In what can be termed as a setback, Merck/Schering-Plough Pharmaceuticals' much awaited ENHANCE trial results showed Vytorin no better than its inexpensive generic in blocking the damaging effects of high cholesterol levels.
ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial compared Vytorin -- a combination of the drugs simvastatin and ezetemibe with Zocor- Simvastatin alone.
The surrogate endpoint trial conducted in 720 patients with Heterozygous Familial Hypercholesterolemia (HeFH) ), a rare condition that affects approximately 0.2 per cent of the population, showed no statistically significant difference between treatment groups on the primary endpoint.
The primary endpoint was the mean change in the intima-media thickness (IMT) measured at three sites in the carotid arteries (the right and left common carotid, internal carotid and carotid bulb) between patients treated with ezetimibe/simvastatin 10/80 mg versus patients treated with simvastatin 80 mg alone over a two year period.
There was also no statistically significant difference between the treatment groups for each of the components of the primary endpoint, including the common carotid artery. Also, the key secondary imaging endpoints showed no statistical difference between treatment groups.
The results indicated that the addition of ezetemibe -- which blocks the absorption of cholesterol in the intestines and is the key component in Vytorin -- produces no additional benefit
The change from baseline in the mean carotid IMT was 0.0111 mm for the ezetimibe/simvastatin 10/80 mg group versus 0.0058 mm for the simvastatin 80 mg group (p =0.29). At baseline, the mean carotid IMT measurement for ezetimibe/simvastatin was 0.68 mm and for simvastatin 80 mg was 0.69 mm.
The overall incidence rates of treatment-related adverse events, serious adverse events or adverse events leading to discontinuation were generally similar between treatment groups. The incidence of consecutive elevations of serum transaminases (= 3x ULN) was 10 out of 356 for ezetimibe/simvastatin (2.8 per cent) as compared to 8 out of 360 for simvastatin (2.2 per cent). Incidence of elevated creatine phosphokinase (=10xULN) was 4 out of 356 (1.1 per cent) in the ezetimibe/simvastatin group and 8 out of 360 (2.2 per cent) in the simvastatin group and two cases (0.6 per cent) of CPK=10xULN associated with muscle symptoms in the ezetimibe/simvastatin group and one case (0.3 per cent) in the simvastatin group. There were no cases of rhabdomyolysis. Both medicines were generally well tolerated.
Overall, the safety profiles of ezetimibe/simvastatin and simvastatin alone were similar and generally consistent with their product labels.
After washout, patients enrolled in the study had baseline LDL cholesterol levels of 319 mg/dL in the group randomised to ezetimibe/simvastatin and 318 mg/dL in the simvastatin group. Approximately eighty per cent of the patients enrolled in the ENHANCE trial had previously been treated with statins.
In the trial, there was a significant difference in low-density lipoprotein (LDL) cholesterol lowering seen between the treatment groups -- 58 per cent LDL cholesterol lowering at 24 months on ezetimibe/simvastatin 10/80 mg as compared to 41 per cent at 24 months on simvastatin 80mg alone, (p<0.01).
The incidence rates of cardiovascular clinical events in ENHANCE for the ezetimibe/simvastatin and simvastatin groups, respectively, were: cardiovascular death 2 out of 357 vs. 1 out of 363, non-fatal myocardial infarction 3 out of 357 vs. 2 out of 363, non-fatal stroke 1 out of 357 vs. 1 out of 363 and revascularisation 6 out of 357 vs. 5 out of 363. There were no non-cardiovascular deaths or incidents of resuscitated cardiac arrests in the ENHANCE trial.
Merck/Schering-Plough Pharmaceuticals is currently conducting three large outcomes trials with ezetimibe/simvastatin, which involve more than 20,000 high-risk patients, including the more than 10,000 patient IMPROVE-IT trial. No incremental benefit of ezetimibe/simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.
ENHANCE was a multinational, randomised, double-blind, active comparator trial that used digitised single-frame ultrasound technology for imaging purposes. There were 357 HeFH patients randomised to ezetimibe/simvastatin and 363 HeFH patients to simvastatin. The study collected more than 30,000 carotid artery and 10,000 femoral artery images from these patients. HeFH is characterized by markedly elevated plasma concentrations of LDL cholesterol; typically well above the 95th percentile for age and sex.1
Vytorin is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B2, triglycerides and non-HDL cholesterol and to increase HDL cholesterol in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.
Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed to develop and market in the United States new prescription medicines in cholesterol management. The collaboration includes worldwide markets (excluding Japan).Vytorin is also marketed as Inegy outside the US.