.

[Gatekeeper]

Title: Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia (ENHANCE — Presented at SCAI-ACC i2 Summit/ACC 2008 )
Trial Sponsor: Merck and Schering-Plough
Year Presented: 2008
Year Published 2008
Topic(s): General Cardiology, Prevention/Vascular
Summary Posted: 3/30/2008
Writer: Dharam J Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., F.A.C.C.
Author Disclosure: Research Grants: Eisai, Significant (>= $10,000); Research Grants: Sanofi Aventis, Significant (>= $10,000); Research Grants: Bristol Myers Squibb, Significant (>= $10,000); Research Grants: Ethicon, Significant (>= $10,000); Research Grants: The Medicines Company, Significant (>= $10,000); Research Grants: Heartscape, Significant (>= $10,000) 
 
Description
The goal of this trial was to compare the mean change in the intima-media thickness (IMT) measured at three sites in the carotid arteries between patients with heterozygous familial hypercholesterolemia (HeFH) treated with ezetimibe/simvastatin 10/80 mg versus patients treated with high-dose simvastatin 80 mg alone, over a 2-year period.
Hypothesis
Ezetimibe 10 mg in combination with simvastatin 80 mg daily would reduce the progression of atherosclerosis in patients with familial hypercholesterolemia (FH) compared with simvastatin 80 mg daily alone.
Drugs/Procedures Used
Patients with HeFH were randomly assigned to receive simvastatin 80 mg plus placebo or simvastatin 80 mg plus ezetimibe 10 mg.
Principal Findings
A total of 720 patients were randomized: 363 were assigned to the simvastatin arm and 357 to the ezetimibe/simvastatin arm. The baseline low-density lipoprotein (LDL) cholesterol levels between the two arms were comparable (317.8 vs. 319 mg/dl; p = 0.85). Approximately 81% of patients enrolled in the trial had been on statins previously. The baseline mean carotid IMT measurements were similar between the two arms.

The primary outcome measure, change from baseline to study endpoint for mean carotid IMT, was 0.0058 ± 0.0037 mm in the simvastatin arm versus 0.0111 ± 0.0038 mm in the simvastatin-ezetimibe arm (p = 0.29). New plaque formation defined as IMT >1.3 mm was seen in 9/320 (2.8%) of the patients in the simvastatin arm versus 15/322 (4.7%) in the ezetimibe/simvastatin arm, respectively (p = 0.20). No significant changes were observed between treatment groups for the IMT means of the common carotid, carotid bulb, internal carotid, femoral, or the average of the mean carotid and femoral IMT values.

There was no difference in the incidence of cardiovascular clinical events between the simvastatin alone and ezetimibe/simvastatin arms: cardiovascular deaths (0.3 vs. 0.6%), nonfatal myocardial infarction (0.6% vs. 0.8%), nonfatal stroke (0.3% vs. 0.3%), and need for revascularization (1.4% vs. 1.7%) (p = not significant [ns] for all). At the end of 24 months, mean LDL levels decreased to 192.7 mg/dl (39% reduction) in the simvastatin arm, and to 141.3 mg/dl in the ezetimibe/simvastatin arm (56% reduction), a 17% difference (p < 0.01).

The overall incidence of treatment-related adverse events was similar between the two groups: consecutive elevations of serum transaminases ≥3x upper limit of normal (ULN) (2.2% vs. 2.8%), elevated creatine phosphokinase (CPK) ≥10 ULN (2.2% vs. 1.1%), and elevated CPK ≥10 ULN with muscle symptoms (0.3% vs. 0.6%) (p = NS for all). No cases of rhabdomyolysis were reported in either arm.
Interpretation
The results of the multicenter, randomized ENHANCE trial seem to suggest that in patients with very high baseline LDL levels, such as those with HeFH, the combination of ezetimibe/simvastatin 10/80 mg does not result in significant changes in the mean carotid IMT at 2 years when compared with high-dose simvastatin 80 mg alone. There was also no difference in the incidence of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and need for revascularization, although this study was not powered to study clinical outcomes. The incidence of adverse events was similar. The LDL-lowering effect of ezetimibe/simvastatin was greater than that achieved with high-dose simvastatin alone.

Carotid IMT has been demonstrated to accurately predict the risk of incident cardiovascular events in several studies, as has LDL lowering. Hence, although this was a surrogate endpoint study, the results seem paradoxical: There was no significant reduction in carotid IMT with ezetimibe/simvastatin compared with simvastatin, despite a significant reduction in LDL cholesterol. One possible explanation is that the LDL reduction, though significant, was not adequate. Mean LDL levels even in the ezetimibe/simvastatin arm were 141 mg/dl. Thus, while setting an inclusion criterion for LDL >210 mg/dl helped to reduce their sample size, it may be the reason for their failure as well.

It will be interesting to see if larger ongoing trials will be able to demonstrate any relative benefit of the combination of ezetimibe/simvastatin in improving cardiovascular outcomes in high-risk patients, compared with simvastatin alone.
Conditions
• Hypercholesterolemia / Hyperlipidemia
• Peripheral vascular disease

Therapies
 • Lipid-lowering agent/ezetimibe
 • Lipid-lowering agent / HMG CoA Reductase Inhibitor / Simvastatin

Study Design
Randomized. Blinded. Parallel.

Patients Screened: 1,180
Patients Enrolled: 720
NYHA Class (% I, II, II, IV): I or II
Mean Follow-Up: 24 months
Mean Patient Age: 45.9 years
% Female: 49


Primary Endpoints
Change from baseline to end of follow-up (24 months) of ultrasound-determined mean carotid IMT
Secondary Endpoints
• Percent of subjects manifesting regression in mean carotid IMT between baseline and study endpoint
• Proportion of subjects developing new carotid artery plaques at study endpoint (lesion thickness >1.3 mm)
• Change from baseline in ultrasound-determined maximum carotid IMT
• Change from baseline in mean carotid IMT plus common femoral artery IMT
• Treatment-related adverse events, defined as consecutive elevations of serum transaminases ≥3x ULN, elevated CPK ≥10 ULN, elevated CPK ≥10 ULN with muscle symptoms, and rhabdomyolysis
• Incidence of major adverse cardiovascular events, including cardiovascular deaths, nonfatal stroke, nonfatal myocardial infarction, and need for revascularization
Patient Population
• Age of 30-75 years
• Diagnosis of FH either by genotyping or by having met the diagnostic criteria outlined by the World Health Organization
• Untreated LDL cholesterol ≥210 mg/dl
Exclusions:
• High-grade stenosis or occlusion of the carotid artery
• History of carotid endarterectomy or carotid stenting
• Homozygous FH
• Congestive heart failure (New York Heart Association class III-IV)
• Cardiac arrhythmias
• Angina
• Recent cardiovascular events
References: Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43.

Simvastatin With or Without Ezetimibe in Familial Hypercholesterolemia: The ENHANCE trial. Presented by Dr. John Kastelein at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.

[Raptor]

Τhe Framingham Heart Study

Δεν είναι ορατοί οι σύνδεσμοι (links). Εγγραφή ή Είσοδος

[Raptor]

THE UNITED KINGDOM PROSPECTIVE DIABETES STUDY (UKPDS)

The United Kingdom Prospective Diabetes Study (UKPDS), the largest clinical research study of diabetes ever conducted, provided conclusive evidence that the life threatening complications of type 2 diabetes can be significantly reduced by appropriate treatment.
5102 patients with newly diagnosed type 2 diabetes were followed-up for a median time of 11 years to test the effects of glycaemic control on complications in diabetes.
This study showed that lowering raised blood glucose and blood pressure levels reduced the risk of heart disease, stroke and death from diabetes-related diseases as well as diabetic eye disease and early kidney damage.

THE RESULTS1,2 SHOWED THAT BETTER BLOOD GLUCOSE CONTROL REDUCED THE RISK OF:
•   major diabetic eye disease by 21%
•   early kidney damage by 33%

BETTER BLOOD PRESSURE CONTROL, IN THE MANY PATIENTS WHO HAVE HIGH BLOOD PRESSURE, REDUCED THE RISK OF1,3:
•   death from long-term complications of diabetes by 32%
•   strokes by 44%
•   serious deterioration of vision by 47%

One of the most striking observations of the UKPDS was the progressive nature of type 2 diabetes and the failure of traditional treatments to maintain glycaemic control over time.4,5 Approximately half of patients on oral monotherapy progressed to polypharmacy within three years, indicating a need for more effective therapies for type 2 diabetes.4
In UKPDS, patients were randomised between a conventional blood glucose control regimen, keeping fasting plasma glucose <15 mmol/l, and an intensive glucose control regimen with sulphonylurea or insulin, aiming for fasting plasma glucose <6 mmol/l. The results showed a marked deterioration of glycaemia with time, due to a progressive decrease in beta-cell function.1
The intensive regimen reduced the risk of any diabetes-related endpoints, (microvascular, macrovascular and cataract extraction) by 12% (p=0.029), microvascular endpoints by 25% (p=0.0099), with a borderline significant 16% risk reduction in myocardial infarction (p=0.052) and a 24% risk reduction in cataract extraction (p=0.046).1
The study further randomised 1,148 people with hypertension in addition to their type 2 diabetes to a less tight blood pressure control regimen or a tight blood pressure control regimen achieving mean blood pressure levels of 154/87 mm Hg and 144/82 mm Hg respectively over median 8.4 years. The tight blood pressure control regimen reduced the risk of any diabetes-related endpoints by 24% (p=0.0046), microvascular endpoints by 37% (p=0.0092) and strokes by 44% (p=0.0013). It also reduced deterioration of visual acuity by 47% (p=0.0036), suggesting less diabetic maculopathy - the major cause of blindness in type 2 diabetes.1

The UKPDS results clearly demonstrated that the complications of type 2 diabetes are not an inevitable outcome of this chronic disease: risk can be reduced by appropriate therapy. Improved therapies may yield even greater improvement in risk if they can offer durable glycaemic control and help preserve beta cell function.

References
1.   Overview of the United Kingdom Prospective Diabetes Study - The UKPDS Diabetes Trials Unit, Radcliffe Infirmary, Woodstock Road, Oxford, UK Δεν είναι ορατοί οι σύνδεσμοι (links). Εγγραφή ή Είσοδος
See also: Diabetes UK, 1999, UKPDS - Implications for the care of people with type 2 diabetes Δεν είναι ορατοί οι σύνδεσμοι (links). Εγγραφή ή Είσοδος
2.   UK Prospective Diabetes Study Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837-853.
3.   UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ 1998; 317:703-713.
4.   Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus. Progressive requirement for multiple therapies (UKPDS 49). JAMA 1999; 281:2005-2012.
5.   Brown J, Nichols G, Glauber H, Bakst A. Ten-year follow-up of antidiabetic drug use, nonadherence, and mortality in a defined population with type 2 diabetes mellitus. Clin Therap 1999; 21:1045-1057.


Δεν είναι ορατοί οι σύνδεσμοι (links). Εγγραφή ή Είσοδος