Angina as a target
WELL-KNOWN for the crushing pain they can produce in the chest, heart attacks don’t usually occur more than a few times. Angina pain, however, can be just as intense -- and sufferers can be doubled over in agony several times a week.
Although the cardiac condition is not fatal, the underlying cause makes it more likely that sufferers will have a heart attack. It typically occurs during physical activity or emotional stress, which can limit mobility and force people to avoid situations that can trigger anger, worry or other stressors. Some patients’ angina is so severe that they are unable to work. Surgery and medications can ease symptoms, but 5% to 15% of patients get no relief from these therapies.
Now a novel drug may reduce the frequency and severity of attacks, greatly improving quality of life for these hard-to-treat patients. “This drug is going to have an enormous impact on cardiac patients who can’t tolerate current treatments,” says Dr. Peter H. Stone, a cardiologist at Harvard Medical School in Boston who has tested the experimental medication.
Chronic angina, which affects more than 6 million Americans, is caused when the heart muscle is deprived of needed oxygen. Angina most often is triggered by coronary artery disease, in which plaque builds up on the walls of the arteries and causes the blood vessels to become narrow and stiff. This reduces blood flow to the heart, which diminishes the oxygen supply to the heart muscle. Angina can also occur when the heart is not pumping properly.
The pain of angina is usually not constant, because sufferers may indeed get enough oxygen-rich blood to their hearts when they’re not exerting themselves. But any physical activity -- climbing stairs or walking up a hill -- can trigger an attack because the heart then needs more oxygen. Even eating a heavy meal or becoming upset or stressed can provoke an episode.
Surgery, such as angioplasty, can open narrowed arteries and increase blood flow, but some patients can’t have surgery. And medications can cause such side effects as fatigue, impotence, swollen ankles and insomnia.
“When you get to be 75, you don’t want someone opening up your chest,” says Dr. Michael Sweeney, vice president of clinical affairs for CV Therapeutics in Palo Alto, which makes the new drug.
The medication, which is called ranolazine (brand name is Ranexa), works differently than existing drugs: It prevents an overload of calcium in the heart muscle cells. Too much calcium causes the electrical system of the heart to become unstable, leading to arrhythmias and abnormal heart contractions; when the heart doesn’t pump properly, not enough blood gets to the heart muscle.
Ranexa prevents too much calcium from entering heart muscle cells by shutting the gate on the sodium channels, which are on the cells’ membranes.
“Sodium drives calcium into the cell, so that a sodium overload will trigger a calcium overload,” says Dr. Luiz Belardinelli, a pharmacologist and cardiac electro physiologist at CV Therapeutics who helped develop Ranexa. “If the gate fails to close or closes too slowly, sodium continues to leak into the cell. Ranexa works by making the gate close faster, which prevents the sodium-dependent calcium overload.”
Recent tests have yielded positive results. A study earlier this year involved 565 patients who had more than three angina attacks per week despite treatment with a conventional angina medication. A twice-a-day dose of the oral drug over a six-week period halved the average number of attacks, from 5.6 to 2.8.
In a 2004 clinical trial of 823 patients with chronic angina, the treated group had about half the number of attacks and was able to exercise 25 seconds longer than the volunteers taking a placebo.
“This gives them that extra exercise capacity to make it up a flight of stairs, or play with their grandchildren,” Sweeney says.
The company hopes to get FDA approval early next year for patients whose angina cannot be controlled by current medications, though it may eventually be used by all angina sufferers. When used in combination with existing drugs, Ranexa might significantly reduce the incidence and severity of angina attacks.
“Since Ranexa targets different mechanisms that provoke inadequate blood flow,” Stone says, “it really fills a niche in the therapeutic arsenal.”
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Current treatments
Treatments for angina include medicine, surgical procedures and lifestyle changes, such as reducing stress or taking rest breaks, to avoid an episode of the excruciating chest pain.
Nitrates, like nitroglycerin, often are used when someone is having an angina attack or expects one to occur. Beta blockers can slow the heart rate and lower blood pressure, which can delay or prevent angina. ACE (angiotensin-converting enzyme) inhibitors can also lower blood pressure, and calcium channel blockers relax blood vessels, which increases blood flow to the heart.
When medication doesn’t help, surgery may improve blood flow to the heart.
These procedures include angioplasties to open up blocked or narrowed coronary arteries, or coronary artery bypass surgery, in which veins or arteries from other areas of the patient’s body are used to bypass blocked coronary arteries.
