In reply: The ENHANCE trial

In Reply: Both Dr. Fee and Dr. Porat recommend cautious utilization of ezetimibe until outcome studies are completed. As I stated in my article, it is unfortunate that for ezetimibe, hard outcome trials are not yet available (the SEAS trial showed a cardiovascular benefit for the combination of simvastatin/ezetimibe, but it was not the primary end point). The main point of my article is that the weight of evidence for the benefits of LDL-C lowering is one of the most proven surrogate measures in clinical medicine. The biology, epidemiology, and clinical trials with multiple LDL-C-lowering therapies (bile-acid resin, niacin, fibrates, diet, ileal bypass surgery, and statins) convincingly demonstrate the validity of this surrogate measure for regulatory approval. In fact, every drug that has been approved for the treatment of hypercholesterolemia has been based on LDL-C reduction and not on outcome trials.

If this requirement was in place, it is doubtful that statins would have been approved. Lovastatin was approved by the US Food and Drug Administration in 1987; the Scandinavian Simvastatin Survival Study (4S) trial¹ was completed in 1994. The 4S trial showed, for the first time, a reduction in total mortality with an LDL-C-lowering therapy. Millions of patients were placed on statins prior to 1994, and it is unlikely the 4S trial would have been funded unless there had been prior regulatory approval.

As a researcher, I truly believe hard outcome trials are essential, but as a clinician, I realize that most of our medical care is based on drugs approved utilizing surrogate measures. Hard outcome trials are not required for antihypertensives, oral hypoglycemics, or smoking cessation treatments prior to approval. Ezetimibe lowers LDL-C by a known mechanism and is well tolerated. The ENHANCE trial, with its well-recognized flaws, should not refute the benefits of LDL-C reduction. For patients not at goal on statin therapy, ezetimibe should remain a widely used option.

In Reply: Both Dr. Fee and Dr. Porat recommend cautious utilization of ezetimibe until outcome studies are completed. As I stated in my article, it is unfortunate that for ezetimibe, hard outcome trials are not yet available (the SEAS trial showed a cardiovascular benefit for the combination of simvastatin/ezetimibe, but it was not the primary end point). The main point of my article is that the weight of evidence for the benefits of LDL-C lowering is one of the most proven surrogate measures in clinical medicine. The biology, epidemiology, and clinical trials with multiple LDL-C-lowering therapies (bile-acid resin, niacin, fibrates, diet, ileal bypass surgery, and statins) convincingly demonstrate the validity of this surrogate measure for regulatory approval. In fact, every drug that has been approved for the treatment of hypercholesterolemia has been based on LDL-C reduction and not on outcome trials.

If this requirement was in place, it is doubtful that statins would have been approved. Lovastatin was approved by the US Food and Drug Administration in 1987; the Scandinavian Simvastatin Survival Study (4S) trial¹ was completed in 1994. The 4S trial showed, for the first time, a reduction in total mortality with an LDL-C-lowering therapy. Millions of patients were placed on statins prior to 1994, and it is unlikely the 4S trial would have been funded unless there had been prior regulatory approval.

As a researcher, I truly believe hard outcome trials are essential, but as a clinician, I realize that most of our medical care is based on drugs approved utilizing surrogate measures. Hard outcome trials are not required for antihypertensives, oral hypoglycemics, or smoking cessation treatments prior to approval. Ezetimibe lowers LDL-C by a known mechanism and is well tolerated. The ENHANCE trial, with its well-recognized flaws, should not refute the benefits of LDL-C reduction. For patients not at goal on statin therapy, ezetimibe should remain a widely used option.

In Reply: Both Dr. Fee and Dr. Porat recommend cautious utilization of ezetimibe until outcome studies are completed. As I stated in my article, it is unfortunate that for ezetimibe, hard outcome trials are not yet available (the SEAS trial showed a cardiovascular benefit for the combination of simvastatin/ezetimibe, but it was not the primary end point). The main point of my article is that the weight of evidence for the benefits of LDL-C lowering is one of the most proven surrogate measures in clinical medicine. The biology, epidemiology, and clinical trials with multiple LDL-C-lowering therapies (bile-acid resin, niacin, fibrates, diet, ileal bypass surgery, and statins) convincingly demonstrate the validity of this surrogate measure for regulatory approval. In fact, every drug that has been approved for the treatment of hypercholesterolemia has been based on LDL-C reduction and not on outcome trials.

If this requirement was in place, it is doubtful that statins would have been approved. Lovastatin was approved by the US Food and Drug Administration in 1987; the Scandinavian Simvastatin Survival Study (4S) trial¹ was completed in 1994. The 4S trial showed, for the first time, a reduction in total mortality with an LDL-C-lowering therapy. Millions of patients were placed on statins prior to 1994, and it is unlikely the 4S trial would have been funded unless there had been prior regulatory approval.

As a researcher, I truly believe hard outcome trials are essential, but as a clinician, I realize that most of our medical care is based on drugs approved utilizing surrogate measures. Hard outcome trials are not required for antihypertensives, oral hypoglycemics, or smoking cessation treatments prior to approval. Ezetimibe lowers LDL-C by a known mechanism and is well tolerated. The ENHANCE trial, with its well-recognized flaws, should not refute the benefits of LDL-C reduction. For patients not at goal on statin therapy, ezetimibe should remain a widely used option.