Seeking the best path (American College of Cardiology scientific session)

Studies indicate that the way heart health markers are lowered may be as important as getting them down.

By Victoria Stagg Elliott — Posted May 19, 2008

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The way blood pressure, lipids or blood sugar levels are reduced may be as important to heart health as getting those numbers to go low, according to studies presented at the American College of Cardiology's scientific session.

For instance, one paper indicated that taking ezetimibe with a statin lowered both LDL cholesterol and C-reactive protein levels more than taking a statin alone, but the combination did not have any added benefit on intima-media thickness. This finding suggests that, although the combination makes an impact on the numbers many physicians regard as important, it may not make a difference to overall cardiovascular health, according to data from the ENHANCE -- Effect of Combination Ezetimibe and High-dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia -- trial.

"There's some evidence that statin therapy has benefits over and above LDL lowering. Could it be that [ezetimibe] lacks some of the other effects that are supposed to be conferred by the statins?" said Dr. John Kastelein, lead author and professor of medicine and chair of vascular medicine at the Academic Medical Center in Amsterdam, the Netherlands.

In the wake of these data, which were released Jan. 14 in limited form by the drug's manufacturers, ACC officials and other experts are calling for physicians to rely more on the cholesterol-lowering drugs with the most outcome data supporting their use.

Ezetimibe "lowered LDL but it did not reduce the progression of atherosclerosis," said Harlan M. Krumholz, MD, a member of the ACC's panel organized to discuss the ENHANCE results. He also is a professor of medicine and epidemiology and public health at Yale University in Connecticut.

"This medication has been rapidly adopted into practices. ... We need to turn back to the statins," he said.

But many physicians said they would continue to prescribe ezetimibe. This study supported its safety, and patients often are either unable to reach their LDL goals on statins alone or cannot stand the amounts required to get there. Other medications that can make an impact on these numbers have their own side-effect issues or limited data supporting their use.

"We are being reminded that we have to optimize statin treatment in our patients because the alternatives are not ready yet," said Dr. Frank Ruschitzka, director of preventive cardiology at the University of Zurich, Switzerland. "But it's not that easy to get to the low levels. With a statin alone, we don't get to goal all the time, and not all of my patients tolerate high doses."

Also, intima-media thickness is a surrogate marker for heart health. Some experts are waiting for outcome data expected in 2012 before making major changes. "We have been too often misled by surrogates," said Dr. Ruschitzka. "I want to see the outcome trials."

Hypertension: Also a two-drug debate

With regard to hypertension, the ACCOMPLISH -- Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension -- trial compared a single pill combining an ACE inhibitor and a calcium channel blocker with one made up of an ACE and a thiazide diuretic. Both reduced blood pressure, but the ACE/CCB combination also decreased the risk of any cardiovascular event or death by 20%. The authors state that two medications may be a better first choice than only one, and the two drugs chosen should be an ACE and a CCB.

"These data suggest an ACE and a CCB might have synergistic effects on vascular health," said Kenneth Jamerson, MD, lead author and professor of internal medicine at the University of Michigan Medical School.

Experts agreed with starting with two drugs and expect guidelines to be revised within the next year, but many disagreed that a diuretic should be taken off the front line.

"It's a very good study. It may change a lot, but I'm not sure it's definitive enough to get rid of diuretics," said Marvin Moser, MD, a Yale University clinical professor of medicine.

Another paper also suggested that some ways to lower blood glucose may be better than others. Drugs that cause the body to use insulin more efficiently or increase the amount of insulin the body secretes both reduce hyperglycemia in those with type 2 diabetes, but one strategy more effectively reduced heart disease risk.

Pioglitazone increased HDL cholesterol, decreased fasting triglycerides and slowed the progression of coronary atherosclerosis better than glimepiride, according to the results of PERISCOPE, or Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation. Those who took glimepiride had more problems with hypoglycemia and angina. Patients on pioglitazone experienced more edema and a greater number of fractures.

"Few studies have compared outcomes for diabetes medications beyond glucose lowering, but we must close this knowledge gap," said Steven E. Nissen, MD, lead author and chair of cardiovascular medicine at the Cleveland Clinic. "We cannot just focus on getting blood sugar down and say that's the goal of therapy. The goal is to prevent the complications, and the first and foremost complication is heart disease. It does make a difference how we lower blood sugar."

This study is also the latest one to shed light on the safety profile of pioglitazone, which -- along with rosiglitazone -- has been the subject of questions over its safety during the past year. The Food and Drug Administration added black-box warnings about the possible increased risk of heart failure associated with both drugs.

Data suggesting that rosiglitazone also may be associated with an increased risk of heart attack are under review.

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Raising HDL still a goal

Despite several setbacks, significant promise is still attached to efforts to increase levels of HDL cholesterol, according to several presentations at the American College of Cardiology's scientific session.

"Yes, there's hope. We have to keep trying. LDL reduction is not enough," said Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic in Ohio.

For example, Dr. Nissen presented an unpublished analysis of data from the torcetrapib trial. He found that participants who were at the most risk from cardiovascular disease received the most benefit and did not experience adverse events. That trial was halted Dec. 2, 2006, because of an increased rate of cardiovascular events and deaths.

Experts say this finding means that HDL-raising should still be pursued, and it may be possible to do so without cardiac side effects. Studies presented at the ACC meeting suggested the other drugs in this class do not raise blood pressure as torcetrapib did.

"The other [cholesteryl ester transfer protein] inhibitors in development do not have the blood pressure toxicity of torcetrapib, so I cautiously predict that these drugs will show success in clinical trials," Dr. Nissen said.

Work also continues to improve the currently available drugs that have an effect on HDL. Several studies documented that a novel version of a fibrate can safely raise this blood lipid. Also, a pair of papers reported that an extended-release version of niacin combined with laropiprant reduces the risk of flushing. Niacin is a well-established medication for HDL-raising, but this side effect has limited the willingness of patients to take it.

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Preventive role of routine imaging weighed against risks

For patients identified as having an intermediate chance of coronary heart disease by their Framingham risk scores, doctors increasingly are turning to imaging modalities to fine-tune preventive strategies. But some experts wonder if imaging for patients who do not have a cardiovascular-related health issue is worth the expense and potential hazards of radiation exposure, said presentations at the ACC's scientific session.

Proponents argue that these tests, such as scans for coronary calcium or intima-media thickness, allow doctors to identify whose possibility of a cardiovascular event is higher than other factors would indicate. In turn, this information lets patients take steps to reduce their risks.

"We have effective screening for breast cancer, but we have not ... implemented an effective screening strategy for heart disease -- which kills far more people," said Harvey S. Hecht, MD, who advocated screening those at intermediate risk with ultrasound or computed tomography. This approach is consistent with guidelines from the Screening for Heart Attack Prevention and Education Task Force in the July 17, 2006, American Journal of Cardiology. Dr. Hecht is director of preventive cardiology at Beth Israel Medical Center in New York City and a task force member.

Improvements in technology have increased the safety and reduced the cost and size of the devices. The radiation required for cardiac computed tomography to measure coronary calcium is low. Ultrasound doesn't require any.

But some say findings are not strong enough to support broader use of this technology. "Do we have evidence that this improves patient outcomes? The answer is no," said Philip Greenland, MD, who rebutted Dr. Hecht's position in a debate. Dr. Greenland is executive associate dean for clinical and translational research at Northwestern University's Feinberg School of Medicine in Chicago.

Experts also question if the health care system can afford all of the suggested scanning, and the early initiation of treatment and the downstream testing that could result. "Testing begets more testing and more therapies, and it snowballs from there," said Leslee J. Shaw, PhD, professor of medicine at Emory University in Atlanta.

Not all of the imaging strategies involve radiation, but experts are most worried about those that do. These risks are not well quantified, but a review in the Nov. 29, 2007, New England Journal of Medicine suggested between 1.5% and 2% of all cancers could be related to medical scanning.

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Research findings: Treating hypertension, quantifying Cox-2 inhibitor risk

Treating hypertension in those older than 80 reduces the risk of stroke, cardiovascular disease and death from any cause, according to a study presented at the American College of Cardiology's 57th annual scientific session in Chicago, March 29 to April 1.

"There does not appear to be any age limit to the benefit of reducing blood pressure if the patient has a reasonable life expectancy," said Dr. Nigel S. Beckett, the study's lead author and a fellow at Imperial College London.

The risks and benefits of treating hypertension in younger patients has long been confirmed, but few trials have included older populations, leaving questions about the value for this group.

However, the Hypertension in the Very Elderly Trial -- HYVET -- randomized 3,845 seniors with hypertension either to be treated to a target blood pressure of 150/80 mm Hg or to receive a placebo. Those who received a diuretic and, as appropriate, an ACE inhibitor reduced their risk of stroke by 30%. The risk of death from any cause was lowered by 21%, and heart failure went down by 64%.

Another paper found that celecoxib, the only Cox-2 inhibitor still on the market, is safer for some patients than others. Researchers pooled data on 7,950 patients from six trials and found that risk for a cardiovascular event was determined by a patient's initial risk profile. Dosage also played a role, although this factor was most relevant for those who already had a significant chance of heart trouble.

"These data may provide a measure of comfort in prescribing celecoxib to patients with very low baseline cardiovascular risk, but would argue for caution in ... those with high risk," said Scott D. Solomon, MD, lead author and director of noninvasive cardiology at Brigham and Women's Hospital in Boston.

A third study found a reason why heart failure patients may still be at risk for influenza despite receiving the vaccine: Their immune systems may not mount as robust a response. Researchers from the University of Wisconsin in Madison analyzed the immune system activity following the vaccination in 17 healthy people, and compared it to that of 29 others with heart failure. All received some protection, but those with heart failure did not produce as many antibodies.

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External links

Information about lectures, presentations and other developments at the American College of Cardiology's 57th annual scientific session (link)

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