The number of patients with disabling angina who are not amenable to revascularization is growing progressively. A majority of these patients have undergone at least one coronary artery bypass procedure and percutaneous coronary interventions and are not suitable candidates for a further percutaneous coronary intervention or repeat coronary bypass surgery. Others have diffuse coronary artery disease or are at very high risk for a revascularization procedure because of comorbid conditions.
A patient with disabling angina not amenable to revascularization is one who remains symptomatic despite optimal medical treatment with beta blockers, calcium channel blockers, and regimens and formulations of long-acting nitrates that do not produce tolerance. The following must be recognized, that in some patients: (1) triple therapy with beta blockers, calcium channel blockers, and nitrates may not be superior to treatment with two agents , and (2) adjustment of doses of a class of drug or changing to a different drug in the same class or withdrawal of a medication may help relieve anginal symptoms.
It is also assumed that comorbid conditions such as anemia, thyrotoxicosis, arrhythmias, and other comorbid conditions that may aggravate angina and myocardial ischemia are absent or, if present, are adequately treated before disabling angina is diagnosed.
In addition to receiving antianginal drugs, all patients with disabling angina must abstain from smoking and should be treated with daily aspirin, lipid-lowering agents (especially statins), , and angiotensin-converting enzyme (ACE) inhibitors. , These drugs are known to reduce serious adverse clinical outcomes in patients with coronary artery disease. Whether these agents decrease angina frequency or improve exercise tolerance in patients with disabling angina has not been adequately studied.
Patients with disabling angina experience angina with minimal activity or at rest. Many of these patients are hospitalized with unstable angina (UA) on multiple occasions, and at times it becomes difficult to evaluate if the pain is of ischemic, extracardiac, or mixed origin. In these circumstances, a perfusion scan obtained during an episode of chest pain can help the diagnosis.
Several therapies have been used or are recommended in addition to standard antianginal drugs, aspirin, statins, and ACE inhibitors to relieve angina and reduce adverse clinical outcomes. A multidisciplinary approach providing psychological support, positive feedback, treatment of depression, pain management by behavioral therapy, and cardiac rehabilitation has been successfully used in some European centers. Trimetazidine, a metabolic modulator, has anti-ischemic effects and when added to standard antianginal medications may provide symptomatic relief in some patients. The usefulness of newer antianginal drugs such as ranolazine, nicorandil, and ivabradine to treat patients with refractory angina remains to be proven. Noninvasive procedures, such as enhanced external counterpulsation (EECP) and transcutaneous nerve stimulation (TENS), and invasive procedures, such as spinal cord stimulation (SCS) and to a lesser extent transmyocardial laser revascularization (TMLR), are gaining popularity. Percutaneous transmyocardial laser revascularization (PTMLR) is ineffective. Gene and cell therapy, and other newer therapeutic modalities remain experimental. The use of many of these treatment modalities in patients with disabling angina is not based on well-designed placebo- or sham-controlled trials. The published data and expert options to treat these patients are discussed in this chapter.
old and New Drugs Used to Treat Angina
Bepridil
Bepridil, a nonspecific calcium channel blocker, exerts potent antianginal and anti-ischemic effects. A study showed that in patients with stable angina, a combination of bepridil and propranolol was superior to propranolol alone. Bepridil was shown to be superior to diltiazem in another study. Overall, published data suggest that bepridil increases exercise duration and reduces angina frequency more than other calcium channel blockers in patients with stable angina. , Unfortunately, bepridil prolongs the QT interval and can cause torsades de pointes in 1% to 2% of treated patients. , This is a major concern in patients with hypokalemia and in the presence of drugs that also prolong the QT interval. There are no controlled trials with bepridil in patients with disabling angina who remain symptomatic despite maximal medical treatment and are not candidates for a revascularization procedure. However, personal experience in several such patients suggests that bepridil is effective when other calcium channel blockers are not. Bepridil in place of other calcium channel blockers should be tried only in patients who remain symptomatic despite optimal medical treatment with beta blockers, other calcium channel blockers, and nitrates and those who are not candidates for revascularization.
Trimetazidine
Trimetazidine, a metabolic modulator, has anti-ischemic effects and improves exercise tolerance in patients with angina. It does not have any significant effects on either heart rate or blood pressure and has been approved in many European and Asian countries for the treatment of angina. In experimental studies, it ameliorates myocardial ischemia by inhibition of oxidative phosphorylation and substrate utilization from free fatty acids to glucose. Improvement in exercise tolerance and reduction in angina frequency has been reported when trimetazidine was added to standard antianginal drugs in patients with stable angina. Many of these patients had previous bypass surgery or percutaneous coronary revascularization procedure. However, from the published data it is unclear if the patients studied truly had refractory angina. Nevertheless, a trial of trimetazidine can be justified in patients with refractory angina. However, before its routine use, adequately powered placebo-controlled studies need to be carried out in patients with refractory angina.
Ranolazine
Ranolazine has been recently approved for the treatment of angina in the United States and some European countries. The exact mechanism of its action is unknown; it does block late sodium channel current and prevents cytosolic calcium accumulation in myocardial cells during periods of myocardial ischemia. Either as monotherapy or when added to a beta blocker or a calcium channel blocker, or amlodipine with or without background treatment with a long-acting nitrate, it reduces angina frequency compared with a placebo. It does not lower either the heart rate or blood pressure. The medication does prolong QT interval but its clinical significance remains unknown. In a large outcome trial in patients with acute coronary syndrome, ranolazine did not lower mortality or myocardial infarction rates compared with placebo, but it was safe and despite the prolongation of QT interval, it reduced the incidence of ventricular and atrial arrhythmias. , There are no studies of ranolazine in patients with refractory angina. However, many physicians including myself have used it as add-on treatment in patients with refractory angina; many of these patients have reported a reduction in their angina frequency. A placebo-controlled study is needed to evaluate the true usefulness of this medication in this group of patients with refractory angina.
Nicorandil
Nicorandil is a nicotinamide ester and a potassium channel opener and is currently being utilized in many European countries and Japan instead of long-acting nitrates for the treatment of stable angina and UA. However, its antianginal effects have been questioned by some, , and its usefulness to treat patients with refractory angina remains to be proven.
Ivabradine
Ivabradine by inhibiting I f , an ion channel in the sinus node, lowers resting and exercise heart rate without exerting any other hemodynamic effects. It exerts significant anti-ischemic and antianginal effects compared with placebo and the effects are comparable to those exerted by atenolol. When added to atenolol, there was a further improvement in exercise duration and reduction in angina frequency in patients with stable angina. In a large outcome trial in patients with ischemic heart failure, ivabradine did not reduce mortality but in a subgroup of patients with baseline heart rate above 76 beats/min, the drug reduced adverse clinical outcomes. , Its role in patients with refractory angina remains to be studied.
Unfractionated and Low-Molecular-Weight Heparin, Antiplatelet Agents, and Thrombolytic Agents
In patients with acute coronary syndrome, subcutaneous low–molecular-weight heparin (LMWH) plus aspirin reduces composite adverse clinical outcomes (death, myocardial infarction (MI), and refractory angina) compared with aspirin plus intravenous unfractionated heparin (UFH) especially in medically treated patients. , In patients with stable angina, however, intravenous UFH did not increase treadmill exercise duration. Treatment with subcutaneous LMWH for several weeks increased exercise duration and exercise time to ischemia and reduced angina frequency in other studies. ,
No placebo-controlled, double-blind trials have studied long-term treatment with either UFH or LMWH in patients with disabling angina.
Published results of the CURE trial in patients with acute coronary syndrome (unstable angina or non-ST-segment elevation myocardial infarction [NSTEMI]) showed that treatment with clopidogrel plus aspirin for up to 11 months reduced the composite endpoint of death, MI, and stroke compared with placebo plus aspirin therapy. Prasugrel is a more potent antiplatelet agent compared with clopidogrel. In a large outcome trial in patients with acute coronary syndromes (ACS) who were treated with percutaneous coronary interventions (PCI), prasugrel plus aspirin reduced the composite endpoint of death, MI, and need for a repeat urgent revascularization compared with clopidogrel plus aspirin treatment in patients undergoing a percutaneous coronary intervention. However, there was an increase in serious bleeding rates in the prasugrel group. The drug has been recently approved for clinical use in Europe and the United States for the treatment of patients with ACS who require PCI for the culprit coronary lesion, but with a black box warning of possible increase in serious and even fatal bleeding including hemorrhagic stroke. No data suggest that antiplatelet agents, including aspirin, clopidogrel, and prasugrel reduce angina frequency or improve exercise performance in patients with disabling angina. At present, data do not support the routine prolonged use of UFH or LMWH or antiplatelet agents (other than aspirin) to manage disabling angina.
In open trials with intermittent but prolonged administration of urokinase, relief of angina in patients with refractory angina was reported. , However, these studies were not placebo-controlled and, given the risks of increased bleeding with urokinase and other thrombolytics, these agents cannot be recommended to manage disabling angina.
Other Medical Therapies of Unproven Value
Chelation Therapy
Chelation therapy with ethylenediaminetetraacetic acid (EDTA) has been used to treat patients with peripheral vascular disease and those with known coronary artery disease. However, placebo-controlled studies have failed to confirm that chelation therapy improves exercise performance in patients with intermittent claudication and those with stable angina pectoris. No good published data suggest that chelation therapy is beneficial in patients with disabling angina.
Enhanced External Counterpulsation
Enhanced external counterpulsation (EECP) mimics the principles of intra-aortic balloon pump counterpulsation in that EECP augments coronary blood flow in diastole and facilitates left-ventricular (LV) emptying in systole. The EECP device currently marketed for clinical use consists of three paired pneumatic cuffs that are applied to the lower extremities. The cuffs are sequentially inflated by applying 250 to 300 mm Hg of external pressure during diastole. This increases venous return to the heart, with a resultant increase in cardiac output. An increase in aortic distention and pressure increases coronary blood flow in diastole. The cuffs are deflated simultaneously in systole, reducing peripheral resistance to flow and thus providing LV unloading and easier emptying in systole.
The EECP device has been in use for several years, but previous devices were cumbersome and difficult to use. The newer device is operator-friendly and patient-friendly and has been approved by the Device Committee of the U.S. Food and Drug Administration (FDA) for clinical use. The approval has led to a wider use of the device in patients whose cases are considered refractory to conventional therapy and are poor candidates for revascularization procedures. Whether such a practice is justified is open to question because of the lack of adequately designed studies in this group of patients.
Mechanism of Action of Enhanced External Counterpulsation
The exact mechanism by which EECP improves and maintains improvement in patients with stable angina remains unclear, although various mechanisms—including an increase in collateral blood flow to the ischemic areas, improvement in diastolic filling, and neovascularization (angiogenesis) in the ischemic areas—have been proposed but not proven ( Box 30-1 ).
BOX 30-1 Possible Mechanisms of Action
- •
Acute hemodynamic improvement mimicking the effects of intra-aortic balloon counterpulsation; increased coronary flow in diastole and improved systolic left-ventricular emptying and increased cardiac output (however, one would expect that the effects should last only during the treatment period of one hour each day)
- •
Increased collateral blood flow (unproven)
- •
Increased angiogenesis (unproven)
- •
Increased endothelial cell production of nitric oxide and prostacyclin (unproven)
Clinical Studies with Enhanced External Counterpulsation
Treatment requires 1-hour sessions, five times a week, for a total of 35 sessions ; and although EECP is noninvasive, it is expensive. Earlier studies with EECP, which were uncontrolled and used small numbers of patients, showed an improvement in stress perfusion imaging associated with an increase in treadmill exercise duration compared with baseline and an improvement in exercise hemodynamics compared with pretreatment ( Table 30-1 ). In a single-center, open study of 50 patients, stress perfusion imaging improved after treatment in 75% of patients. In one of the studies, the lowest response rate was noted in patients with the most extensive disease and the fewest proximally patent conduits, including both native coronary arteries and bypass grafts. , These uncontrolled studies also reported that patients treated with EECP continued to show an improvement in myocardial perfusion and angina frequency for up to 5 years.
| Study Design * | Outcome |
|---|---|
| Open-label studies with baseline as control | Increase in exercise duration |
| Improvement in stress thallium perfusion imaging | |
| Reduction in angina Canadian Cardiovascular Class (CCC) functional class by 1 or 2 grades | |
| Lower response rate in patients with extensive disease and with poor conduits | |
| MUST-EECP sham-controlled trial in stable angina | No improvement in exercise duration |
| Increase in exercise time to electrocardiographic myocardial ischemia (ST-segment depression) | |
| Reduction in angina frequency but not nitroglycerin consumption | |
| Registry data with baseline as control in patients presumably refractory to conventional treatment , | Improvement in CCS functional class by 1 or 2 grades |
| Local complication rate of 4% | |
| Safe in patients with heart failure |
* Double-blind, sham-controlled studies in patients with disabling angina who are not candidates for a revascularization procedure have not been performed.
The only controlled study to evaluate EECP was the MUlticenter STudy of Enhanced External CounterPulsation (MUST-EECP). Effects of active EECP treatment on exercise-induced electrocardiographic myocardial ischemia, total exercise duration, and anginal episodes were compared with sham EECP. Only patients with stable exertional angina with Canadian Cardiovascular Society (CCS) classes I to III were considered for the study. Patients were excluded for the following reasons: UA, a recent acute coronary syndrome, an MI or bypass surgery within the previous 3 months, a history of heart failure, a left-ventricular ejection fraction (LVEF) less than 30%, hypertension with blood pressure greater than 180/100 mm Hg, a history of phlebitis or severe peripheral vascular disease, warfarin therapy, atrial fibrillation, and frequent ventricular premature beats. A total of 500 patients were screened, of whom 139 were randomized. All had evidence of electrocardiographic myocardial ischemia (ST-segment depression) during treadmill exercise in addition to exercise-induced angina. The ages ranged from 21 to 81 years. Patients received either active EECP with inflation pressures of 300 mm Hg or sham EECP with an inflation pressure of 75 mm Hg.
Of the 139 patients randomized, exercise data were available in only 115 patients. There were more patients in the active treatment group ( n = 14) than the inactive treatment group ( n = 4) who did not complete the study. The results failed to confirm that EECP improved total treadmill exercise duration. Improvement in exercise duration was 42 plus or minus 11 seconds in the active EECP group and 26 plus or minus 12 seconds in the sham-EECP group ( P > .3). However, time to stress-induced myocardial ischemia (1-mm ST-segment depression) increased significantly in the active treatment group compared with the sham-treated group (37 ± 11 seconds vs. -4 ± 12 seconds; P = .01), and there was also a decrease in angina frequency and improvement in functional class but no change in the sublingual nitroglycerin consumption in the active treatment group compared with the sham-treated group.
One of the drawbacks of the study regarding the evaluation of angina frequency was that patients were not asked to keep an anginal diary or an account of daily activities throughout the study. They were asked to remember whether they had any anginal attacks in the 24 hours preceding each treatment session. More patients in the active EECP group experienced adverse events compared with the sham-treated EECP group (55% vs. 26%; P < .001). Device-related adverse experiences occurred in 33% of active EECP group members compared with 15% of sham-treated group members; paresthesias (2% vs. 1%), edema and swelling of legs (2% vs. 0%), skin abrasion, bruise, and blisters (13% vs. 2%), and pain in the back or legs (20% vs. 7%) were other findings in the active versus sham-EECP groups. The same investigators published a substudy in 71 patients on quality-of-life measures 12 months after treatment. They reported a significant health-related quality-of-life improvement for up to 12 months after the completion of treatment with EECP.
The EECP device was approved on the basis of this single trial in patients with stable angina. The approved indications included not only stable angina but also those with UA not responsive to conventional therapy. Subsequent to the approval of the device, registry data were prospectively collected.
The International EECP Patient Registry reported the safety and benefit of EECP treatment in 548 patients with a history of heart failure. At 6 months’ follow-up, the procedure was well tolerated compared with patients without heart failure. However, significantly fewer patients with heart failure completed the course of EECP, and exacerbation of heart failure was more frequent, although angina class improved in 68% of patients with comparable quality-of-life benefit in the heart failure cohort. At 6 months’ follow-up, patients with congestive heart failure maintained their reduction in angina frequency but were significantly more likely to have experienced major adverse cardiac events (death, MI, and revascularization).
In a 1996 report of 2289 consecutive patients enrolled in an EECP consortium, EECP was found to be safe and well tolerated with a 4.0% rate of adverse experiences. Angina class improved in 74% of patients with limiting angina (CCS functional class III to IV); patients who were most impaired at baseline demonstrated the greatest improvement, with 39.5% of patients in CCS classes III and IV improving two or more classes. It is of interest that patients with CCS functional classes I and II, as well as III and IV, were included in the registry and that the results in the two groups were compared.
The registry data were updated ( Fig. 30-1 ) and presented at the annual meeting of the American College of Cardiology in 2002 and showed marked improvement in functional class over time in the majority of patients. EECP’s beneficial effects on psychosocial functions have been reported.
International registry data confirmed the beneficial effects of EECP in 1458 patients with refractory angina. Reduction in angina frequency following EECP therapy was still present at 2 years following the completion of a course of EECP compared with baseline angina frequency in 112 (8%) patients who had CCS angina class II at baseline (6.7 ± 10.2 vs. 2.4 ± 4.2 angina attacks per week) and in 1346 (92%) of patients with CCS class III and IV (12.2 ± 13.8 vs. 4.1 ± 8.7 angina attacks per week). It is surprising that despite refractory angina at baseline by 2 years, nearly 20% of patients underwent either a bypass procedure or percutaneous coronary intervention.
In another study in 86 consecutive patients with refractory angina and CCS angina class III and IV, 79% of patients experienced initial improvement and at 24 months 29% showed sustained improvement.
It is unclear from the publications of the registry data whether all patients were on maximal medical treatment and whether they were candidates for revascularization. The reasons for treatment with EECP were diverse, including angina refractory to medical and surgical therapy, patient or physician preference, and poor candidates for surgery due to lack of graft material or targets or operative risk. During the study, only 0.2% of patients worsened by one CCS class. The majority of the patients limited by their angina (CCS functional class II to IV) either improved their angina class (1531, or 73.4% of patients) or remained unchanged in functional class after EECP (554, or 26.5% of patients). Angina class improved by two or more functional classes in 48.5% of pretreatment angina class IV patients and in 34.9% of pretreatment functional class III patients. It is unclear whether any of the patients included in the registry had an ACS at the time of the study. In previous studies, patients with unstable and acute coronary syndrome were excluded.
Review of the published data leaves one to doubt whether the EECP treatment can be routinely recommended in patients with disabling angina who are not candidates for revascularization. No specific data have been published in this group of patients, and no controlled trials have been conducted. The only sham-controlled trial reported was in patients with stable angina, and that study failed to show an objective improvement in exercise tolerance, although there was an increase in time to ischemic threshold and a reduction in anginal episodes. Registry data are observational, not sham-controlled. Given a high rate of placebo response in patients with angina pectoris, it remains speculative whether EECP is effective in patients with disabling angina whose conditions are refractory to maximal medical therapy and who are not candidates for revascularization.
Thus, EECP treatment cannot be routinely recommended in patients with disabling angina whose conditions are refractory to maximum medical therapy and who are not candidates for revascularization. If the patient is very symptomatic, such therapy may be tried with the caveat that complete relief of angina or a reduction in anginal attacks might be a placebo effect during and after EECP. Such an approach may be justified if there are no other alternatives. However, before we accept routine EECP to treat patients with disabling angina who are not candidates for revascularization, adequately powered, sham-controlled studies need to be conducted to evaluate the effects of treatment on angina attacks, exercise tolerance, and the incidence of death and MI.
Neuromodulation (Spinal Cord Stimulation and Other Neurologically Based Therapies)
Several procedures have been used, some of which have been abandoned because of high complication rates.
Acupuncture
Acupuncture has been used to treat intractable pain including refractory angina. Unfortunately, no sham-controlled studies have been published and the procedure is not widely used in the Western Hemisphere.
Thoracic Epidural Anesthesia
Anesthesiologists have used thoracic epidural anesthesia (TEDA) to control pain. Although successful, the procedure produces only temporary relief of pain and requires repeated administration of the local anesthetic; thus, this modality is not widely used.
Stellate Ganglion Block
Temporary left stellate ganglion block relieves angina. Permanent destruction of the left ganglion with relief of refractory angina has been documented in case reports. No controlled series have been published.
Transcutaneous Nerve Stimulation
For TENS, electrodes are applied to the chest, one in the dermatome with the highest intensity of projected or referred pain and the other in the contralateral dermatome. , The stimulus intensity is adjusted to just below the individual’s pain threshold. TENS leads to high-frequency stimulation of large non-nociceptive myelinated type A fibers and inhibits the impulse through smaller, unmyelinated type C fibers, thereby reducing the activation of central pain receptors. Studies from Scandinavia show that TENS improved exercise performance and reduced electrocardiographic myocardial ischemia during exercise or pacing and reduced lactate production during pacing-induced ischemia. Sympathetic discharge also was reduced. No sham-controlled trials have been reported, although in a presentation at the American College of Cardiology in 2002, the lead investigator suggested a possible placebo effect.
TENS units have been used successfully to treat refractory angina, and data suggest that this mode of therapy reduces myocardial ischemia and delays the onset of angina. However, the procedure is not widely used because of local skin complications of the device and the only support for using TENS to reduce angina frequency in patients with disabling angina has come from case reports.
Spinal Cord Stimulation
Spinal cord stimulation (SCS) is primarily used in the Scandinavian countries, with few cases being performed in Europe, the United States, and other parts of the world.
Procedure and Mechanism of Action
Low-voltage electric stimulation of the spinal cord inhibits the sensation of pain ( Box 30-2 ). The sensation of stimuli is perceived as paresthesia. The dural space is opened, and an electrode is placed at the level of the T4 and T5 vertebra; a lead is placed at the T1 and T2 level. During the procedure, the field of paresthesia produced is noted in the awake patient, and this should be in the area of referred pain. The stimulation device is connected to the lead and implanted under the skin in the abdomen or left lower thorax, and the patient is left with a small scar. The current applied varies from 2 to 7 volts, at rates of 30 to 90 Hz and a pulse width of 210 to 450 µJEK. The patient has a simple control mechanism and can turn the device on or off and can increase or decrease the amplitude of the current depending on the pain’s intensity. The mechanism by which pain is alleviated is either direct inhibition of sensory pathways carrying the pain stimuli or a reduction of myocardial ischemia.
BOX 30-2 Clinical Studies
Improvement in exercise duration and an increase in time to ST-segment depression and a reduction of total ischemic burden with SCS compared with controls has been well documented ( Table 30-2 ). Lactate production was also reduced during pacing-induced angina and SCS. Unfortunately, it is difficult to perform a placebo-controlled trial because the stimulation produces paresthesia. There has been a concern that abolition of pain with SCS may lead to myocardial ischemia not perceived by the patient and that a prolonged episode of silent ischemia might lead to MI. Studies under controlled pacing conditions show that the pain threshold is diminished but not abolished , and that higher pacing rates are required to produce angina. , Under conditions of exercise-induced increase in heart rate, the patient still perceives anginal pain despite SCS, though at a higher heart rate.
| Studies * | Results |
|---|---|
| Open trials | Marked reduction in angina frequency, improvement in exercise tolerance |
| Holter monitor data compared with baseline data | Reduction of ischemic episodes and angina frequency |
| SCS compared with coronary bypass surgery in patients with Canadian Cardiovascular Score (CCS) class III and IV angina | Similar reduction of angina frequency |
| Greater increase in maximum workload and reduction in exercise-induced ischemia with coronary bypass surgery | |
| Higher mortality in the coronary bypass group |
* Double-blind sham-controlled studies in patients with disabling angina who are not candidates for a revascularization procedure have not been performed.
Holter monitoring studies in 19 patients showed a marked reduction of ischemic episodes and relief of symptoms during SCS compared with pre-SCS baseline values. No ventricular ectopy was induced by SCS. Studies also have shown that SCS exerts antianginal effects and reduces myocardial oxygen demand. Myocardial ischemia is pacified but not abolished, and pain threshold is increased during SCS stimulation.
In a recent trial in patients with stable angina pectoris and CCS class III and IV angina, 104 patients were either randomized to coronary bypass surgery or to SCS treatment. Relief of symptoms was experienced by 80% of patients in the coronary bypass surgery group and 84% of patients in the SCS group. There was a marked reduction in angina frequency in both groups. There was a greater increase in maximum work performed in the surgical group than in the SCS group, and patients achieved a higher rate pressure product and had less ST-segment depression in the coronary artery bypass group. Mortality in the coronary bypass surgical group was high compared with the SCS group (seven patients vs. one patient), with similar rates of nonfatal myocardial infarction (seven patients vs. seven patients).
In a retrospective analysis of patients treated with SCS, 103 of the 517 patients had died by 23 months but had previously experienced a reduction in angina frequency. This was an observational study and not a controlled trial; therefore, results must be interpreted with caution.
In an open-label, single-center, randomized trial of spinal cord stimulation versus percutaneous myocardial revascularization (PTMR) in patients with refractory angina, there were no differences in main endpoint of exercise time or secondary endpoint of angina class between the two treatments. This raises a question regarding the reported efficacy of SCS for the treatment of refractory angina as PTMR has been shown to be no more effective than a sham procedure.
The following conclusions can be derived from the published data. The SCS procedure in experienced hands is safe and relieves angina. However, only a relatively small number of patients have been treated with SCS. There are no placebo-controlled trials, and it remains to be proven whether SCS is effective because of a marked placebo effect that has been documented in patients with angina. The reason for the infrequent use of SCS to treat refractory angina, according to a lead proponent of SCS, is that the procedure is performed by neurologists, whereas patients with disabling angina or no-option angina are treated by cardiologists, who do not receive any monetary gain for a procedure they do not perform themselves.
The reported safety of the procedure is reassuring, and SCS may be offered to patients with disabling angina despite maximal therapy who are not candidates for revascularization, even if the procedure were to produce a placebo-derived beneficial effect.
Sympathectomy
In patients with intractable angina, sympathectomy has been tried with success but the procedure is associated with significant morbidity and an increased mortality. For these reasons, the procedure has been essentially abandoned. ,
Transmyocardial Laser Revascularization
The concept of creating transmyocardial channels to increase myocardial blood flow and oxygen supply goes back to an observation in reptiles, in whom a network of channels in the myocardium communicates directly with the ventricular cavity. In humans, there are no communications between the ventricular cavity and the myocardium. The concept to increase myocardial blood flow via ventriculocoronary anastomosis (sinusoidal network) was proposed by Wearn and colleagues in 1933. Subsequently, successful channels were created by direct myocardial punctures in animals and with lasers in humans in 1986.
Two types of laser devices have been used to create intramyocardial channels, the CO 2 laser and holmium:YAG laser. It has been claimed that more channels remain patent after the CO 2 laser device than after use of the holmium:YAG laser procedure, and the lesions created by the two procedures are histologically different.
Through a lateral thoracotomy, under direct vision but without cardioplegia or cardiopulmonary bypass, 10 to 50 (average, 24) laser channels are created in the left ventricle. The epicardial openings either close spontaneously or with light direct compression.
Mechanism of Action
It has been proposed that transmyocardial channels remain open after TMLR and may lead to angiogenesis ( Box 30-3 ). Unfortunately, many of the channels close soon after the procedure and there are few objective data to support increased angiogenesis. , One autopsy study showed microinfarcts in the areas around the TMLR channels, with evidence of local fibrosis and cardiac denervation. The exact mechanism by which TMLR relieves angina remains speculative, although cardiac denervation remains a likely mechanism. ,
BOX 30-3 Clinical Studies
Transmyocardial laser revascularization (TMLR) has been performed only in patients who are not candidates for revascularization and have viable but ischemic myocardium. The procedure performed with CO 2 lasers and holmium:YAG lasers was approved by the Device Committee of the FDA for clinical use in nonoption patients (i.e., patients who are not candidates for revascularization or who are at very high risk because of comorbid conditions).
Initial open uncontrolled trials in patients with refractory angina reported significant improvement in anginal symptoms and myocardial perfusion on thallium imaging in more than 75% of patients over a 12-month follow-up period after TMLR compared with baseline observations ( Table 30-3 ). Uncontrolled open studies have confirmed these observations for up to 3 to 5 years of observations. However, these studies were observational and not randomized or sham-controlled. Improvement in myocardial perfusion reported in earlier studies is questionable because of lack of reproducibility during sequential studies.
| Trial * | Outcome |
|---|---|
| Open, uncontrolled reports | Improvement in anginal symptoms. |
| Improvement in myocardial perfusion in >75% of patients. | |
| CO 2 laser plus medical treatment vs. medical treatment | No difference in exercise capacity or 12-minute walk test. |
| Significant reduction in angina frequency. | |
| Periprocedural mortality (5%). | |
| No difference in mortality at 12 months. | |
| CO 2 laser plus medical treatment vs. medical treatment , | Improvement in Canadian Cardiovascular Score (CCS) angina class and quality-of-life score. |
| Improvement in thallium perfusion. | |
| Periprocedural mortality 3%. | |
| No difference in mortality at 12 months. | |
| High crossover rate in medical group. | |
| CO 2 laser plus medical treatment vs. medical treatment | Improvement in New York Heart Association (NYHA) angina class.Reduction in hospitalizations for unstable angina by 55% at 3-5 years follow-up. |
| Increased incidence of heart failure; no difference in mortality or incidence of myocardial infarction at 3-5 years. | |
| Holmium: YAG laser plus medical treatment | No difference in myocardial perfusion or ejection fraction or mortality at 12 months in treatment vs. medical treatment. |
| Significant increase in exercise duration and angina functional class. |
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