Top Medical Stories of 2008 Challenged 'Lower Is Better' Mantra

By Peggy Peck

27 dec 2008--When it comes to LDLs and glycosylated hemoglobin, the philosophy of lower is better was dealt evidence-based blows this year with a series of surprising findings. In this year-end review, the editors of present their picks of the medical news events in 2008 that influenced clinical practice or triggered ongoing discussion among clinicians. Among them was a handful of studies that reassessed interpretation of surrogate endpoints such as HbA1c and LDL cholesterol that emerged as a theme. Take the potent lipid-lowering action of the combination of ezetimibe and simvastatin, marketed as Vytorin. It was reported in January that it brought levels down by 50% or more. But that, it turned out, did not slow or regress the progression of atherosclerosis. The disappointing bottom-line effect of the dramatic drops in lipids, as revealed in the ENHANCE trial, was supposed to come from findings that had been expected in March 2007 at the American College of Cardiology and then in November 2007 at the American Heart Association, but the data failed to materialize at either venue. By last January the rumor mill was abuzz, and the word was that that ENHANCE would provide proof that ezetimibe/simvastatin did not slow atherosclerosis as measured by plaque volume in the carotid arteries. And on Jan. 14 the naysayers were proven correct when Merck/Schering-Plough released the ENHANCE findings in a press release. (See: ENHANCE Finds No Slowing of Plaque Burden With Ezetimibe/Simvastatin (Vytorin)) That was just the beginning for events focused on this once blockbuster drug. Before the year was out, ENHANCE would be the subject of a controversial session at the ACC meeting, an FDA review, and a congressional investigation. (See: ACC: ENHANCE Data on Ezetimibe/Simvastatin (Vytorin) Reveal Wavy Bottom Line) The other shoe dropped in July when the SEAS investigators reported -- again at a press conference -- that the ezetimibe/simvastatin combination reversed aortic stenosis, but use of the drug appeared to be associated with an increase in cancer mortality. The cancer link, they said, appeared to be explained by the play of chance. (See: ESC: SEAS Data Fail to Quiet Ezetimibe/Simvastatin Controversy) But lipids aren't everything, and at the start of the year it still seemed logical to argue that if well controlled, low blood glucose levels were good. That being so, aggressive control with a glycosylated hemoglobin target of less than 6% would be even better. So it seemed. That presumption, it turned out, was not only wrong, but also dangerously so. On Feb. 6, the National Heart, Lung, and Blood Institute shocked both diabetologists and cardiologists with the news that it was pulling the plug on intensive-glucose-lowering arm of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial because that strategy was associated with excess mortality. At a press conference, Elizabeth G. Nabel, M.D., director of the NHLBI, said there were 257 deaths in the intensive-treatment group and 203 in the standard-treatment group, an excess of 54 deaths, or three per 1,000 participants each year, since the 10,251-patient trial was started in 2001. (See: Deaths Force NHLBI to Drop Intensive Glucose-Lowering Strategy in Type 2 Diabetes) The FDA had more than its share of headaches this year -- and most of them started on foreign shores. Late last year and continuing well into this year, the FDA began receiving reports that led to a massive recall of heparin that linked to serious and sometimes fatal allergic reactions. Months of sleuthing, finally identified the contaminant as chemically altered chondroitin-sulfate added to the crude heparin manufactured in plants in China. (See: Chemically Altered Chondroitin-Sulfate Found in Recalled Heparin) The FDA had barely caught its breath when the CDC began receiving reports of a salmonella outbreak. The source, initially, was believed to be tomatoes, and the FDA blocked shipments from a number of tomato farms -- most of which were in south central Florida. But the "DNA fingerprint" identified Salmonella saintpaul in water from an irrigation system at a farm in Nuevo Leon, Mexico, and serrano peppers grown there. And by that time, almost 400 salmonella cases were reported to the CDC. (See: More Salmonella Cases Reported as Trail of Infected Tomatoes Goes Cold FDA Finds Salmonella Saintpaul in Water and Peppers at Mexican Farm) On top of those import woes, the FDA had to deal with reports of melamine contamination in coffee and tea drinks imported from China and shut down import of generic drugs from two plants located in India. (See: Chinese Melamine Contamination Triggers U.S. Recall of Instant Coffee and Tea Products FDA Blocks Imports of 30 Generics from Two Plants in India) Meanwhile, the mounting toll of traumatic head injury and post traumatic stress disorder was a major medical story this year. (See: APA: PTSD May Be Major Combat Scar of Iraq Vets IOM Cites Poor Preparedness for Brain Injuries of Iraq and Afghanistan Vets ) One is never too old for blood pressure control, as was demonstrated in the 3,800-patient Hypertension in the Very Elderly Trial (HYVET), which found that even at age 80 blood pressure-lowering treatments were beneficial. (See: ACC: Octogenarians and Older Derive Benefits from Hypertension Therapy) And it might be that one is never too healthy for a statin -- or maybe not. The results of the 17,800-participant JUPITER trial suggest that patients ages 60 or older who had elevated C-reactive protein but no real evidence of atherosclerosis reduced cardiovascular events -- including deaths due to heart attacks and stroke -- compared with controls. But cardiologists attending the American Heart Association meeting where the data were released said it was still too early to add statins to the water. (See: AHA: JUPITER Results Point to Role of Statins for 'Apparently Healthy' Patients ) And rounding out the year, there were a pair of reports dealing with unusual and unique therapies -- the first U.S. face transplantation and an unexpected side effect of a bone marrow transplant for acute myeloid leukemia. The face transplant took occurred at the Cleveland Clinic, which has been sitting on an IRB approval for the procedure for more than four years. The ideal patient and a suitable donor finally showed up several weeks ago. The clinic team went public with the news at a press conference December 16. (See: First U.S. Face Transplant Reported at Cleveland Clinic) The news of a potential cure for HIV first surfaced last February at the Conference on Retroviruses and Opportunistic Infections, but it wasn't until last month when Gero Hütter, M.D., and colleagues at the Charité-Medical University in Berlin, discussed the results at a press conference that the story really gained traction. It's now been more than eight months and the 42-year-old American man, who received the bone marrow transplant to treat acute myeloid leukemia, is still free of HIV virus.

ACC: ENHANCE Data on Ezetimibe/ Simvastatin (Vytorin) Reveal Wavy Bottom Line

By Peggy Peck
CHICAGO, March 30 -- A full-airing here today of findings of the ENHANCE trial did nothing to blunt the null finding for the combination of ezetimibe/simvastatin (Vytorin) that were prefaced in a press release in January.
That press release, issued by Merck and Schering Plough, described a significant reduction in LDL cholesterol with ezetimibe/simvastatin (Vytorin) without a significant slowing of atherosclerosis progression.
But today's "showcase" scientific presentation of the results at the American College of Cardiology meeting, along with an analysis of ezetimibe (Zetia) and ezetimibe/simvastatin (Vytorin) use in the United States and Canada, may help calm concerns that ENHANCE suggested cholesterol-lowering does not correlate with clinical outcomes.
A clear clinical message from the ACC presentation, plus a simultaneous online release of the ENHANCE results by the New England Journal of Medicine, as well as a marketing analysis and two editorials, however, left the issue clearly open to interpretation. Advocates on both sides of the ezetimibe issue offered conflicting views.
To recap the ENHANCE story, the trial found no significant difference in the primary endpoint -- mean change in carotid intima-media thickness -- between patients randomized to ezetimibe/simvastatin versus 360 control patients who received simvastatin alone (P=0.29).
The combination therapy led to a significantly greater decrease in LDLs, a 58% reduction in LDLs for the ezetimibe/simvastatin group versus 42% for simvastatin controls after 24 months (P<0.01), said principal investigator John Kastelein, M.D., of the Academic Medical Center in Amsterdam in Holland.
There were also significant reductions in triglycerides (6%) and C-reactive protein (25.7%) between the two groups and those were significant (P<0.01), he said.
Nonetheless, those reductions did not result in significant reductions in the surrogate endpoint of carotid intima-media thickness, which begs two questions. First, is LDL reduction an invalid clinical goal? Second, what is the clinical evidence to support the use of ezetimibe?
The second question becomes especially crucial in light of data reported online today in the NEJM by Cynthia A. Jackevicius, Pharm.D., of the Western University of Health Sciences in Pomona, Calif., and colleagues. They found that ezetimibe had captured more than 15% of the market for lipid-lowering medications by 2006. This translates in to 3.1 million prescriptions for ezetimibe or ezetimibe/simvastatin in December 2006.
Moreover, the increased use of ezetimibe appears to have gained market share by cutting into statin prescriptions, which declined by 6.5% since ezetimibe was introduced in 2006.
Ezetimibe use also increased in Canada but the rise was markedly less, from 0.2% of prescriptions for lipid-lowering drugs in 2003 to 3.4% in 2006.
Two factors, Dr. Jackevicius and colleagues said, may explain the difference between U.S. and Canadian use. The combination of ezetimibe and simvastatin is not approved in Canada, and Canada does not permit direct-to-consumer advertising of prescription drugs.
In the U.S., Merck and Schering Plough spent $200 million on marketing ezetimibe and the combination product and sales here have "eclipsed $5 billion," Dr. Jackevicius and colleagues said.
Addressing the issue of the clinical value of LDL cholesterol lowering, two editorials concluded that the ENHANCE data should not be taken as evidence that cholesterol doesn't really matter.
Rather, the editorials hinted, there is a need to broaden the message so that it encompasses both lower is better and how you get there counts.

Merck/Schering-Plough Pharmaceuticals Provides Results of the ENHANCE Trial

WHITEHOUSE STATION, NJ and KENILWORTH, NJ -- January 14, 2008 -- Merck/Schering-Plough Pharmaceuticals announced today the primary endpoint and other results of the ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial. Merck/Schering-Plough has submitted an abstract on the ENHANCE trial for presentation at the American College of Cardiology meeting, which will be held in March 2008, and is awaiting notification of acceptance from the College.ENHANCE was a surrogate endpoint trial conducted in 720 patients with Heterozygous Familial Hypercholesterolemia (HeFH), a rare condition that affects approximately 0.2 percent of the population. All analyses were conducted in accordance with the original statistical analysis plan. 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 no statistically significant difference between treatment groups on the primary endpoint. 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. 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. Key secondary imaging endpoints showed no statistical difference between treatment groups.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 percent) as compared to 8 out of 360 for simvastatin (2.2 percent). Incidence of elevated creatine phosphokinase (≥10xULN) was 4 out of 356 (1.1 percent) in the ezetimibe/simvastatin group and 8 out of 360 (2.2 percent) in the simvastatin group and two cases (0.6 percent) of CPK≥10xULN associated with muscle symptoms in the ezetimibe/simvastatin group and one case (0.3 percent) 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 randomized to ezetimibe/simvastatin and 318 mg/dL in the simvastatin group. Approximately eighty percent 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 percent LDL cholesterol lowering at 24 months on ezetimibe/simvastatin 10/80 mg as compared to 41 percent 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 as follows: 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 revascularization 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. This surrogate endpoint study was not powered nor designed to assess cardiovascular clinical event outcomes.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.SOURCE: Merck & Co.