~Cardiovascular Disease Comprehensive 19 - Invasive vs Noninvasive Testing
Invasive Versus Noninvasive Testing And Heart Procedures, continued
Angioplasty vs. Thrombolytic Therapy For Acute Heart Attack
An interesting study with far-reaching implications compared primary angioplasty to intravenous thrombolytic therapy for acute myocardial infarctions (heart attacks). An example of a thrombolytic is streptokinase (Streptase), which enhances the conversion of plasminogen to the fibrinolytic enzyme plasmin. Plasmin has a high specificity for fibrin and the particular ability to dissolve formed fibrin clots. Other drugs used to open clogged arteries during and after a heart attack are t-PA (Activase) and anistreplase (Eminase). Angioplasty is fully described in the preceding section.
Most cases of acute myocardial infarctions are caused by thrombotic occlusion of a ruptured plaque, diminishing blood circulation. Earlier research suggested there might be a time frame in human beings during which restoration of blood flow in the infarct-related artery might limit infarct size (Reimer et al. 1977). Research verified the concept, showing that timely reperfusion (a procedure in which blocked arteries are opened to reestablish forward flow of blood) resulted in less heart muscle damage and enhanced survival (Davies et al. 1985). The period from symptom onset to thrombolytic administration was related to reduced infarct size and mortality, with the greatest benefits within the first several hours following early symptoms. From these observations arose the premise that "time is muscle," establishing the need for swift treatment in progressive cardiac care (FTTCG 1994).
Based on its widespread availability, intravenous thrombolytic therapy has been the standard care for patients with acute myocardial infarction. Despite its popularity, thrombolytic therapy has limitations. Of those patients deemed candidates for anticoagulants, 10 to 15% had persistent occlusion or re-occlusion of the infarct-related artery. Consequently, primary percutaneous transluminal coronary angioplasty (primary PTCA) has been advocated as a better treatment for patients with acute myocardial infarction.
Proponents cited higher rates of opened vessels and improved blood flow to the heart among users of PTCA. In addition, avoiding thrombolytic administration virtually eliminates the approximate 1% risk of intracranial hemorrhage inherent with systemic clot-reducing procedures (Stone et al. 2001a). Naysayers (in turn) pointed out negatives associated with primary angioplasty, citing excessive delays to treatment compared with thrombolytic therapy, unproven results in large clinical trials, and a lack of widespread availability of treatment centers.
Yet, 22 trials (involving 6889 patients) demonstrated that for every 1000 patients treated with primary angioplasty (rather than thrombolytic therapy) an additional 20 lives were saved, 43 reinfarctions were prevented, 10 less strokes occurred, and 13 intracranial hemorrhages were avoided (meta-analysis by Ellen C. Keeley, University of Texas Southwestern, and Cindy L Grines, William Beaumont Hospital in Detroit). The angioplasty advantage was still observed even if the patient had to be transported (by 3 hour ambulance trip) to a center equipped to perform the procedure. (It typically takes about 2 hours to mobilize the medical team to perform the angiography and angioplasty in the United States compared to 60 to 90 minutes in European hospitals) (Cannon et al. 2000; Weaver et al. 2000).
Despite the inherent delays apparent with angioplasty, the evidence that primary PTCA offers advantage compared to thrombolytic therapy appears convincing. Optimizing angioplasty with coronary stents and drug regimens has significantly improved the early safety profile and long-term results of percutaneous intervention in acute myocardial infarctions (Stone et al. 2002a).
In conclusion, The Lancet recently described the CAPTIM trial (a current appraisal of the worth of angioplasty compared to thrombolytic therapy). In CAPTIM, 840 patients (within 6 hours of the onset of a heart attack) were randomized to fibrinolysis with accelerated doses of tissue plasminogen activators or to primary PTCA. Because of funding woes and slow enrollment, the trial ended before the planned recruitment of 1200 patients was reached (the number needed to demonstrate a 40% relative reduction in 30-day composite endpoints). Even so, the results demonstrated a trend toward a 24% reduction in the occurrence of adverse events.
Survival trends were similar between patients undergoing angioplasty and those receiving thrombolytic therapy, but the lower-risk population initially enrolled in the study appeared to explain the similarity in mortality statistics. (The survival benefit of primary angioplasty is mostly seen in high-risk patients, such as the elderly, and those with anterior myocardial infarction, or in shock) (Stone et al. 2001a; Zahn et al. 2001). The lack of a survival benefit in low-risk patients does not diminish the clinical relevance of fewer strokes, reinfarctions, a reduction in urgent revascularization procedures, and shorter hospital stays with primary PTCA, compared to fibrinolytic therapies.
Some advocate facilitated primary PTCA trials, i.e., combining thrombolysis with primary PTCA. However, the additional costs and bleeding complications that will certainly accrue by adding thrombolytic therapy before primary angioplasty cannot be dismissed without evidence of overriding benefit. To date, four modest-sized randomized trials have found facilitated PTCA either inferior to or no better than primary PTCA alone.
PTCA enthusiasts avow that (currently) the best therapy for most patients with developing acute heart attack should no longer be debated: administer antiplatelet therapy (aspirin, a thienopyridine, and possibly abciximab), and transfer the patient for primary PTCA to an experienced center, regardless of whether the nearest catheterization suite is three floors or three hours away. To do less, they caution, can no longer be considered standard care (Stone 2002b). Comment: According to Dr. Philip O'Dowd, the thienopyridines (clopidogrel and ticlopidine) are slightly more effective than aspirin in preventing morbid vascular events in certain patients (O'Dowd).
Angioplasty Among Diabetics
Although about 700,000 angioplasties are performed annually in the United States, the procedure is not a worthy consideration for everyone. Patients with diabetes mellitus, who are in need of revascularization, have better survival odds with coronary artery bypass grafting (CABG) compared to angioplasty, according to study findings published in the Journal of the American College of Cardiology (Bari Investigators 2000). According to Dr. Katherine M. Detre (University of Pittsburgh): "Diabetic patients did very much worse in both respects, heart attacks and mortality, when undergoing angioplasty." For diabetics, the 7-year survival rate was 76.4% in the CABG group and 55.7% in the angioplasty group. Among non-diabetics, the survival rates were 86.4% in the CABG group and 86.8% in the angioplasty group.
Does Multivessel Stenting Improve Odds?
More than 80% of patients worldwide are treated with endovascular prostheses during coronary procedures. So great are the numbers, Martin Leon, M.D., refers to the year 2000 as the era of the stent frenzy. A stent is a rod or threadlike device inserted within a closed or partially closed artery to allow adequate blood flow through the vessel (Leon 1998).
According to Korean researchers, the excitement regarding stents appears to be justified. In fact, research suggests that some patients with coronary artery disease may be excellent candidates for multivessel coronary artery stenting, instead of bypass surgery. Dr. Seung-Jung Park (University of Ulsan, Seoul) reviewed observational data, evaluating 200 patients with multivessel coronary artery disease and normal left ventricular function. Half of the patients underwent bypass surgery and the other half had multivessel stenting. Complete revascularization, the restoration of blood flow, was achieved in 95% of the patients who had bypass surgery and in 69% of the stent group. Over a 21-month follow-up period, survival in the two groups was similar (99% for the stent group and 97% for the bypass group), but a higher incidence of angina recurrence and target lesion revascularization occurred in the stent group (Kim et al. 2000).
What Is Brachytherapy?
Because restenosis (closure) is a major concern after angioplasty, strategies that will benefit patients prone to vascular reclosure are being developed. Vascular brachytherapy, the placement of intracoronary radioactive sources, has dramatically lowered neo (new) intimal growth patterns following angioplasty trauma.
A Scripps research team in LaJolla, California, headed by Dr. Paul S. Teirstein, inserted a ribbon of radioactive pellets into the artery for 20--45 minutes to help prevent the growth of scar tissue. In a preliminary clinical study conducted by Teirstein and colleagues, the incidence of in-stent restenosis (at the 6-month follow-up) declined from 54% without intra-coronary radiation to 17% with radiation, a difference of almost 70%. At 3-year follow-up, restenosis was reduced by 48% (a significant reduction considering the time frame). The need for repeat revascularization procedures was reduced 74% (from 45% to 12%) at 6 months. The clinical efficacy observed at 6 months was maintained at the 3-year follow-up (Teirstein et al. 2000; Carrington 2000).
Research carried out at the Division of Cardiology (Washington Hospital Center) showed overwhelmingly that gamma-radiation therapy delivers impressive results. For example, at 6 months, the in-stent restenosis rate was 21% among 60 patients assigned brachytherapy compared to 44% in a control group. At 12 months, the rate of revascularization of the target lesion was 70% less among the persons receiving gamma-radiation therapy; the incidence of a major cardiac event was 49% less (Waksman et al. 2002).
The one-time exposure to radiation does no apparent harm to heart tissue or the artery. The Journal of the American Heart Association reported that an assessment of the procedure at the 3-year interval indicated it was both safe and effective. However, Dr. Teirstein cautions that until much longer follow-ups demonstrate the benefits and safety of the radiation technique, it would be premature to recommend radiation therapy for the first line of treatment for patients with clogged coronary arteries (Teirstein et al. 2000). In the interim, major hospitals are gearing for brachytherapy as an option for patients with chronic coronary artery disease who are subject to adhesions following cardiac procedures.
Chelation Therapy: Is It a Bonafide Alternative to Heart Surgery?
Chelation therapy represents to some a safe, effective, and relatively inexpensive treatment to restore blood flow through atherosclerotic vessels. The word chelation is derived from a Greek translation meaning "claw-like," or capable of expunging accumulated atheromatous materials from the body.
During chelation, ethylenediaminetetraacetic acid (EDTA), a synthetic amino acid, is intravenously infused, along with other nutrients, to enact the extraction process. EDTA encircles and holds elements, passing them from the body in urine. With progressive treatments, accumulated pollutants are exhumed from body stores, along with materials that encourage free-radical damage and cellular breakdown. The heart-related conditions currently treatable with chelation therapy include arteriosclerosis and atherosclerosis, angina pectoris, hypertension, transient ischemic attacks, circulatory diseases, hemochromatosis, and Type II diabetes (Walker 1990; Powell et al. 1999).
Historically, chelation had an inception quite different from that of an antiarteriosclerotic. EDTA's first medicinal usage appears to have been around 1941 when it was used to extract lead accumulations. A decade later, Dr. Norman Clarke (director of research at Providence Hospital in Detroit) observed that patients treated for lead poisoning with chelation therapy had a simultaneous cessation of angina attacks. This chance beginning introduced EDTA to a few cardiovascular physicians who were searching for alternatives, apart from heart surgery, to remove plaque from diseased arteries.
Chelation therapy has had many deterrents along its controversial pathway. Even today, the American Heart Association, after reviewing the literature in regard to chelation and arteriosclerotic heart disease, has announced that the scientific evidence does not demonstrate any benefit from the therapy. The American Medical Association compared its effectiveness to that of a sugar pill. JAMA recently reported that based on exercise time to ischemia and exercise capacity, there is no evidence to support a chelation benefit in patients with ischemic heart disease, stable angina, or a positive treadmill test for ischemia (Knudtson et al. 2002).
Chelation supporters quickly rose to the accusation, among them Dr. Elmer Cranton, author of Bypassing Bypass. Dr. Cranton referred to the JAMA report as "sham science," citing statistical errors and patient disparities as compromising factors. One-third of the patients did not have angina, according to Cranton, and almost twice as many patients in the placebo group received antianginal drugs--and angina was supposedly one of the endpoints. Cranton avows that the study was inadequate to show any response, beneficial or otherwise. Researchers agreed (in part), citing the need for larger trials with a broad range of patients.
Dr. Terry Chappell (former president of ACAM) enrolled 32 physicians who were using the standard ACAM chelation protocol--20-30 treatments of EDTA, oral nutritional supplements, and lifestyle changes--in a study to assess the cardiovascular value of treatment. All of the patients participating in the study were appropriately diagnosed with vascular disease before the therapy began. Objective testing was done before and after each treatment. The results showed that chelation therapy (in union with supplements and lifestyle intervention) was yielding positive results. The patients, 1086 of 1241, or 88%, reported subjective betterment; physicians reported "significant clinical improvement" (Walker 1990).
Dr. Morton Walker, author of The Chelation Way, reminds us that an aspirin is less than one-third as safe as IV EDTA. The LD50 of aspirin is only 558 mg/kg in humans, while EDTA's LD50 is 2000 mg/kg. Note: LD50 indicates the pharmaceutical term lethal dose 50, or the dose of a substance that is fatal to 50% of test animals. Dr. Walker, a staunch advocate of chelation therapy, believes that the danger of death from bypass surgery is about 6000 times greater than from chelation therapy (Walker 1990).
The success of chelation therapy appears directly related to the refusion of minerals withdrawn during the extraction process. A physician trained in autonomic balancing, a process described earlier in the material, appears essential to the success or failure of the process.
Dr. Edward Olszewer and associates published two reports (a retrospective analysis of 2870 patients with vascular and other chronic degenerative diseases and a single-blind, crossover study of a small group of patients with peripheral vascular disease) suggesting a beneficial effect from chelation. In the former study, objective testing indicated marked or good improvement in 87% of patients. In the latter study, all 10 subjects receiving chelation benefited (Olszewer et al. 1988, 1990). Note: The National Center for Complementary and Alternative Medicine and the National Heart, Lung, and Blood Institute have launched the first large-scale clinical trial to determine the safety and efficacy of EDTA chelation therapy in individuals with confirmed coronary artery disease. Plans for the 5-year study, involving over 2300 patients at more than 100 research sites across the country, are currently being finalized.
Coronary Gene Therapy
Coronary gene therapy is another alternative to either angioplasty or coronary artery bypass surgery for high risk patients. Gene therapy increases the options of individuals who have failed drug treatment and appear to be poor candidates for aggressive surgical procedures. A battery of tests confirms the acceptability of a patient wishing to be enrolled in the gene program.
During coronary gene therapy, x-ray imaging allows the gene for the human vascular endothelial growth factor (VEGF2) to be delivered to the heart via a catheter inserted through a puncture in the inguinal (groin) region. A needle is advanced out of the catheter and used to inject DNA into the inner wall of the heart, a sequence that produces the vascular endothelial growth factor and stimulates the growth of new blood vessels. Data reported in the New York Times (August 29, 1999) suggest that VEGF2 is capable of invoking the growth of new blood vessels, with some individuals experiencing regrowth in about 60% of the area previously occluded. Although the process is constantly being advanced and refined, many patients have successfully undergone the treatment since 1998.
Two concerns researchers had concerning gene therapy were that blood vessel growth factors might nourish the blood supply of undetected cancers and cause damaging overgrowth of vessels in tissues such as the retina of the eye. Dr. Timothy Henry (Hennepin County Medical Center, Minneapolis) reported that among 106 patients enrolled in a VEGF trial, four patients in the placebo group developed cancer compared with one patient in the low dose VEGF group and none in the high dose group. Overall mortality was 3% in the placebo group, 6% in the low dose VEGF group, and 0% in the high dose group. The incidence of myocardial infarction was 3% in the placebo patients, 0% in the low dose group, and 6% in the high dose VEGF group.
Currently, there appears to be no retinal damage in diabetic patients who have undergone the procedure. These results are preliminary and inconclusive, but early assessments deem VEGF therapy a burgeoning alternative to either bypass surgery or angioplasty for coronary and vascular disease. For more information concerning coronary gene therapy, contact St. Elizabeth's Medical Center of Boston at (888) 311-GENE.
Continued . . .
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