Novel drugs for anticoagulation and heart failure, a new approach to arterial plaque reduction, and revised guidelines for treatment of hypertension are among the major advances in cardiovascular medicine in 2003, according to the list of top 10 advances published by the American Heart Association. The Top 10 list, which was created in 1996, is designed to highlight major gains made each year in research and clinical care related to heart disease and stroke.

The first item for 2003 is a revision of U.S. hypertension treatment guidelines, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. This year the committee defined a new risk class called ‘prehypertension,’ defined by blood pressure between 120-139 mmHg systolic pressure and 80 to 89 mmHg diastolic pressure. The Report advocates lifestyle measures such as a healthier diet, regular exercise, and smoking cessation for this population, which may reduce risk for stroke and kidney disease as well as heart disease.

The guidelines also state that people over age 50 years with systolic pressure greater than 140 mmHg should be treated regardless of diastolic pressure because systolic pressure is the dominant risk factor. In addition, the guidelines suggest that most hypertensive patients will require 2 or more antihypertensive medications to achieve goal blood pressure (less than 140/90, or less than 130/80 for patients with diabetes or chronic kidney disease).

The second item is a new oral anticoagulant, ximelagatran, the first potential alternative in 50 years for warfarin. In the Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran In Patients with Nonvalvular Atrial Fibrillation (SPORTIF V) trial, anticoagulation with warfarin was compared with anticoagulation with the oral direct thrombin inhibitor ximelagatran. Patients with atrial fibrillation and at least 1 stroke risk factor (3,922 individuals) were randomized to adjusted-dose warfarin or fixed-dose ximelagatran.

The primary endpoints were strokes (ischemic and hemorrhagic) and systemic embolic events; the observed primary event rates were statistically without difference for the 2 treatment arms. When all-cause mortality was included with the primary events, the rate difference between groups was even less. The study authors concluded that fixed-dose, oral ximelagatran is at least as effective as well-controlled warfarin for preventing stroke and systemic embolic events.

Ximelagatran was developed as an alternative to warfarin in an effort to find a drug that was easier for patients and doctors to manage. Although warfarin is widely prescribed after strokes, myocardial infarctions, and knee surgery, warfarin requires close laboratory monitoring for dose adjustment and interacts with certain foods and drugs. Studies show ximelagatran does not require adjustments or close monitoring, and it has no known food or drug interactions.

The third advance is the recognition that automated external defibrillators in public settings along with training of volunteers can double the likelihood that cardiac arrest victims will survive, a finding reported at the American Heart Association's Scientific Sessions 2003. The study involved placement of defibrillators in nearly 1,000 places such as shopping centers and apartment complexes in 24 U.S. and Canadian cities and training of roughly 20,000 volunteers, all of whom were taught cardiopulmonary resuscitation; half were also taught how to use the defibrillators. Over the next 21.5 months, the volunteers attempted to resuscitate nearly 300 cardiac arrest victims. Of the total, there were 44 survivors, with 29 treated by a study volunteer who used resuscitation plus defibrillation and 15 treated only with cardiopulmonary resuscitation.

Fourth on the list is a new drug for treatment of congestive heart failure following myocardial infarction. Eplerenone, an aldosterone blocker, was approved for use in the U.S. following the spring release of findings from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).

This study (6,632 people) showed that patients who took eplerenone in addition to standard congestive heart failure treatment were 15 percent less likely to die from any cause, 17 percent less likely to die from heart disease, and 13 percent less likely to die of heart disease or be hospitalized compared with patients who took placebo plus standard therapy. According to the study authors, standard treatment includes surgery, angiotensin-converting enzyme inhibitors, aspirin, beta blockers, and statins.

The fifth advance on the list is the recognition that stem cells from bone marrow can help to restore a failing heart following myocardial infarction, a finding that was reported at the American Heart Association's Scientific Sessions 2003. German researchers studied 40 patients with acute myocardial infarction who were treated with balloon angioplasty and stenting. Half of the patients also received bone marrow stem cells during the procedures, while 20 patients who declined the experimental procedure formed the control group. Three months after the procedure, the stem cell patients had less myocardial damage and an increase in ejection fraction compared with the control group.

The sixth item is the finding that drug-coated stents are effective in real-world practice, where patients are often sicker, older, or both than the patients selected for clinical trials. The 1-year results from the Rampamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry of 958 patients with previously untreated blocked arteries show that 9.7 percent of patients who received the experimental stents had a major adverse cardiac event compared with 14.8 percent of those who received bare stents. Only 3.7 percent of the patients treated with drug-eluting stents had restenosis requiring repeat procedures, whereas 10.9 percent of patients in the bare stent group required repeat interventions.

The seventh advance on the list is identification of an additional gene that can cause familial thoracic aortic aneurysm and dissection when mutated. Currently, people at risk because of genotype are unaware because the condition is asymptomatic until aortic dissection or rupture occurs.

Previous work had identified 2 likely chromosomal sites, although some families had disease that could not be linked to either. In the new study, researchers examined 4 generations of a family with a history of the condition unlinked to the previously identified chromosome locations to identify the new gene location, called TAAD2. As researchers continue to search for other chromosome sites, they are trying to pinpoint the sequences of the responsible mutations. After sequencing is done, a screening test may be possible to identify high-risk patients.

The eighth item is the development of a new plasminogen activator from the saliva of vampire bats, which may significantly increase the number of future patients with ischemic stroke who are eligible for thrombolytic therapy. The agent, called Desmodus rotundus salivary plasminogen activator, or desmoteplase, may be able to be used up to 3 times longer than the current stroke treatment window ? without increasing the risk for additional brain damage.

The only drug currently approved in the U.S. for this application is intravenous tissue plasminogen activator, (rt-PA). However, rt-PA is administered to only a small percentage of potential patients because current protocols allow treatment only within 3 hours of stroke onset. In addition, data from some animal studies suggest that rt-PA can promote brain cell death. Although most of the experiments with desmoteplase have been limited to animal models, the agent is now being tested up to 9 hours after stroke onset in a European clinical study.

The ninth advance is the possibility that infusions of high-density lipoprotein cholesterol (HDL) can promote significant reductions in the amount of plaque in coronary arteries. In the study, 5 once-per-week infusions of a synthetic form of the compound were tested in 57 patients with unstable angina or non-ST- or ST-elevation myocardial infarction. Patients were randomized to a low dose or a high dose of a synthetic version of HDL known as apolipoprotein Milano AI/phospholipid complexes (ETC-216) or to a placebo. Of 47 patients who completed the study, 11 were in the placebo group, 21 in the low-dose treatment group, and 15 in the high-dose treatment group.

The synthetic substance mimics a naturally occurring genetic variation found in a small group of people living in northern Italy that appears to be protective against atherosclerosis. As determined by intravascular ultrasound at baseline and 6 weeks after treatment, the volume of arterial plaque decreased by an average of 1.06 percent in the combined treatment group, whereas atheroma volume increased by 0.14 percent in the placebo group. Although the numbers are small, researchers noted that no treatment to date has been associated with regression of plaque in such a short amount of time.

The final advance is the recommendation from the American Heart Association and the U.S. Centers for Disease Control and Prevention that physicians initiate limited use of blood testing for C- reactive protein level as part of risk stratification for cardiovascular disease. Several studies have demonstrated that increased concentrations appear to be associated with increased risk for coronary heart disease, sudden death, and peripheral
arterial disease.

The writing group emphasized that the new test -- known as a highly sensitive C-reactive protein (hs-CRP) test -- does not fit in the same category as cholesterol testing or hypertension screening, suggesting instead that the test might be useful when a physician is undecided about a course of treatment for a patient who is at intermediate or unclear risk.