REVIEW ARTICLE
Refractory angina pectoris
Mechanism and therapeutic options
Michael C. Kim, MDa,
Annapoorna Kini, MDa and
Samin K. Sharma, MD, FACCa,*
a Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA
Manuscript received October 11, 2001;
revised manuscript received December 26, 2001,
accepted January 2, 2002.
* Reprint requests and correspondence: Dr. Samin K. Sharma, Mount Sinai Medical Center, P.O. Box 1030, One Gustave L. Levy Place, New York, New York 10029, USA.
samin.sharma{at}msnyuhealth.org
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Abstract
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As the survival of patients with primary coronary events continues to increase, the number of patients presenting with coronary artery disease unsuitable to further revascularization techniques and symptoms refractory to medical therapy also continues to rise. The aims of this review were to define the population of patients with refractory angina pectoris and to present the therapeutic options currently available for this condition. Refractory angina pectoris is defined, and traditional medical therapies are discussed. Then, current therapeutic options for patients with refractory angina are extensively reviewed. A multitude of therapeutic options exist for patients with refractory angina pectoris. Small, uncontrolled studies have shown a potential benefit for additional antiplatelet and antithrombotic therapy. In randomized trials, neurostimulation has been shown to be effective in reducing angina symptoms. Enhanced external counterpulsation is a viable treatment option for select patients with refractory angina. In many randomized trials, laser revascularization has been shown to diminish angina symptoms, although no placebo-controlled studies exist to date. Gene therapy is a promising area of research in this field. Percutaneous in situ coronary venous arterialization is in its infancy, but may be able to treat many patients if proved successful. No data support the role of chelation therapy in this population. Heart transplantation remains a final option for these patients. Further research of the techniques mentioned in this review is warranted. The importance of randomized, double-blinded, placebo-controlled trials cannot be overemphasized, as the placebo effect of these therapies is probably marked.
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Abbreviations and Acronyms
| | PTMLR | | ACE | | angiotensin-converting enzyme | | bFGF | | basic fibroblast growth factor | | CABG | | coronary artery bypass graft surgery | | CAD | | coronary artery disease | | CCS | | Canadian Cardiovascular Society | | EDTA | | ethylenediamine-tetraacetic acid | | EECP | | enhanced external counterpulsation | | EMM | | electromechanical mapping | | LAD | | left anterior descending coronary artery | | LDL | | low-density lipoprotein | | LMWH | | low-molecular-weight heparin | | PCI | | percutaneous coronary intervention | | PICAB | | percutaneous in situ coronary venous arterialization | | PICVA | | percutaneous in situ coronary venous arterialization | | PTMLR | | percutaneous transmyocardial laser revascularization | | rFGF | | recombinant fibroblast growth factor | | SCS | | spinal cord stimulation | | SPECT | | single-photon emission computed tomography | | TENS | | transcutaneous electrical nerve stimulation | | TMLR | | transmyocardial laser revascularization | | VEGF | | vascular-endothelial growth factor |
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Angina pectoris, the symptom that most often brings patients with ischemic heart disease to medical attention, represents an imbalance between myocardial oxygen supply and demand. This condition is most commonly due to atherosclerotic disease of the coronary arteries, resulting in a critical narrowing of the vessels. Conventional approaches to restoring this balance between oxygen supply and demand focus on disruption of the underlying disease process through medications, life-style modifications or revascularization techniques, such as coronary artery bypass graft surgery (CABG) or percutaneous coronary interventions (PCI), including balloon angioplasty, stents and atherectomy techniques.
An increasing number of patients with coronary artery disease (CAD), however, have ischemic symptoms that are unresponsive to both conventional medical therapy and revascularization techniques. This is because life expectancy is increasing, even for very sick patients, many of whom have already undergone multiple PCIs or previous surgical revascularization, and thus are not candidates for additional procedures. Such patients are said to have refractory angina pectoris, and an understanding of the therapeutic options for these patients is becoming more vital for physicians treating patients with CAD today. It has been estimated that >100,000 patients each year may be diagnosed as having this condition (1).
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Defining patients with refractory angina
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Two criteria must be met before a patient is labeled to have refractory angina pectoris: objective ischemia must produce severe symptoms, and all known conventional therapies must be exhausted. Patients with refractory angina have either marked limitation of ordinary physical activity or are unable to perform any ordinary physical activity without discomfort (Canadian Cardiovascular Society [CCS] functional class III or IV). There must be some objective evidence of ischemia, as demonstrated by exercise treadmill testing, stress imaging studies or coronary physiologic studies.
Symptoms must continue despite maximally tolerated medical therapy and with a consensus that revascularization by either PCI or CABG is not feasible. It should be noted that many patients are not able to benefit from traditional medical therapy due to side effects of the medications. All attempts at "maximizing" medical and life-style treatments, including the use of drug combinations, avoidance of nitrate tolerance, initiation of an exercise program and discontinuation of tobacco, must be made. Secondary causes of angina, such as anemia and uncontrolled hypertension, should be excluded.
Furthermore, a consensus regarding the inappropriateness of revascularization procedures should be established. Coronary artery disease that is not amenable to PCI or CABG may be deemed amenable for revascularization when different interventional cardiologists or cardiac surgeons are asked for their evaluation. Hence, a second and sometimes third opinion regarding the potential for revascularization should always be sought before labeling a patient as having refractory angina pectoris.
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Traditional therapies
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The majority of patients with mild to moderate angina (CCS class I/II) can be treated adequately with anti-anginal medications. Medications commonly used for the treatment of angina pectoris are listed in Table 1.
Beta-blockers remain the first-line drug for the treatment of angina pectoris. Beta-blockers decrease myocardial oxygen demand by decreasing heart rate and contractility during stress. A slower heart rate also increases the diastolic filling time available for coronary perfusion (which occurs mostly in diastole). This is important for patients with fixed coronary stenoses in whom the ratio of systolic to diastolic perfusion is abnormally high. Beta-blockers thereby increase exercise tolerance and reduce the frequency of anginal attacks.
Calcium channel blockers act as pure arterial (including coronary) vasodilators, with variable effects on cardiac conduction and contractility. Phenylalkylamines, such as verapamil, and benzothiazepenes, such as diltiazem, have negative inotropic and chronotropic effects. Thus, verapamil and diltiazem retard the increase in myocardial oxygen demand at submaximal work loads, resulting in an increase in the anginal threshold. Dihydropyridines, such as nifedipine, produce negligible decreases in myocardial oxygen demand; instead, they increase myocardial oxygen supply by increasing coronary blood flow through changes in vascular tone. They should not be used as the sole medical therapy.
Nitrates are endothelial-independent vasodilators. They dilate vascular smooth muscles even in vessels without endothelium. At therapeutic doses, nitrates exert their most prominent vasodilatory effects on systemic veins and conductance arteries. This results in an increase in myocardial oxygen supply and a decrease in myocardial oxygen demand. Venodilation leads to decreased left ventricular volume and thus diminished systolic wall stress and oxygen requirements. Furthermore, nitrates have been shown to cause modest stenosis dilation and to relieve coronary vasoconstriction related to endothelial dysfunction. Flow through collateral channels feeding ischemic myocardial regions is also increased. Clinically, exercise tolerance increases and anginal attacks decrease.
Aspirin is recommended for all patients with known CAD. It irreversibly acetylates platelet cyclooxygenase, thereby limiting the production of proaggregatory thromboxane A2. Platelets have been implicated in the disruption of atherosclerotic plaque, with subsequent thrombus formation, leading to the development of unstable angina or myocardial infarction, or both. For patients allergic to aspirin, clopidogrel or ticlopidine can be used as antiplatelet therapy.
With the recent publication of the Heart Outcomes Prevention Evaluation (HOPE) study (2), angiotensin-converting enzyme (ACE) inhibitors have received renewed interest as an anti-ischemic medication. This large, randomized, placebo-controlled trial demonstrated a significant 22% decrease in mortality and recurrent ischemic events in patients with known vascular disease or diabetes plus one other cardiovascular risk factor and normal left ventricular function who received the ACE inhibitor ramipril versus placebo. Two similar multicenter studies—the Prevention of Events with ACE inhibition (PEACE) and European Trial on the Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA)—are also evaluating the anti-ischemic effects of ACE inhibitors in patients with CAD and normal left ventricular function. The role of ACE inhibitors in patients with mild anginal symptoms is unknown.
In multiple trials, lipid-lowering agents have been shown to decrease recurrent coronary events in patients with known CAD and even to prevent CAD episodes in patients without known CAD (3). Besides reducing low-density lipoprotein (LDL) cholesterol, hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) possess anti-inflammatory and plaque-stabilizing properties (4). Recently, the Atorvastatin Versus Revascularization Treatment (AVERT) trial, using high-dose atorvastatin in patients with mild to moderate anginal symptoms, showed a reduction in recurrent coronary events, as compared with patients treated with conventional lipid-lowering therapy and elective angioplasty (5). It is not known what level of LDL cholesterol reduction is optimal in refractory angina, nor has any study been performed on the efficacy of lipid lowering in patients with such chronic symptoms.
For the majority of patients in whom medical therapy is unable to control ischemic symptoms, revascularization techniques are widely available in the U.S. In 1999, over 700,000 PCIs were performed, and the number of patients able to receive percutaneous interventions should only increase as technology and operator experience advance (6). For those patients requiring surgical revascularization, the introduction of less invasive techniques will also increase the already large numbers (over 400,000 in the U.S.) of CABG procedures performed worldwide (6).
Still, a large group of patients are inadequately managed with these traditional therapies. These patients cannot tolerate additional medications and have an anatomy unsuitable for initial or further mechanical revascularization. Furthermore, because the underlying process of atherosclerosis is not completely halted by these traditional therapies, new lesions can and usually do develop. These patients with refractory angina pectoris continue to have severe symptoms limiting their quality of life. The therapeutic options available for these generally desperate patients are outlined in Table 2.
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Alternative medical therapy
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Additional antiplatelet agents.
Although aspirin use is widespread among patients treated with CAD, platelet inhibition is only attenuated, and coronary events continue to occur. Clopidogrel is a thienopyridine derivative that blocks adenosine diphosphate–mediated platelet aggregation. Combination therapy with aspirin and clopidogrel has already been studied, with promising results in cerebrovascular diseases (7).
Despite results from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, which demonstrated a 20% relative reduction in cardiac events in patients presenting with an acute coronary syndrome when given the combination of aspirin and clopidogrel, caution must be used in extending these results to patients with refractory angina (8). It is speculative whether this benefit would be demonstrated in patients with more stable refractory angina.
Low-molecular-weight heparins.
The recent development of low-molecular-weight heparins (LMWH) allows for the outpatient use of this pharmacologic therapy. In addition, thrombin generation is ameliorated by the increased ratio of anti–factor Xa to anti–factor II activity seen in LMWH, as compared with unfractionated heparin (9). This has led to speculation that these agents may be useful in patients with refractory angina.
There have been two randomized trials evaluating the efficacy of LMWH in the outpatient management of patients with stable angina pectoris. Melandri et al. (10) conducted a double-blinded, randomized, placebo-controlled trial in 29 patients with stable, effort-induced angina and angiographically proven CAD. This study compared conventional anti-anginal treatment with the study medication, which added the LMWH parnaparin over three months. The patients who received parnaparin showed a statistically significant decrease in fibrinogen levels and an improvement in the time to both 1-mm ST-segment depression and peak ST-segment depression. There was no increase in major bleeding events in the LMWH group.
In a second study, Quyyami et al. (11) studied 23 patients with stable CAD in a randomized, placebo-controlled fashion, comparing conventional anti-anginal therapy with similar therapy plus subcutaneous dalteparin sodium for four weeks. Compared with placebo, patients who received dalteparin had significantly less frequent anginal episodes, an increase in exercise tolerance and an increase in the rate–pressure product during the time to ischemia. Finally, a smaller percentage of patients had a decrease in left ventricular function with exercise. There was no increase in major bleeding episodes. There was a marked placebo effect in this trial, however.
It remains to be seen whether LMWH should be recommended in patients with refractory angina pectoris. Concerns about its safety profile have not been appropriately addressed, to date. A larger randomized, placebo-controlled, double-blinded study will be needed before this therapy can unequivocally be deemed efficacious and safe.
Thrombolytic agents.
Although thrombolytic therapy has been proven to reduce morbidity and mortality in the setting of acute ST-segment elevation myocardial infarction, it has not been proven to be beneficial in patients who present with unstable angina or non–ST-segment elevation myocardial infarction (12). Given its ability to improve blood viscosity, however, it has been postulated that intermittent low-dose thrombolytic therapy may lead to enhanced coronary blood flow at both the microcirculatory and macrocirculatory levels in patients with refractory angina pectoris.
Two trials showing the potential benefits of this therapy have been conducted. First Schoebel et al. (13) performed a pilot study using bolus intravenous urokinase in 20 patients with refractory angina pectoris. Each patient had elevated baseline fibrinogen levels. After 12 weeks of therapy, fibrinogen levels declined by 34%. The number of anginal events per week decreased by 74% in the urokinase group, as compared with baseline. There was a 51% increase in exercise tolerance and time to 1-mm ST-segment depression. However, no placebo group was compared with the urokinase arm, and thus the placebo effect of this therapy cannot be fully determined.
Leschke et al. (14) conducted a randomized, dose-response trial comparing weekly high-dose versus low-dose urokinase. Ninety-eight patients were followed for 12 weeks. Only the high-dose group had significant changes from baseline when measuring pre- and post-fibrinogen levels, plasma viscosity and red cell aggregation. Patients in the high-dose urokinase group reported significantly decreased anginal events. Furthermore, only the high-dose group noted increased exercise capacity and time to 1-mm ST-segment depression. Bleeding complications were similar in both groups. A major limitation of this study was the absence of a placebo control group.
Currently, intermittent administration of thrombolytic therapy for the treatment of refractory angina pectoris appears safe. Fibrinogen levels are reduced, leading to decreased red blood cell aggregation and plasma viscosity. Clinically, exercise capacity is increased and subjective anginal episodes are also decreased. However, because of the small number of patients studied and the lack of a placebo control group, the value of thrombolytic therapy in patients with refractory angina is uncertain.
Partial fatty acid oxidation inhibitors.
Ranolazine represents a new class of compounds called partial fatty acid oxidation inhibitors, which has the potential to be the first new anti-anginal drug class in the U.S. in more than 20 years. Ranolazine increases efficient cardiac utilization of oxygen during stress by maximizing glucose utilization of oxygen versus fatty acid oxidation, which is far more inefficient. In the recently completed Combination Assessment of Ranolazine In Stable Angina (CARISA) trial, 823 patients already taking background beta-blocker or calcium channel blocker therapy were randomized to either ranolazine (high or low dose) or placebo (15). Patients in both ranolazine groups demonstrated a significant increase in exercise duration after two weeks of therapy, which was maintained after 12 weeks. Furthermore, the high-dose ranolazine group demonstrated a decreased frequency in anginal events per week, as compared with the placebo group. Long-term studies with this new class of drugs are planned.
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Neurostimulation
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Various methods have been described for the palliation of angina by interruption or modification of the afferent neural signals through which pain is perceived. Different surgical techniques have been used to interrupt the innervation of the heart, including autotransplantation, sympathectomy and plexectomy. More recent studies using transcutaneous electrical nerve stimulation (TENS) and spinal cord stimulation (SCS) have produced the most promising results.
Mannheimer et al. (16) first described the beneficial effects of TENS in the early 1980s. Based on the "gate-control theory," high-frequency stimulation of large non-nociceptive myelinated type A fibers inhibits the impulse through smaller, unmyelinated type C fibers, thereby reducing the activation of central pain receptors. In addition, there is a reduction in sympathetic discharge, leading to a decrease in cardiac work load and myocardial oxygen demand.
In TENS, two electrodes are applied to the chest—one in the dermatome with the highest intensity of projected pain and the other in the contralateral dermatome. The stimulus intensity is adjusted to just below the individual’s pain threshold. Early studies demonstrated an increase of exercise capacity with a concurrent reduction of ischemia noted on the exercise electrocardiogram (ECG) (17). There was a decrease in the anginal symptoms reported, and nitrate use was noticeably decreased. Side effects included skin irritation as a result of the high-frequency direct current and limited physical activity during treatment. Because of the paresthesias associated with effective treatment, no randomized, placebo-controlled trial is possible, considering the difficulty in producing similar paresthesias in a placebo group.
Spinal cord stimulation appears to be the most promising neurostimulatory technique for refractory angina. In SCS, the epidural space is punctured at the level of the fourth or sixth thoracic vertebra, and an electrode is introduced to the level of the first or second thoracic vertebra. An electrode stimulator is then placed subcutaneously in the upper left abdomen. By a mechanism similar to TENS, stimulation of these electrodes leads to decreased pain sensation and sympathetic outflow, as well as redistribution of myocardial blood flow to ischemic areas (18). Mannheimer et al. (19) noted a reduction in anginal symptoms, an increase in exercise capacity and a reduction in the degree of ST-segment depression at a given work load in patients receiving SCS versus control subjects. In another study, Hautvast et al. (20) demonstrated decreased ischemic ECG changes on ambulatory 48-h monitoring in a group of patients with refractory angina pectoris.
Two larger studies evaluating SCS have shown more convincing evidence. The Electrical Stimulation versus Coronary Bypass Surgery (ESBY) trial was a randomized, prospective study comparing SCS with CABG in 104 patients with known CAD who were considered at high risk for CABG or who would have no proven benefit from CABG (21). After six-month follow-up, CABG and SCS appeared to be equivalent in terms of symptom relief, with significant decreases in angina reported by both groups. The CABG group had a significant increase in exercise capacity and less ST-segment depression, as compared with the SCS group. However, 7 of the 51 patients in the CABG group died during the follow-up period, whereas there was only one death in the SCS group.
Greco et al. (22) recently published a multicenter, retrospective study of patients treated with SCS. After 23 months, 103 of the 517 patients studied had died. Spinal cord stimulation resulted in a significant decrease in New York Heart Association functional class. This study concluded that chronic SCS does not adversely affect mortality in patients with refractory angina pectoris, but it does improve symptoms. On a cautionary note, no placebo group was included.
In summary, neurostimulation is an emerging therapeutic option for patients with refractory angina pectoris. Symptoms appear to improve with either TENS or SCS, although the data for SCS are more convincing. There is objective evidence that both modalities may improve ischemia. Concerns include the invasive nature of SCS and the cutaneous side effects of TENS. Furthermore, a strong placebo component may be present. Currently, interest in neurostimulation is centered mainly in Europe.
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Enhanced external counterpulsation
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Enhanced external counterpulsation (EECP) uses timed, sequential inflation of pressure cuffs located around the legs to increase venous return, decrease left ventricular afterload and increase diastolic filling pressure. The end result is an increase in coronary perfusion pressure and, theoretically, less angina. Using a mechanism similar to the intra-aortic balloon pump (i.e., counterpulsation), the cuffs in EECP inflate, as shown on the ECG during diastole, sequentially from the calves to the upper thighs, resulting in augmented diastolic aortic pressure. Venous return is also increased during cuff inflation. The cuffs then deflate at the beginning of systole, thereby reducing diastolic aortic pressures and lowering myocardial afterload.
The exact mechanism by which EECP may improve anginal symptoms is controversial. Besides the effects of diastolic augmentation and increased coronary perfusion pressure, as described previously, animal models have suggested an increase in the collateral circulation with counterpulsation. Basic science reports have suggested that an increase in sheer stress in the coronary circulation activates multiple pathways, leading to possible angiogenesis or opening of previously dormant vessels or both (23).
In 1999, Arora et al. (24) published the results of the MUlticenter STudy of Enhanced External Counter Pulsation (MUST-EECP) trial, the first randomized, placebo-controlled, multicenter trial evaluating the efficacy of EECP in patients with refractory angina. This trial enrolled 139 outpatients with end-stage CAD and persistent symptoms. The patients were randomized to either the active EECP group (300 mm Hg cuff inflation) or the inactive sham EECP group (75 mm Hg cuff inflation). All patients received a total of 35 one-hour sessions over four to seven weeks. Pre- and post-measurements on average exercise duration, time to 1-mm ST-segment depression, daily average number of anginal attacks and nitroglycerin use were recorded. Figure 1 outlines the study protocol and results.
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Figure 1 Trial design and results of MUST-EECP. Source: Arora et al. (24), with permission. CAD = coronary artery disease; CCSC = Canadian Cardiovascular Society class; ETT = exercise treadmill test.
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After treatment, the EECP group showed a significant increase in the time to 1-mm ST-segment depression and a decrease in anginal episodes. There was a trend toward decreased nitroglycerin use in the active EECP group. Exercise duration increased in both groups, but the intergroup difference was not significant. Adverse effects included abrasions on the skin, lower leg and back. It should be noted that many patients were excluded from this study, including those with a recent myocardial infarction, recent CABG, recent cardiac catheterization, unstable angina, overt congestive heart failure or left ventricular ejection fraction <30%, significant valvular disease, significant pulmonary vascular disease, severe hypertension, arrhythmias interfering with ECG triggering and bleeding diathesis.
A more recent study by Urano et al. (25) supports the findings seen in the MUST-EECP trial. Twelve patients with stable angina pectoris, similar to those enrolled in the MUST-EECP trial, were given a total of 35 h of treatment with EECP. Compared with baseline, post-EECP exercise variables were all significantly improved, including exercise duration, time to 1-mm ST-segment depression and rate–pressure product at peak exercise. Reversible perfusion defects on thallium imaging decreased from 35% to 21%. Furthermore, hemodynamic measurements also significantly improved (diastolic filling, left ventricular end-diastolic pressure, left ventricular peak filling rate, end-diastolic volume per second and time to peak filling rate). A decrease in plasma brain natriuretic peptide levels after EECP treatment was noted.
Most recently, the International EECP Patient Registry showed an improvement of at least one angina class in 81% of the patients (n = 978) with CCS class III or IV refractory angina pectoris (26). Only 1.1% of the patients withdrew from the study, and quality-of-life measurements after EECP were significantly improved. The major limitation of this study is the lack of a control group.
At this time, EECP is not applicable for all patients with refractory angina pectoris. Many patients are ineligible for therapy, including those with severe pulmonary vascular disease and congestive heart failure. The sessions are time-consuming, awkward and uncomfortable. Although the exact mechanism by which angina may improve is still undefined, EECP represents a viable treatment option for certain patients with severe, uncontrollable ischemia.
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Laser revascularization
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Laser revascularization creates channels through heart muscle for the purpose of directly revascularizing ischemic myocardium. Techniques to accomplish this task have been advanced over the last century. Reptilian heart physiology provided the basis of modern laser revascularization. Reptiles do not have significant epicardial coronary circulation. Instead, 90% of the heart’s blood supply is delivered directly to heart muscle from the ventricle through a network of channels.
The development of laser revascularization dates back to 1933, when Wearn et al. (27) hypothesized the importance of epicardial conductance vessels and extracardiac and ventriculocoronary anastamoses (sinusoidal network) in myocardial perfusion. In 1954, Vineberg (28) reported successful tunneling of the left internal mammary artery into the myocardium (the Vineberg procedure), but this approach was not pursued because CABG began soon after. In 1986, Okada et al. (29) were the first to successfully create laser channels in the human myocardium.
In modern transmyocardial laser revascularization (TMLR), a left lateral thoracotomy is performed and 10 to 50 transmural channels are created using a high-energy carbon dioxide laser, which is triggered electrocardiographically. Intraoperative transesophageal echocardiography can confirm the presence of successful transmyocardial puncture by the appearance of bubbles or microcavities within the myocardium or left ventricular cavity. The epicardial channel opening usually closes spontaneously or after brief manual compression, and the entire procedure can be performed within 2 to 3 h. There is no need for cardiopulmonary bypass or cardioplegia.
Horvath et al. (30) published the results of TMLR as the sole therapy in patients with refractory angina in a nonrandomized, multicenter study. They reported significant improvements in anginal symptoms and myocardial perfusion on thallium imaging in >75% of these patients over 12-month follow-up. This study provided the impetus for four future randomized, prospective, controlled surgical trials assessing the safety and efficacy of TMLR in patients with refractory angina pectoris.
The first trial comparing TMLR in addition to conventional medical management versus medical management alone was conducted by Schofield et al. (31) in Europe. A total of 188 patients with CCS class III or IV (69% class III) angina were randomly assigned to either group. After 12 months of follow-up, there was no statistically significant difference in exercise capacity or 12-min walking distance. Although anginal class scores significantly decreased in the TMLR group, and there was a significantly decreased need for anti-anginal medications and few hospital admissions in the laser group, these were secondary end points. The perioperative mortality rate in the TMLR group was 5%. Overall survival at 12 months was not significantly different. The investigators concluded that no objective evidence from TMLR could be seen from this trial, and that TMLR could not be advocated as an effective alternative for patients with refractory angina.
In a second study, Frazier et al. (32) randomized 192 patients with mostly CCS class IV angina (69%) to receive either TMLR or continued medical therapy. After 12 months of follow-up, the TMLR group had a significant improvement in anginal class, quality-of-life scores and single-photon emission computed tomographic (SPECT) thallium imaging. Finally, only 2% of the patients treated with TMLR were hospitalized with unstable angina over the following 12 months, as compared with a 69% hospitalization rate seen in the medically managed group. There was no difference in overall survival. The perioperative mortality rate associated with TMLR was 3%. Of note, there was a 59% crossover rate from the medical therapy group to the TMLR group over the duration of the study. Frazier et al. (32) concluded that TMLR improved cardiac perfusion and clinical status over a 12-month period in patients with predominantly refractory CCS class IV angina.
Allen et al. (33) published a third, similar study comparing TMLR plus medical therapy versus medical therapy alone in patients with refractory angina pectoris. This trial enrolled 275 patients, all with CCS class IV refractory angina. After one year, the TMLR group had a significant improvement in anginal class scores, a higher rate of cardiac event-free survival, a decrease in cardiac-related hospital admissions and a higher rate of freedom from treatment failure. Quality-of-life scores and exercise tolerance were also statistically significantly improved. Interestingly, there were no differences in myocardial perfusion between the two groups, as assessed by thallium imaging. There was no significant difference in overall survival. Of note, 32% of the patients originally assigned to the medical therapy only arm crossed over into the TMLR arm over the course of the study.
Most recently, Burkhoff et al. (34) published the results of the Angina Treatments-Lasers And Normal Therapies In Comparison (ATLANTIC) study comparing TMLR plus medical therapy to medical therapy alone. A total of 182 patients with mostly (62%) CCS class IV refractory angina were followed for 12 months. The TMLR group demonstrated a significant increase in exercise tolerance, an improvement in anginal class scores and superior quality-of-life measurements. However, there was no difference in myocardial perfusion or ejection fraction between the groups, as measured by echocardiography and dipyridamole thallium scanning. There was no statistically significant difference in overall mortality.
In an editorial on TMLR, Lange and Hillis (35) remained cautious about the results of the TMLR trials. They emphasized the desperate nature of these patients with refractory angina and noted the lack of objective evidence of improvement (e.g., mortality benefit, ejection fraction, myocardial perfusion) in the TMLR trials. Furthermore, they noted the high crossover rates seen in Frazier and Allen’s studies, the lack of a placebo arm and the wide variation in improvements in anginal class scores from each different study.
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Percutaneous transmyocardial laser revascularization
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Transmyocardial laser revascularization is now being performed percutaneously, using a less invasive catheter-based approach. Results with this so-called "percutaneous transmyocardial laser revascularization (PTMLR)," while preliminary, are similar to those reported in the surgical TMLR data (36).
Oesterle et al. (37) recently published the results of the Potential Angina Class Improvement From Intramyocardial Channels (PACIFIC) trial, a multicenter, randomized study comparing PTMLR in addition to medical therapy versus medical therapy alone in 221 patients with both CCS class III or IV refractory angina. At 12 months, exercise tolerance significantly increased in the PTMLR group, as did anginal class scores and quality-of-life measurements. There was no significant difference in overall mortality. There was no measurement of myocardial perfusion in this trial.
A similar trial by Whitlow (38) compared PTMLR plus medical therapy to medical therapy alone in 330 patients with CCS class II, III or IV refractory angina. After 12 months, there was a significant improvement in anginal class scores, exercise tolerance and quality-of-life measures. There was no difference in one-year survival between the groups.
The results of the DMR In Regeneration of Endomyocardial Channels Trial (DIRECT), led by Leon (39), however, have tempered the initial enthusiasm surrounding myocardial laser therapy. This randomized, placebo-controlled, prospective trial enrolled 298 patients into three treatment arms: placebo PTMLR procedure, low-dose PTMLR (10 to 15 channels created) or high-dose PTMLR (20 to 25 channels created). The unique aspect of the trial was that none of the patients enrolled knew which arm of the study they were in. After six months of follow-up, the trial was stopped prematurely after all three groups noted a similar increase in exercise duration, exercise time to symptoms and exercise time to 1-mm ST-segment depression. Furthermore, there was a similar increase in the percentage of patients who reported at least a two-class improvement in anginal symptoms after six months and in all indexes reflecting quality of life. There were no differences in major adverse cardiac events after six months of follow-up.
In summary, TMLR is the only Food and Drug Administration-approved device used for the treatment of refractory angina pectoris. The mechanism of improvement in symptoms is unclear at present. It is debatable whether laser channels remain patent for any significant amount of time. Randomized clinical trials without a placebo control group have produced consistent improvements in anginal symptoms, exercise duration and quality-of-life perceptions. Improvement in myocardial perfusion has not been validated by this technique. More research is needed before TMLR and PTMLR can be considered scientifically sound, rather than just producing an improvement by a large placebo effect. Table 3 summarizes the trials performed to date using TMLR/PTMLR.
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Gene therapy
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Gene therapy has been proposed as a potential means of treating multiple clinical conditions, such as post-PCI restenosis, bypass graft restenosis and refractory angina pectoris. Over the past decade, substantial progress has been made in the field of cardiovascular gene therapy. Research in animal models has already shown promising results on the feasibility of gene transfer technology as a viable treatment modality for severe CAD (40). Still, although proof of principle has been established in these preclinical animal models, the task of demonstrating convincing efficacy data in humans has been meticulous and slow.
Fundamentally, angiogenesis should be distinguished from arteriogenesis. The former is the process of formation of new vessels that lack tunica media, whereas the latter describes the phenomenon of new arteries appearing with fully developed tunica media. An example of arteriogenesis would be the formation of visible angiographic collateral channels in patients with severe CAD or peripheral vascular disease. An example of angiogenesis is the formation of capillaries along the border zone of a myocardial infarction.
Isner et al. (41) reported the first evidence of clinical efficacy of vascular angiogenesis in a patient in 1996. Improvement in blood supply to an ischemic limb after intra-arterial gene transfer of a plasmid encoding for vascular endothelial growth factor (VEGF) was documented. Using an angioplasty balloon coated with plasmid in the distal popliteal artery, the patient showed an increase in collateral vessels at the knee, mid-tibia and ankle after four weeks, as verified by angiography and Doppler flow studies. However, after five months, the patient’s leg was removed below the knee, as gangrene of the limb could not be reversed.
After this seminal report, Baumgartner et al. (42) reported a phase-1 trial employing plasmid-encoding VEGF delivered intramuscularly in patients with critical limb ischemia. Gene transfer was performed in 10 limbs of nine patients with nonhealing ischemic foot ulcers. After intramuscular gene delivery, circulating levels of VEGF were increased, and various clinical measurements, including the ankle-brachial index and magnetic resonance angiography, showed qualitative evidence of improved distal flow in eight limbs. Ulcers improved or healed in four of seven patients, and after 10 weeks, tissue samples in the injected regions showed evidence of proliferating endothelial cells.
Losordo et al. (43) published the first randomized, phase-1 clinical trial testing the safety of intramyocardial delivery of VEGF plasmid in humans with myocardial ischemia. Using a left anterior thoracotomy, the plasmid VEGF deoxyribonucleic acid (DNA) was directly injected into the myocardium at risk in five patients with symptomatic angina in whom conventional therapy had failed. Dobutamine SPECT showed evidence of reduced ischemia in all five patients after 30 and 60 days. Rentrop collateral flow was increased in all five patients after 60 days. No adverse events were reported in this small group of patients.
Although these preliminary, small-scale reports provided initial promise with regard to the efficacy of vascular gene therapy, questions on the use of plasmids have arisen. Plasmids (small, circular DNA pieces) represent a relatively inefficient means of delivering a gene protein. They are taken up inefficiently by most cells and are unprotected against cellular defense mechanisms. Hence, it has been presumed that proteins expressed by plasmids would be expressed only transiently. Still, the safety of these plasmids has been confirmed by numerous animal studies and preliminary human studies.
Recent studies have used an adenoviral vector for gene transport. Although the adenoviral vector is able to achieve a much higher titer of gene product in a cell line, the potential for vector-induced cytotoxicity remains. Gene expression using this system, however, is still transient, and a subsequent dose is not recommended because of potential immune responses.
Using the adenoviral vector, Rosengart et al. (44) reported the delivery of VEGF to 21 patients by direct myocardial injection into an area of reversible ischemia, either as an adjunct to conventional CABG or as the sole therapy through a mini-thoracotomy. After 30 days, all patients reported a subjective decrease in their anginal symptoms. Coronary angiography and stress sestamibi scanning of wall motion showed improvement in the majority of patients. In patients given only gene transfer with revascularization, treadmill exercise assessment showed improvement in half of the patients, although there was no improvement in those patients who received CABG in addition to gene transfer. There were no systemic or cardiac-related adverse events.
In animal studies, basic fibroblast growth factor (bFGF) has reportedly promoted angiogenesis, improved endothelial vasodilatory function and improved myocardial perfusion. Laham et al. (45) were the first to study the transfer of bFGF in humans as a stimulus for angiogenesis in those with severe CAD. This randomized, double-blinded, placebo-controlled, phase-1 trial compared high- and low-dose bFGF administration, delivered through sustained-release microcapsules in ischemic, viable, but ungraftable myocardium, versus placebo, in patients undergoing CABG. After three months of follow-up on 24 patients, stress nuclear imaging showed no improvement in the placebo and low-dose group, although the high-dose group showed significant improvement in the ischemic territory. Magnetic resonance imaging also showed a strong trend toward a reduction in the target ischemic area in the high-dose group. There were two operative deaths reported, in addition to three Q-wave myocardial infarctions perioperatively.
Udelson et al. (46) studied 59 patients with refractory angina pectoris after administration of both intracoronary (n = 45) or intravenous (n = 14) recombinant fibroblast growth factor (rFGF). After 180 days, improvements in both stress and rest myocardial perfusion abnormalities using SPECT perfusion imaging were noted. This phase-1 trial, however, was not placebo-controlled and showed no improvement in the left ventricular ejection fraction.
Vale et al. (47) used left ventricular electromechanical mapping (EMM) as a means of assessing efficacy in 13 patients with chronic refractory angina who had been given plasmid DNA encoding for VEGF directly into the myocardium through a mini-thoracotomy. Electromechanical mapping uses electromagnetic field sensors to integrate real-time information from intracardiac electrograms acquired at multiple endocardial locations. By detecting electrical activity in areas of poor local shortening, viable myocardium can be located. After 60 days, EEM showed a decrease in the area of ischemic myocardium, which was confirmed by SPECT perfusion imaging. All patients reported a significant decrease in their anginal symptoms and nitroglycerin use, and their exercise capacity had significantly increased after 180 days. No control group, however, was present, and no change in ejection fraction was noted.
Questions concerning a possible placebo effect in these previous studies provided the impetus for the Adenovirus GENe Therapy (AGENT) trial (48). This is the first randomized, double-blinded, placebo-controlled trial of gene therapy. This trial enrolled 79 patients with documented CAD by angiography, objective evidence of ischemia during a 3-min exercise treadmill test and baseline CCS class II or III angina. Sixty patients received direct injection of recombinant adenovirus 5 FGF-4 and 19 patients received placebo. Follow-up treadmill tests were performed at 4 and 12 weeks, and the active treatment group had a greater improvement in exercise duration and a >30% increase in exercise tolerance time, as compared with the placebo group. It should be noted that the placebo group showed marked improvement from baseline, demonstrating the importance of double-blinded, placebo-controlled trials in this population.
Currently, gene therapy represents an exciting avenue of research in the treatment of ischemic vascular disease. However, because there is a lack of randomized, placebo-controlled trials, the true efficacy of gene therapy cannot be definitively evaluated. It is still not known whether the improvements in myocardial perfusion can be attributed to angiogenesis. There remains a theoretic risk of worsening the atherosclerotic process in native vessels. Hopefully, the proper vector, yielding high efficiency without toxicity, will be identified in future trials, in addition to the ideal mode of delivery (intravenous vs. intracoronary; percutaneous vs. surgical). Table 4 summarizes the current trials performed in vascular gene therapy to date.
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Percutaneous in situ coronary venous arterialization
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Percutaneous in situ coronary venous arterialization (PICVA) is a percutaneous approach to CABG that redirects arterial blood flow from the occluded, offending artery into an adjacent coronary vein, thereby arterializing the vein and providing retroperfusion to ischemic myocardium. Even in the most severe cases of CAD, the venous system is generally free of atherosclerosis, and the individual veins are dispensable, owing to a redundant venous system. Anecdotal reports documenting relief from angina using coronary retroperfusion from the 1940s to the 1970s inspired the modern-day revival of this technique (49).
Oesterle et al. (50) reported the first successful case of PICVA in a 53-year-old diabetic German man diagnosed with CCS class IV angina refractory to medical therapy and not a good candidate for CABG or PCI. The patient had a chronic total occlusion of his mid-left anterior descending coronary artery (LAD), with diffuse, distal LAD disease. Figure 2 outlines the technical aspects of this procedure. The procedure requires that the occluded artery and corresponding great vein be imaged. A needle is advanced proximal to the occlusion in the artery and into the adjacent vein under ultrasound guidance. A connector is then placed in between the structures, and a plug is placed proximal to the coronary sinus so that venous retroperfusion may occur.
This patient has been free of anginal symptoms for over one year, and the follow-up angiogram at three months showed complete patency of the arterialized anterior interventricular vein. A three-month stress sestamibi scan showed increased perfusion in the previously ischemic area, and stress testing showed no exercise-induced chest pain at previously ischemic levels.
Percutaneous in situ coronary artery bypass (PICAB) is also an advancing technology for this group of patients with refractory angina in whom arterial blood flow is redirected from a diseased artery to an adjacent coronary vein, and then rerouted back to the artery after the lesion (51). Thus, the coronary vein acts as an in situ coronary bypass conduit rather than as a means of retroperfusion. This technology requires that two arteriovenous fistulae be created—one on either side of the artery blockage—and that the vein be blocked both distally and proximally.
Although the potential for PICVA and PICAB, as treatment for patients with poor anatomy for traditional revascularization procedures, is enormous, currently these technologies must be considered experimental. A larger clinical trial proving its safety and feasibility must be completed before these newer forms of revascularization can become a practical option for patients with refractory angina.
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Chelation therapy
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Chelation therapy is the least scientifically grounded option for patients with refractory angina pectoris. It was first proposed as a potential treatment for atherosclerosis in the 1950s, after it was noted that patients treated for lead poisoning felt relief of their anginal symptoms after undergoing ethylenediamine-tetraacetic acid (EDTA) therapy. Since then, various small, uncontrolled studies have been published, with conflicting results.
The hypothesis for atherosclerosis regression involves the ability of EDTA to extract calcium from the atherosclerotic plaque. This hypothesis has never been scientifically validated and, in fact, is no longer applicable to the present understanding of the atherosclerotic process. Still, as the debate over the efficacy of chelation therapy continues, numerous alternative medicine clinics have sprung up in Europe and the U.S., promoting its efficacy.
Ernst (52) systematically reviewed the evidence from randomized, placebo-controlled, double-blinded trials evaluating chelation therapy (intravenous EDTA with vitamin and trace mineral supplementation) for the treatment of peripheral arterial occlusive disease. After reviewing four studies involving over 220 patients, he concluded that chelation therapy was not superior to placebo. There was no significant improvement in walking distance, nor any difference in objective measures, such as angiographic regression or ankle-arm index in both the short- and long-term studies. Furthermore, Ernst advocated that chelation therapy be considered "obsolete," considering the potential for serious side effects, including potentially lethal hypocalcemia and severe kidney dysfunction.
Most recently, the Program to assess Alternative Treatment strategies to achieve Cardiac Health (PATCH) trial released its results, showing the ineffectiveness of chelation therapy (53). Eighty-four patients with stable angina were randomized to receive either EDTA treatment or placebo. After six months, there was no difference in exercise tolerance, as both groups showed similar improvement. There were no deaths or heart attacks and no difference in hospital re-admission rates. This trial also demonstrated the power of a placebo effect in certain populations.
Currently, there is no convincing evidence that chelation therapy has any benefits. It has potentially lethal side effects and should not be considered a viable alternative therapeutic option for patients with refractory angina pectoris. The American Heart Association has published an official recommendation concerning chelation therapy in patients with CAD after a review of the published data, and it concluded that there was no scientific evidence to demonstrate any benefit from this form of therapy (54). The American College of Cardiology, Food and Drug Administration and National Institutes of Health have all concurred with this statement.
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Heart transplantation
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For patients who have disabling angina and in whom all conventional and alternative treatment modalities have failed, heart transplantation should be considered. Heart transplants are severely limited in number, with only  3,000 transplantations being performed worldwide. One-year survival is 80%, with an average 10-year survival rate of 40% (55). This must be discussed with each patient, as some patients may be expected to live longer with their current symptoms, as compared with their survival expectancy after receiving a transplant.
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Conclusions
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End-stage angina pectoris refractory to conventional medical therapy and not amenable to either CABG or PCI represents a truly desperate and frustrating condition for both the patient and physician. This ever-growing population of patients requires a thorough re-evaluation of conventional therapeutic options. These patients must be placed on the maximal tolerable doses of current anti-anginal medications. Furthermore, it is imperative to confirm that the patient’s coronary anatomy is truly not amenable to revascularization. A number of interventional cardiologists and cardiac surgeons may need to assess the patient before he or she is labeled as having "refractory angina pectoris."
For those patients with no other options, new emerging therapies for refractory angina provide hope. Additional antiplatelet/antithrombotic therapy may improve anginal symptoms and improve exercise capacity. Innovative revascularization techniques, such as PICVA and PICAB, are currently being investigated. Neurostimulation and EECP may benefit select groups of patients. Angiogenic gene therapy is a promising field that has yet to show convincing efficacy in humans. Laser revascularization is currently the most thoroughly studied modality and has been shown to significantly decrease anginal symptoms in most studies. However, given the lack of placebo-controlled groups in the majority of all studies in this population, the placebo effect cannot be ruled out as an important component of improvement for all of the options just mentioned. Heart transplantation is available as a final option. Ultimately, both the physician and patient must determine which alternative treatment may work best for them.
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[PDF]
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M. Shechter, S. Matetzky, M. S. Feinberg, P. Chouraqui, Z. Rotstein, and H. Hod
External counterpulsation therapy improves endothelial function in patients with refractory angina pectoris
J. Am. Coll. Cardiol.,
December 17, 2003;
42(12):
2090 - 2095.
[Abstract]
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R M Sinvhal, R M Gowda, and I A Khan
Enhanced external counterpulsation for refractory angina pectoris
Heart,
August 1, 2003;
89(8):
830 - 833.
[Abstract]
[Full Text]
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P. O. Bonetti, D. R. Holmes Jr, A. Lerman, and G. W. Barsness
Enhanced external counterpulsation for ischemic heart disease: What's behind the curtain?
J. Am. Coll. Cardiol.,
June 4, 2003;
41(11):
1918 - 1925.
[Abstract]
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L. O'Toole and E. D Grech
Chronic stable angina: treatment options
BMJ,
May 29, 2003;
326(7400):
1185 - 1188.
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P. O. Bonetti, G. W. Barsness, P. C. Keelan, T. I. Schnell, G. M. Pumper, J. T. Kuvin, R. P. Schnall, D. R. Holmes Jr, S. T. Higano, and A. Lerman
Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease
J. Am. Coll. Cardiol.,
May 21, 2003;
41(10):
1761 - 1768.
[Abstract]
[Full Text]
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M. J. L. DeJongste, R. W. M. Hautvast, and R. A. Tio
Therapeutic options for patients with chronic refractory angina pectoris
J. Am. Coll. Cardiol.,
October 16, 2002;
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M. C. Kim, A. S. Kini, and S. K. Sharma
Therapeutic options for patients with chronic refractory angina pectoris: Reply
J. Am. Coll. Cardiol.,
October 16, 2002;
40(8):
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Top
Abstract
Defining patients with...