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What’s New? Stem Cell Research, Drug Therapies & Devices

In the realm of heart disease, there are no miraculous cures, however, new treatment modalities sound like sci-fi technology.

* Stem cell research has spawned possibilities for treating myocardial infarction-damaged heart muscle by injecting the patient’s own stem cells into the scar tissue.
* A synthetic protein has been developed that is a type of HDL that removes cholesterol from plaque and is excreted by the liver.
* A new drug shifts cholesterol from LDL to HDL, making it easier for the liver to excrete.
* Anticoagulant therapy risks are reduced by new alternative to warfarin.
* A pacemaker device is developed to prevent CHF by utilizing an electric current.

These are a few of the leading edge trials that Stern Cardiovascular Group has engaged in under the direction of Frank A. McGrew, III, MD, the group’s distinguished clinical research director. (See related story below.)

While stem cell research and gene therapy hold promise for many diseases such as Alzheimer’s, Parkinson’s and paralysis, stem cell therapy is a reality for treating some blood disorders like sickle cell anemia and leukemia. For cardiology, the answers are still unclear but dramatic discoveries cause us to wonder just how far scientists will advance toward renewing and healing our beating hearts.

According to McGrew, the latest treatment modality to receive attention is the new FDA approved Pradaxa® (dabigatran etexilate mesylate), the first pharmaceutical alternative to warfarin (Coumadin) in over 50 years and one of the first new treatment options available to prevent stroke in patients with atrial fibrillation. The RE-LY study was a three year multicenter randomized study which enrolled more than 18,000 patients from U.S. and non-U.S. sites with (non-valvular) atrial fibrillation – the largest atrial fib study ever conducted. Pradaxa prevented more strokes than the warfarin group. The only safety concern reported by the FDA was bleeding but there was less bleeding in the brain with Pradaxa compared to the warfarin group, but there were more GI bleeds in the Pradaxa group.

“Unlike warfarin, the mechanism of the new drug is simpler in that it has less interaction with other drugs and food,” said McGrew. There is no need for INR (pro-time) testing and there is no interaction with leafy green vegetables loaded with vitamin K. The new drug blocks the effect of thrombin, “whereas, warfarin works by stopping the production of clotting factors.”

“There was an unusual aspect of the study,” McGrew continued. “The drug benefited every subgroup, male and female, young and old. No matter what the CHADS score was, the patients benefited from Pradaxa. The CHADS score predicts the risk of stoke in patients with atrial fibrillation, based on 5 risk factors: Congestive heart failure history; Hypertension history; Age greater than 75; Diabetes Mellitus history; and previous Stroke or TIA symptoms.” The CHADS score helps physicians predict the risk of not using anticoagulation in patients with atrial fib.

“There are determinants for switching patients to Pradaxa. For the patient who has difficulty adjusting the warfarin dose and whose INR changes inexplicably – the decision is relatively easy to place the patient on the new drug. At the other end of the spectrum, there are patients who have repetitive GI bleeds but are otherwise stable on warfarin, in which case we might stick with the status quo. For the patients in between, the decision is not easy. In general, the hard data shows that the tougher the warfarin is to control, the more likely it is that the new drug may benefit.” Pradaxa is superior for certain patients but each individual’s therapy should be tailored to meet the patient’s specific situation.

“We would not use the drug in patients with severe kidney disease on dialysis, but in those with moderately severe kidney disease,” McGrew continued, “we might place them on the drug at a lower dose. Another group who might benefit from the drug would include those without ready access to testing pro-times, although Medicare does cover an INR monitor for at-home testing.

“It is likely that the cost will be prohibitive for some patients. Like other drugs, cost will vary with insurance coverage,” said McGrew.

Among the stem cell trials McGrew is engaged in is a heart muscle study. In spring 2010, enrollment began for patients experiencing an acute myocardial infarction (MI) who have a coronary artery that can be opened rapidly and who are seen within 7 days of the MI. “Stem cells have been harvested and prepared from a donor pool of healthy people and are given to the patient by IV into a peripheral vein. The stem cells are pulled like a magnet to the heart and, once there, presumably the cells grow and replace the injured heart cells. It’s possible they allow the heart muscle to heal faster. The mechanism of benefit is not known,” admitted McGrew. The enrollment for this study has been slow all over North America due to there being fewer severe heart attacks. “Most MIs are aborted successfully these days,” explained McGrew. “Although there are 45 centers to enroll patients, only two have been enrolled thus far. Both patients are doing well with no side effects reported but it is a randomized study so half of the patients are receiving placebos.”

Another stem cell trial planned will enroll patients who have stable heart disease and who have had an MI and have a major “scar” in their heart. “Using a muscle biopsy, the cells will be taken from the patient’s thigh and grown in tissue medium for 14-20 days. The cells (myeloblasts, moderately mature stem cells) will then be injected into the patient’s scar tissue with a small needle using the NOGA catheter, which we acquired through a grant from the BMH Heart Institute.” This is a special mapping cath-based system which visualizes the scar, its size and location, maps myocardial function and delivers therapeutics. “We don’t know if this therapy works yet. It is several years away from common usage but I do think there is some evidence that it may be effective.”

When asked if uncontrolled proliferation of stem cell growth is a concern, McGrew indicated that if embryonic stem cells are harvested, aberrant tissue growth could result. This is not a concern with the type of stem cells used in the heart muscle studies because the cells are not from embryos.

Two different approaches to preventing CHF are planned with the Montreal Heart Institute, which is affiliated with the NIH. The first trial will give post-MI patients a synthetic protein infusion similar to HDL on a weekly basis. The protein binds cholesterol and carries it to the liver for excretion. A heart cath with intracardiac ultrasound will be performed at baseline and again after two years to see if the plaque shrinks.

The second trial will use ultrasound to measure the size of plaque at the beginning and end of the study. Patients will be given CEPT (cholesterol ester transfer protein) which causes cholesterol to bind to HDL so it moves to the liver where it is excreted. These studies will provide new insights into whether HDL can be “fooled” into ridding the body of more of its unwelcome “cousin” precursor to plaque formation.

Yet another area of exploration is “The ‘Optimizer™,” an investigational pacemaker device that elicits an electrical current,” McGrew continued. “The current causes calcium ions to move from the storage part of the heart to the active part.” The modulating effect of the Optimizer System—Cardiac Contractility Modulation (CCM) Therapy for CHF—is thought to provide “intracardiac positive inotropic support.” McGrew reported that they have several patients who have had Optimizer device implants and are doing well. Plans are to launch a larger trial in early 2011.

Other drugs of interest include ranolazine (Ranexa®), approved for the angina syndrome, and may help women more than men, McGrew believes. New antiarrhythmics include dronedarone (Multaq®), which is a first cousin to amiodarone but without the toxic side effects. “We are doing a trial on dronedarone to test four groups of patients with atrial fib: the drug’s effectiveness in patients with pacemakers; in patients with permanent atrial fib; in patients after by-passes to prevent atrial fib; and finally, we will test its ability to prevent heart chamber enlargement in patients with atrial fib.”

Regarding clinical trials, McGrew advised, “There are many reasons for patients to participate in clinical trials. Because of the close follow-up and monitoring, they seem to do better. I have classic examples of patients who might not be alive had they not enrolled in a study. They had life threatening conditions diagnosed during the follow-up care which most likely would have gone untreated. Even when patients are not in studies, doctors don’t know the outcome or how they are going to react to drugs so it can be beneficial to participate in a clinical trial.”


Related Story

The Prevention Paradigm

By CONSTANCE ADCOCK



When asked about the effect of health reform on the practice of cardiology, Frank A. McGrew, III, MD, said his group does two things which may be considered unusual. First, they focus on prevention which involves specialized cholesterol testing. Berkeley HeartLab’s 4myheart Program is widely used to measure additional components of cholesterol, which are not included in routine lipid profiles, and they order more advanced cardiovascular tests. The Lp(a) protein is a fairly good predictor of heart disease and the tests measuring particle sizes of HDL and LDL can determine the rate of plaque build-up. “It also helps us to tailor medications to the patient. Secondly, we use the calcium scoring system. The heart CT scan measures calcium in arterial walls. As a general screening technique, the presence of calcium indicates a need to treat plaque aggressively.

“I will always be indebted to Dr. Tom Stern for his lipid analogy,” said McGrew. “The LDL protein is like a waiter at a table and the HDL is like the busboy – he cleans the table off. Stern was the greatest proponent for measuring cholesterol, its components and for treating high cholesterol very aggressively.”

When asked about his vision for cardiology in the next decade, McGrew predicted, “I think we are a long way from realizing stem cell therapy – knowing which stem cells to use, how the cells will interact with normal cells. Certain studies have suggested irregularities in the heart rhythm, which may be transient but it is an unknown. And the prospect of gene therapy is something we will pursue if technology is available to promote arterial growth in patients with angina. In cardiology, we can suppress problems but we can’t cure heart disease.
We have artery blocks and arrhythmias. They need monitoring; they recur. We have made great advances but there are few instances of total cure. We are always searching for new treatments because there is still an unacceptable rate of symptoms and mortality.”

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Frank A. McGrew, III, MD Frank McGrew, MD Pradaxa Berkeley HeartLab Calcium scoring system Berkeley HeartLa, MD Stern Cardiovascular Center Stern Cardio Group Tom Stern

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