Half of eligible patients not getting mitral-valve surgery, single center reports

by Shelley Wood

Ann Arbor, MI - Overblown fears about surgical risks or a lack of awareness of the risks of not operating may partly explain a lack of surgery referrals for mitral-valve repair, authors of a new study say [1]. Writing in the August 25, 2009 issue of the Journal of the American College of Cardiology, Dr David S Bach (University of Michigan, Ann Arbor) and colleagues report that just half of all patients with mitral regurgitation assessed at their hospital over a one-year period actually ended up getting surgery, and of those not operated on, three-quarters had at least one indication for surgery, according to American College of Cardiology/American Heart Association guidelines.

"The most common reason that people were not operated on was that physicians thought the risk associated with surgery was relatively high or that the mitral regurgitation did not pose a risk to the patient. And I think the pertinent findings are that our assessment, as cardiologists, of operative risk, is probably inflated compared with what the objectively calculated risks were. And our assessment of risk for unoperated mitral regurgitation was probably underestimated," Bach told heartwire. "The take-home message for cardiologists is that we need to be more careful about our assessment of operative risk."

Bach et al's study retrospectively identified 300 patients with moderate to severe mitral regurgitation screened by echocardiography over a one-year period. They identified 188 with functional mitral regurgitation, of whom just 30 underwent surgery, and 112 with "organic" mitral regurgitation, of whom 59 (53%) underwent surgery. According to the authors, a review of patients' charts indicated that the most common reasons for not referring patients for surgery was the existence of "stable" left ventricular size or function, an absence of symptoms, or major comorbidities.

But when the Society of Thoracic Surgery risk score was applied to patients who both had or had not had surgery, Bach et al found that predicted risk of perioperative mortality was similar between the two groups. Moreover, when ACC/AHA guidelines for surgery were applied to patient records, Bach et al found that a full 74% of the 53 patients deemed "inoperable" actually had one or more indications for surgery, according to the guidelines.

Importantly, Bach told heartwire, almost all patients who were referred for surgery did end up getting mitral-valve interventions, suggesting that it was not an unwillingness on the part of the surgeons that explained the disconnect between patient indications and subsequent interventions.

"I think there remains something of a bias in medicine and cardiology that surgery is risk, and surgery is a failure of our ability to manage the patient. . . . [Mitral-valve] diseases are not as benign as they were once thought to be, and the surgery is not as morbid as it was thought of in the past."

Bach believes cardiologists need to become better acquainted with the literature, discuss options more fully with their patients, and where possible, involve a surgeon in the consult. "I don't want to say that the cardiologist, if presented with a patient who has indications for surgery would say, no, I'm not willing to send that patient to surgery. I think what it is is a lack of familiarity with the guidelines or some hesitation about the risk/benefits of surgery."

Source

1. Bach DS, Awais M, Gurm HS, et al. Failure of guideline adherence for intervention in patients with severe mitral regurgitation. J Am Coll Cardiol 2009; 54:860-865.

Technorati Tags: Valvular heart disease,mitral valve surgery,mitral regurgitation

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Significant improvements in short-term acute-MI mortality in US hospitals

by Michael O'Riordan

New Haven, CT - In the past decade, 30-day mortality rates for patients discharged with acute MI have significantly declined, as has the variation in AMI mortality in hospitals across the US, a new study has shown [1]. Overall, the 30-day mortality rates declined from 18.8% in 1995 to 15.8% in 2006, an approximate one-sixth reduction in short-term mortality over the 12-year study period, report investigators.

"A challenge was really set down about a decade ago, where we really needed to achieve a better system and wanted to shift the entire spectrum of performance toward better care," said lead investigator Dr Harlan Krumholz (Yale University School of Medicine, New Haven, CT). "That meant that we weren't really looking at the outliers but saying that the status quo is not acceptable. This paper is showing the realization of what we hoped to accomplish, which is a shift in the distribution of mortality, and the variation shrinking. We've improved performance and shrunk some of that variation between hospitals."

The results of the study are published in the August 19, 2009 issue of the Journal of the American Medical Association.

Plans made 10 years ago

Speaking with heartwire, Krumholz said that while there is some surveillance and patient-level data looking at AMI outcomes, there wasn't a systematic look at outcomes at the hospital level in the US. Also, during the early 1990s, much of the research was focused on outliers and "trying to figure out if there was a bad apple, someone that was practicing in a way that might be harmful or at odds with how everybody else was practicing," he said.

Now, however, much of the focus has been to improve the entire system by measuring and improving care at all hospitals, and not just those performing poorly, added Krumholz. This focus has included interventions and efforts toward improving quality of care as they relate to clinical guidelines and performance measures.

In this study, the researchers examined hospital-level 30-day risk-standardized mortality rates by obtaining data from the Centers for Medicare and Medicaid Services (CMS) analysis and review files. Between 1995 and 2006, there were more than three million hospital discharges of patients 65 years of age and older from acute-care hospitals in the US.

As noted, there was a reduction in hospital-specific 30-day all-cause mortality. According to the researchers, for every 33 patients admitted in 2006 for an AMI compared with 1995, there was additional patient alive at 30 days.

All-cause mortality from 1995 to 2006

Year	30-day risk standardized all-cause mortality rate (range)
1995	18.8 (10.4-27.5)
1996	18.2 (9.1-26.7)
1997	17.7 (9.0-26.5)
1998	17.8 (12.3-25.3)
1999	19.3 (14.4-25.4)
2000	18.8 (12.9-27.0)
2001	18.5 (13.1-26.1)
2002	17.9 (13.1-25.0)
2003	17.6 (12.1-24.1)
2004	17.0 (12.3-22.9)
2005	16.5 (11.0-24.8)
2006	15.8 (14.7-16.8)

The group also observed a reduction of between-hospital heterogeneity in mortality. Nationally, the largest absolute reduction in AMI mortality was observed in the South, specifically the West-South-Central region, while the Pacific region had the smallest improvements.

Krumholz told heartwire that hospitals that would have been considered "average" in 1995 would be considered poor performers in 2006 if they didn't improve over time.

"They would have been left behind," he said. "It really shows the importance of continual improvement and not being complacent with the status quo, especially if you're considered average, because if we're doing things right we're really pushing the curve toward getting better. The fact is that, even now, we still see this distribution where there is still room for improvement. If we can take the bottom 75% and push them toward the performance of the top 25%, then we can still save a lot more lives."

Krumholz noted that Dr Eugene Braunwald (Harvard Medical School, Boston, MA) identified in 1997 two eras of innovation that reduced mortality for patients with AMI, the first being the introduction of cardiac units and defibrillation in the 1960s, and the second being interventional and pharmacologic strategies. Since then, the increased focus on systems and ensuring that people are adhering to quality-improvement measures has also helped reduce the hospital-specific AMI mortality rates, he said.

Source

1. Krumholz HK, Wang Y, Chen J, et al. Reduction in acute myocardial infarction mortality in the United States. JAMA 2009; 302:767-773.

Technorati Tags: coronary heart disease,AMI,coronary artery diseases

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Prasugrel also reduces cardiovascular events in patients who receive GP IIb/IIIa inhibitors

by Michael O'Riordan

Boston, MA (updated) - An analysis of the TRITON-TIMI 38 trial has shown that prasugrel (Effient, Daiichi Sankyo/Eli Lilly) significantly reduces the risk of cardiovascular events even in the setting of potent platelet inhibition with a GP IIb/IIIa inhibitor [1]. Like the overall study, bleeding risks were higher with prasugrel, but the use of a GP IIb/IIIa inhibitor did not heighten the relative risk of bleeding when compared with clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb).

Lead investigator Dr Michelle O'Donoghue (Brigham and Women's Hospital, Boston, MA) said the new analysis answers an important question because until now it was unknown whether there was any role for a more potent blockade of the platelet P2Y₁₂ receptor, which prasugrel and clopidogrel both inhibit, in the setting of near-complete and rapid platelet inhibition with a GP IIb/IIIa inhibitor.

"The results of the current study suggest that more potent platelet inhibition with prasugrel compared with clopidogrel significantly reduces the risk of death, MI, or stroke at 30 days by 22% to 24%, regardless of whether a GP IIb/IIIa inhibitor is used," said O'Donoghue to heartwire. "Although prasugrel increased the risk of bleeding as compared with clopidogrel, the use of a GP IIb/IIIa inhibitor did not accentuate the risk of bleeding with prasugrel as compared with clopidogrel."

Glycoprotein IIb/IIIa inhibitor use not randomized

To heartwire, O'Donoghue said the current analysis was not designed to look at the question of whether there is any additional benefit for using GP IIb/IIIa inhibition in patients who are also treated with prasugrel. Since the use of glycoprotein IIb/IIIa inhibitors was left to the discretion of the treating physician and not randomized, it is not possible to directly compare outcomes for patients who did or did not receive the drugs in the TRITON-TIMI 38 population, she said. Patients treated with GP IIb/IIIa inhibitors might differ markedly from the other patients, for instance, and might have a poor angiographic result, a complicated PCI, or other baseline medical conditions that placed them at higher risk.

"For this reason, it may be misleading to compare MI or bleeding rates in patients who did or did not receive a GP IIb/IIIa inhibitor," according to O'Donoghue. "Patients treated with a GP IIb/IIIa inhibitor in TRITON-TIMI 38 had a higher incidence of [major adverse cardiac events] MACE; however, this finding is confounded by differences in other characteristics."

Full results of the TRITON-TIMI 38 study have been previously reported by heartwire. Briefly, investigators randomized 13 608 individuals with an acute coronary syndrome undergoing PCI to prasugrel or clopidogrel. Of these patients, 7414, or 54.5%, received a GP IIb/IIIa during their index hospitalization.

At 30 days, and similar to the overall findings, there was a significant benefit of prasugrel over clopidogrel in reducing the primary end point of cardiovascular death, MI, and stroke in patients who received GP IIb/IIIa inhibitors and those who did not. Like the main trial, the reduction was driven primarily by a reduction in the risk of MI. Investigators also report reductions in stent thrombosis and urgent target vessel revascularization in patients who received and those who did not receive GP IIb/IIIa inhibition.

Efficacy outcomes at 30 days stratified by use of GP IIb/IIIa inhibition

Outcome	Hazard ratio (95% CI)
Cardiovascular death, MI, stroke (GP IIb/IIIa)	0.76 (0.64-0.90)
Cardiovascular death, MI, stroke (no GP IIb/IIIa)	0.78 (0.63-0.97)
Cardiovascular death (GP IIb/IIIa)	0.88 (0.57-1.35)
Cardiovascular death (no GP IIb/IIIa)	0.69 (0.41-1.16)
MI (GP IIb/IIIa)	0.75 (0.62-0.90)
MI (no GP IIb/IIIa)	0.74 (0.59-0.93)
Periprocedural MI (GP IIb/IIIa)	0.83 (0.67-1.01)
Periprocedural MI (no GP IIb/IIIa)	0.89 (0.69-1.16)
Stent thrombosis (GP IIb/IIIa)	0.46 (0.29-0.71)
Stent thrombosis (no GP IIb/IIIa)	0.34 (0.17-0.65)
Urgent target vessel revascularization (GP IIb/IIIa)	0.56 (0.38-0.82)
Urgent target vessel revascularization (no GP IIb/IIIa)	0.47 (0.26-0.84)

In the overall study, prasugrel significantly increased the risk of bleeding at 30 days compared with clopidogrel. In this analysis, investigators report that patients treated with a GP IIb/IIIa inhibitor did have higher rates of bleeding than those who did not receive the drugs, but the excess risk with prasugrel was comparable in both patient groups.

Safety outcomes at 30 days stratified by use of GP IIb/IIIa inhibition

End point	Prasugrel (%)	Clopidogrel (%)	Hazard ratio (95% CI)	p for interaction
TIMI major or minor bleed (GP IIb/IIIa)	3.3	2.9	1.16 (0.89-1.50)	0.19
TIMI major or minor bleed (no GP IIb/IIIa)	1.7	1.1	1.63 (1.05-2.52)	—
TIMI major bleed (GP IIb/IIIa)	1.2	1.1	1.06 (0.69-1.64)	0.39
TIMI major bleed (no GP IIb/IIIa)	0.9	0.6	1.47 (0.81-2.66)	—

"The results of this study will be particularly relevant to cardiologists who may wish to use prasugrel in combination with a GP IIb/IIIa inhibitor following PCI," said O'Donoghue.

Speaking with heartwire, Dr Paul Gurbel (Johns Hopkins School of Medicine, Baltimore, MD), who was not involved in the TRITON study, said that patients receiving GP IIb/IIIa inhibition in this study were not randomized, and it is possible that there were clinical differences that accounted for the benefit of prasugrel over clopidogrel.

"It might be that demographically the patients are balanced, but angiographically they differed," added Gurbel. "What determines a lot of periprocedural infarctions and early event rates has to do with the anatomy you're dealing with in the cath lab."

Gurbel said that he agreed with the authors' conclusions that bleeding isn't accentuated with prasugrel on board with a GP IIb/IIIa inhibitor when compared with clopidogrel. Because the GP IIb/IIIa inhibitors are such potent antiplatelet agents, he said that he wouldn't expect bleeding to increase further with the addition of prasugrel, especially since events were assessed early, at 30 days. However, he said that it doesn't help him commit to prasugrel over clopidogrel, because patients will bleed more with the potent antiplatelet agent beyond 30 days.

Added benefit

To heartwire, O'Donoghue said the findings also provide some insight into platelet biology, especially since there appears to be added benefit of the more potent prasugrel in the setting of platelet-aggregation inhibition with a GP IIb/IIIa inhibitor. This may suggest that the P2Y₁₂ receptor has a variety of downstream effects that influence clinical outcomes and yet are independent from the IIb/IIIa receptor, she noted.

"These insights into platelet biology also lend proof of concept to the idea of targeting multiple platelet receptors," she continued. "It will be interesting to see the results of ongoing trials that are evaluating drugs that inhibit other platelet receptors. For instance, the TRA2P-TIMI 50 and TRACER trials are currently evaluating the additive benefit of blocking the platelet thrombin receptor on top of a background of aspirin and/or clopidogrel."

Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA), who was not part of the study, said the authors were cautious in their conclusions but, like Gurbel, was critical of the lack of randomization in the study. Kaul told heartwire that it is only possible to determine the added benefits of GP IIb/IIIa inhibition on top of a thienopyridine in a randomized trial. The ideal trial, he said, would be a 2x2 factorial design where patients were randomized to clopidogrel or prasugrel and then randomized to a GP IIb/IIIa inhibitor or no GP IIb/IIIa inhibitor.

Various studies, among them ISAR-REACT, ISAR-REACT 2, and BRAVE-3, all studied the use of GP IIb/IIIa inhibition against the backdrop of clopidogrel pretreatment, and only ISAR-REACT 2, which studied high-risk ACS patients, showed a benefit, noted Kaul.

The Food and Drug Administration approved prasugrel for use during PCI on July 10, 2009. The drug debuted on the shelves of US pharmacies August 5, 2009.

Source

1. O'Donoghue M, Antman EM, Braunwald E, et al. The efficacy and safety of prasugrel with and without a glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes undergoing percutaneous intervention. J Am Coll Cardiol 2009; 54:678-85.

Technorati Tags: prasugrel,Clopidogrel,coronary heart disease,anti platelet,Effient,plavix,acute coronary syndrome

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Do ACE inhibitors increase mortality in CABG patients?

by Shelley Wood

Bristol, UK - Authors of a large, observational study say preoperative use of ACE inhibitors may double the risk of dying after CABG surgery [1]. Dr Antonio Miceli (University of Bristol, UK) and colleagues say their findings support a strategy of stopping ACE inhibitors presurgery and then restarting them postoperatively. But not everyone agrees with the results of the new analysis: commenting on the study for heartwire, Dr Harold Lazar (Boston University School of Medicine, MA) argued that there are some patients in whom ACE inhibitors should not be stopped, particularly patients with hypertension and/or diabetes, who have had a recent MI.

The study will be published in an upcoming issue of the Journal of the American College of Cardiology and was published online August 13, 2009.

Miceli et al's research adds a generous dollop of data to an already confusing mélange of studies supporting or rejecting a role for ACE inhibitors in CABG patients. As Miceli et al explain, ACE inhibitors lower blood pressure and have antiatherosclerotic, antithrombotic, and anti-inflammatory effects—all of which paved the way for recommendations to use them in patients with coronary artery disease. But their effect when used preoperatively in CABG patients "is still controversial," they note.

To gauge these effects, Miceli and colleagues reviewed data on preoperative ACE-inhibitor use among more than 10 000 patients who had CABG surgery between April 1996 and May 2008 at the Bristol Heart Institute, UK. In all, 3052 were taking ACE inhibitors prior to their surgery and were matched with a control group using propensity scores.

Miceli et al report that the mortality rate in the ACE-inhibitor group was nearly double that of patients not taking ACE inhibitors: 1.3% vs 0.7%. As well, new-onset atrial fibrillation, renal dysfunction, and use of inotropic support were all higher among patients taking ACE inhibitors preoperatively. Use of ACE inhibitors remained an independent predictor of mortality after multivariate analysis.

Postoperative outcomes

Outcome	ACE inhibitors (%)	Control (%)	Odds ratio (95% CI)	p
Mortality	1.3	0.7	2.0 (1.17-3.42)	0.013
Atrial fibrillation	25	20	1.34 (1.18-1.51)	<0.0001
Renal dysfunction	7.1	5.4	1.36 (1.1-1.67)	0.006
Use of inotropic support	45.9	41.1	1.22 (1.1-1.36)	<0.0001

The authors note that their findings on the link between preoperative ACE-inhibitor use and need for inotropic support largely reflect earlier studies, while the findings regarding kidney disease, atrial fibrillation, and mortality are at odds with at least some of the published literature. The different findings are partially explained by the fact that the current study includes a larger sample size than most of the prior studies and was restricted to patients undergoing CABG, the authors write.

Asked to review the paper for heartwire, Lazar took issue what he identified as a number of limitations of the study (many of which were also acknowledged by Miceli et al in their paper). Lazar pointed to the shortcomings of a propensity analysis, when a randomized clinical trial is the only way to properly address the safety of ACE inhibitors in the setting of CABG. He also questioned the 12-year duration of the study, noting that the kinds of patients being treated for CABG changed substantially over the study period. He also pointed to "missing information" in the paper, such as that regarding dose, type, and duration of ACE-inhibitor therapy; indications for, dose, type, and duration of inotropic support; details on atrial fibrillation and its management in the study cohort; and a breakdown of the cause of death reported in the study. "Were these cardiac deaths, or were they other things that ACE inhibitors have no effect on?" Lazar asked.

Overall, Lazar concluded, "the results are very soft. . . . The use of ACE inhibitors in this study was associated with a higher incidence of death; however, although this may be true statistically, clinically I don't think we're talking about a real, significant end point."

Even the mortality difference between the two groups—a difference of 0.6%—"that's really splitting hairs," he said.

"In my own practice, for an elective operation, we will ask the patient to stop the ACE inhibitor 48 hours before the surgery, and if it's an in-house patient and we can stop it safely, again we'll stop ACE inhibitors 48 hours beforehand. However, in those patients who have had a recent MI with hypertension and those who are diabetic, we will keep the ACE inhibitor going right up to the time of surgery. We will also lower the dose sometimes as well. We feel that gives us the protection of the ACE inhibitor but minimizes the vasodilatation associated with the drug."

But the authors stand by their findings, insisting the best strategy is to stop the ACE inhibitors two days prior to surgery and restart them after the patient is stable again postsurgery. Speaking with heartwire, senior author on the study, Dr Massimo Caputo (University of Bristol), agreed that survival after CABG is higher now than ever before, "so the fact that we found a statistically significant difference in mortality is quite astonishing," he said. But he agrees, in terms of clinical impact, that the adverse effects of ACE inhibitors are even more important for atrial fibrillation and renal dysfunction, "where there is a much clearer difference between the groups."

"Our goal was not to say that ACE inhibitors are bad or should not be used. We're just saying that in the perioperative period, you should stop ACE inhibitors two to five days before and restart them probably two days postoperatively, to reduce the risk of the complications we saw."

And while a large, prospective, randomized trial would be ideal, Caputo said his study fills an important gap and "used the best possible data, to determine the best possible therapy for our patients."

Source

1. Miceli A, Capoun R, Fino C, et al. Effects of angiotensin-converting enzyme inhibitor therapy on clinical outcome in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol 2009; DOIi:10.1016/j.jacc.2009.07.008. Available at: http://content.onlinejacc.org.

Technorati Tags: ACE inhibitors,CABG,hypertension,CAD

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Cardiac MRI shows promise in European study

by Marlene Busko

Essen, Germany - A pilot study in 20 German centers suggests that cardiac magnetic resonance (CMR) imaging is safe, used frequently in clinical practice, provides high-quality images, and strongly affects patient care [1].

The main indications for CMR imaging were for patients with hypertrophic cardiomyopathy, CHF, and CAD.

Importantly, in 16% of cases, CMR imaging led to a new, unsuspected final diagnosis, and in 45% of cases, patient treatment was altered as a result of CMR findings.

"Having a constantly growing number of sites clearly demonstrates that CMR has already made its way into clinical routine," lead author Dr Oliver Bruder (Elisabeth Hospital, Essen, Germany) told heartwire. "However, more widespread use in some countries is still limited by the availability of CMR scanners, trained personnel, and low reimbursement rates."

The study is published online August 12, 2009 in the Journal of the American College of Cardiology.

Three main clinical indications

In the past five years CMR has been increasingly used in clinical practice in European countries such as Germany, Spain, the United Kingdom, and Portugal, coauthor Dr Anja Wagner (Drexel University College of Medicine, Philadelphia, PA) told heartwire. However, little information existed about the impact of this procedure on clinical practice.

To evaluate the indications, image quality, safety, and impact on patient management from using CMR imaging, the researchers analyzed data from the European Cardiovascular Magnetic Resonance (EuroCMR) registry for 11 040 consecutive patients who underwent CMR imaging in 20 centers in Germany.

Two-thirds of the patients had prior echocardiography, but CMR imaging was the first imaging procedure for 23% of the patients.

Severe complications requiring an overnight stay in hospital occurred in only five patients and were related to stress testing. No patients died during or due to the procedure. Mild complications occurred in 1.1% of patients.

Most patients (86%) did not require further imaging tests after CMR imaging.

The top three indications of CMR were workup of myocarditis/cardiomyopathies (32% of patients), risk stratification in CAD (31%), and myocardial viability imaging (15%).

"The presence and pattern of late gadolinium enhancement of the left ventricular myocardium is particularly helpful to differentiate the etiology of reduced left ventricular function in patients with new onset of heart failure," Bruder said.

Risk stratification in patients with suspected CAD is another important application, he added, noting that "single-center data, such as studies from the Eike Nagel group [2], have clearly demonstrated that patients with a normal stress CMR have an excellent prognosis."

These findings from multiple centers with imaging instruments from multiple vendors document the potential of CMR imaging for clinical, routine use, since CMR was capable of answering relevant clinical questions in more than 98% of cases, the authors write.

Impact of CMR on prognosis

Next, the researchers will analyze data from the EuroCMR registry to determine the prognosis for patients who undergo CMR imaging for the three most common indications.

"As soon as these prognostic data are available, we speculate that CMR will become the main imaging procedure in many major clinical indications," Bruder said.

Unlike other procedures, CMR does not involve ionizing radiation. The current study also suggests that a substantial number of invasive coronary angiographies can be avoided in patients undergoing CMR stress testing for workup of suspected CAD, he added.

"We are very excited that we will soon expand our research [from currently more than 50 European centers] to the United States," Wagner, who will coordinate the US research, said.

Implications for US practice

"In the US, CMR is available in clinical practice but is limited to large hospitals, academic centers, and advanced outpatient clinics," Dr Ricardo C Cury (Baptist Cardiac and Vascular Institute, Miami, FL), who was not involved in the study, commented to heartwire.

He identified three key findings:

• The main clinical indications that MRI was used for in this registry are similar to those in the US.
• MRI is a very safe procedure, even during pharmacological stress.
• In two-thirds of patients, CMR affected patient management, and in 16% of patients there was a new important finding that was not suspected before the MRI study.

CMR can be used to replace or supplement more invasive procedures, he noted, and although the use of CMR in clinical practice is growing, this is occurring at a slower pace than in research, he added.

According to Cury, "More physicians need to be trained in CMR, and referring cardiologists need better education about CMR."

Sources

1. Bruder O, Schneider S, Nothnagel D, et al. EuroCMR (European Cardiovascular Magnetic Resonance) registry: Results of the German pilot phase. J Am Coll Cardiol 2009; DOI: 10.1016/j.jacc.2009.07.003. Available at: http://content.onlinejacc.org.
2. Jahnke C, Nagel E, Gebker R, et al. Prognostic value of cardiac magnetic resonance stress tests. Circulation 2007; 115:1769-1776.

Technorati Tags: CMR,cardiac MRI,cardiomyopathy,CHF,CAD

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Management of Angina Pectoris: The Role of Spinal Cord Stimulation

Siegfried Eckert; Dieter Horstkotte. Published: 06/02/2009

Abstract and Introduction

Abstract

Progress in prevention as well as drug and interventional therapy has improved the prognosis of patients with cardiovascular disorders. Many patients at risk have advanced coronary artery disease (CAD), have had multiple coronary interventions, and present with significant co-morbidity. Despite adequate risk factor modulation and often several revascularization procedures, some of these patients still have refractory angina pectoris. Apart from advanced CAD and insufficient collateralization, the cause is often endothelial dysfunction. For this situation, one treatment option is neuromodulation. Controlled studies suggest that, in patients with chronic refractory angina pectoris, spinal cord stimulation (SCS) provides a relief from symptoms equivalent to that provided by surgical therapy, but with fewer complications and lower rehospitalization rates. SCS may result in significant long-term pain relief with improved quality of life. In patients with refractory angina undergoing SCS, some studies have shown not only a symptomatic improvement, but also a decrease in myocardial ischemia and an increase in coronary blood flow. Discussion is ongoing as to whether this is a direct effect on parasympathetic vascodilation or merely a secondary phenomenon resulting from increased physical activity following an improvement in clinical symptoms. Results from nuclear medical studies have sparked discussion about improved endothelial function and increased collateralization. SCS is a safe treatment option for patients with refractory angina pectoris, and its long-term effects are evident. It is a procedure without significant complications that is easy to tolerate. SCS does not interact with pacemakers, provided that strict bipolar right-ventricular sensing is used. Use in patients with implanted cardioverter defibrillators is under discussion. Individual testing is mandatory in order to assess optimal safety in each patient.

Introduction

Therapeutic options for the management of angina pectoris in patients with coronary artery disease (CAD) have improved over the past 2 decades. Nevertheless, angina pectoris is a common and important symptom affecting many patients with CAD, as well as some with endothelial dysfunction.

Despite optimal drug therapy and no option for coronary revascularization procedures (percutaneous coronary intervention [PCI] or aortocoronary bypass [ACB]), some patients with CAD have persistent angina pectoris class III or IV according to the Canadian Cardiovascular Society (CCS).[1] The treatment of these patients with non-responding angina pectoris presents a medical challenge. We have no accurate figures on the occurrence and frequency of refractory angina, nor is the prevalence of angina pectoris known in most communities. The overall prevalence of patients referred for coronary angiography with refractory angina varies from 5% to 15%.[2]

Various treatment concepts have been developed for patients with therapy-resistant angina pectoris and have been applied in clinical studies: long-term intermittent urokinase therapy,[3] surgical and percutaneous transmyocardial laser revascularization,[4-6] enhanced external counterpulsation,[7,8] percutaneous in situ coronary venous arterialization,[9] and transcutaneous electrical nerve and spinal cord stimulation (SCS).[10-19] The latter has been established as the most applicable. It is recommended as the therapy of choice by the European Society of Cardiology Joint Study Group on the Treatment of Refractory Angina.[2]

In this article, we review the role of SCS in the management of severe angina pectoris in patients with ischemic heart disease and endothelial dysfunction.

Endothelial Dysfunction and Coronary Artery Disease

Stable and Refractory Angina Pectoris

Endothelial dysfunction is usually diagnosed in the presence of angina pectoris without obstructive CAD and coronary artery spasm. Patients with such a diagnoses experience typical anginal chest pain and experience positive exercise stress testing. About 15-20% of patients undergoing cardiac catheterization for the assessment of typical chest pain have these characteristics,[20] and most of them have a good prognosis.[21]

Endothelial dysfunction often marks the onset of atherosclerosis, stays with the patient for the rest of his or her life, and at the end-stages of CAD following PCI, causes higher rates of relapse and re-intervention.[22] Endothelial dysfunction can be ascertained invasively and non-invasively. After excluding hemodynamically relevant epicardial stenoses by determining the fractional flow reserve (FFR), the functional status of a coronary artery can be determined by coronary flow reserve (CFR).[23] As a non-invasive procedure, ammonia positron emission tomography (PET)[24] and flow-mediated dilatation of the brachial artery (FMD) can be used.[22]

The survival of patients with CAD is increasing as a result of improved prevention and coronary intervention, which in turn is leading to an increase in the prevalence of patients with refractory angina pectoris.

It is important to underline that angina pectoris is a clinic diagnosis. Imbalance in myocardial oxygen demand and supply can produce myocardial ischemia. This may cause angina pectoris and lead to a reduction in left-ventricular contractility, as well as cause arrhythmia, myocardial infarction, and possibly death. Angina pectoris is commonly due to atherosclerosis of the coronary arteries, but it can also occur in conjunction with endothelial dysfunction due to insufficient coronary vasodilatation.

Anti-anginal drug therapy improves the imbalance of the myocardium by interacting with heart rate, cardiac pre- and afterload, as well as coronary vascular tone. Hemodynamically significant coronary stenoses with and without angina pectoris may be dilated (PCI) or operated on (ACB).[22]

Refractory angina pectoris (CCS class III and IV)[1] is a chronic condition characterized by the presence of angina due to coronary insufficiency in the co-presence of CAD that cannot be controlled by a combination of medical therapy, angioplasty, and coronary bypass surgery.[2] Patients with endothelial dysfunction can also experience refractory angina.

Before selecting patients with refractory angina for SCS, a re-evaluation of their medical therapy is required in order to ensure an optimal treatment regimen[2,25] (Table I). Myocardial ischemia should be present, and other causes of chest pain, such as musculoskeletal pain, esophageal reflux, gastrointestinal disorder, pericardial disease, vascular disease (aortic dissection, pulmonary embolism), infection, panic disorder, and pulmonary conditions that cause chest pain, must be excluded.[1,26]

Table I. Steps in Optimizing Medication and Management in Patients With Chronic Refractory Angina.

Pharmacologic Therapy

The therapeutic options for endothelial dysfunction and stable CAD are comparable and aim at correcting the imbalanced redox potential. Treating the classical risk factors with lifestyle modification and drug therapy has facilitated the successful prevention of clinical cardiovascular events and has prolonged life expectancy.

In many randomized studies, a reduction in increased low-density lipoprotein cholesterol and triglyceride, as well as an increase in reduced high-density lipoprotein cholesterol have contributed to stabilizing plaque, have frequently demonstrated a regression of coronary atherosclerosis, and have improved endothelial function.[22] Controlling hypertension, cessation of smoking, increasing physical activity, and reducing weight all help to halt the progress of atherosclerosis and to reduce acute events. Lifestyle changes in the form of increased physical activity with or without weight reduction frequently lead to a reduction in angina pectoris and improved myocardial perfusion.[22] In randomized studies, it was possible to show that, compared with coronary intervention (PCI), increasing physical activity resulted in a better event-free survival rate, a higher exercise capacity, and a higher oxygen uptake, and was more cost effective; it achieved clinical improvement in CCS class I at half the total cost of the interventional strategy.[27,28]

Spinal Cord Stimulation (SCS) in Angina Pectoris

Pathophysiologic Mechanisms of Pain

Pain arises when specific nerve endings in organs (nociceptors) are stimulated. Nociceptors end as free, non-corpuscular nerve endings in all the different types of tissue within our bodies, e.g. in the adventitia of coronary arteries. Angina pectoris results from ischemic episodes, reduced blood flow through hemodynamically significant stenoses of the epicardial vessels or endothelial dysfunction, stimulating chemosensitive and mechanoreceptive receptors in the heart. Activation of these receptors results in the release of prostaglandins, adenosine, bradykinin, and other substances that excite the sensory ends of the sympathetic and vagal afferent fibers.[29] The nociceptive information of the elicited stimulus that causes angina pectoris is conveyed by visceral afferent nerve fibers, converging in common pathways, into the dorsal spinal cord at C7-T5 level where they have synaptic connections with other neurons.[30] Afferent fibers from the heart and cutaneous input are assumed to converge on specific interneurons in the same segment of the spinal cord.[31] Angina pectoris is felt in areas that refer to the dermatome, from where afferent nerves project to the same segment of spinal cord as from the heart. Two different classes of fibers conduct the received signals to the central nervous system: thin medullated Aδ-fibers and non-medullated C-fibers. The majority of nociceptors are slow-conducting C-fibers that convey dull pain, whereas the fast-conducting Aδ-fibers convey stabbing pain.

SCS Techniques

During transcutaneous electric nerve stimulation (TENS), two or four adhesive electrodes are attached epicutaneously so that the induced paresthesia is located by the patient in the area with the highest projected pain intensity during typical angina pectoris. The stimulation intensity is selected below the individual pain threshold.

During SCS, a 4- or 8-pole electrode is advanced to C7/T1 using x-ray vision after puncturing of the epidural space under a local anesthetic at T6-7. The electrodes are placed according to the area of distribution of the electrically induced paresthesia. This area should correlate as closely as possible with the area affected by angina pectoris.[19,32] The stimulation electrode is guided under sterile conditions and connected to an external portable stimulation device followed by a positive test period, the duration of which depends on the frequency of angina. As soon as the frequency and intensity of angina pectoris have significantly decreased (more than 50%), the stimulation electrode is subcutaneously lengthened under general anesthesia and usually connected to a stimulation aggregate implanted in the left upper abdomen. Using a programming device, the patient can then switch the aggregate on and off telemetrically, as well as alter the stimulation intensity within stipulated ranges.

Mechanisms of Action of SCS in the Treatment of Cardiac Ischemic Syndromes

The following mechanisms may explain the positive effects of SCS in chronic refactory angina pectoris: reduced pain perception, decreased sympathetic tone, reduced myocardial oxygen demand, improved coronary microcirculatory blood flow, and positive effects on cerebral blood flow (CBF).[33]

Reduction of Pain Perception. Segmental pain inhibition through neurostimulation has been under discussion since the mid-1960s.[34] By applying electrical stimulation regionally and below the pain threshold, sensitive afferent fibers (A-fibers) are selectively activated. In the spinal dorsal horn, this should then lead to a consecutive presynaptic inhibition of nociceptive afferences (A- and C-fibers) with local analgesia. In the last few years, mechanisms involved in the modulation of important neurotransmitters have been discovered, contributing to our understanding of pain inhibition through SCS. SCS leads to an augmented release of the inhibitory neurotransmitter GABA. This results in a decrease in the release of exitatory amino acids (glutamate and aspartate). In a rat model, local infusion with a GABAb-receptor antagonist in the dorsal horn transiently abolished the SCS-induced suppression of glutamate and aspartate release. The elevation in GABA release, in response to SCS, did not reach statistical significance.[35,36] A combination of subtherapeutic intrathecal doses of a GABAb-receptor agonist and an adenosine A1 agonist has been found to potentiate the effects of SCS in rats that were not initially responsive to SCS.[35,36] SCS has been found to enhance the release of β-endorphin.[37] β-Endorphin can help to reduce pain perception. It can unfold a cardioprotective effect following myocardial ischemia by decreasing myocardial contractility and subsequent oxygen consumption, and possibly by decreasing the release of norepinephrine (noradrenaline).[38]

Decreased Sympathetic Tone. Several studies on the effect of TENS and SCS on cardiac metabolism and hemodynamics have demonstrated that no changes occur under basal conditions, but manifest when the heart is stressed.[39]

The anti-ischemic effect of SCS is not due to reduced cardiac sympathetic activity. SCS decreases overall sympathetic activity, which may benefit the heart, possibly by reducing oxygen demand.[11] This could be demonstrated with SCS during tachycardial atrial stimulation. The total body norepinephrine spillover was reduced while the cardiac norepinephrine spillover was not affected.[11] Regional and overall sympathetic activity can be differentiated using the isotope dilution technique.[40] In this technique, the norepinephrine spillover and clearance are determined simultaneously in a steady state by infusing tritium-labeled norepinephrine. This avoids an increase in cardiac norepinephrine spillover, which can happen when total body norepinephrine spillover is determined individually in addition to determination of the plasma concentration of endogenous norepinephrine.

Neurostimulation suppressed activity generated by intrinsic cardiac neurons in animal experiments.[41] Spinal cord neurons primarily influence the intrinsic nervous system via axons coursing the intrathoracic sympathetic nervous system. Transient regional myocardial ischemias can markedly increase the activity of the intrinsic nervous system and thus lead to cardiac dysrhythmia.[42] In sympathetic stress situations, SCS is able to lower heart rate.[43] This reduced cardiac sympathetic activity under SCS can also be ascertained in an influencing of heart rate variability.[44] Activation of spinal cord neurons during SCS induces a conformational change in the intrinsic cardiac nervous system that persists for a considerable period of time after termination. This remodeling of the intrinsic cardiac nervous system can override excitatory inputs to it arising from the ischemic myocardium.[45] Further studies are required to investigate whether ventricular tachycardia or sudden cardiac death could thus be avoided.

Effect on Cerebral Blood Flow. Non-invasive techniques for determining cerebral perfusion and measuring functional activity (e.g. PET, functional MRI, or magnetoencephalography) have contributed to a better understanding of cerebral function in healthy subjects and in those with various diseases and the ways in which cerebral function can be influenced through interventions.[45] Changes in regional blood flow in areas involved with nociception and cardiovascular control have been documented in patients treated with SCS for refractory angina.[46] The cerebral areas demonstrating a relative increase or decrease in CBF could possibly be determined by the underlying disease (pain during clinical examination, one-sided or two-sided for paired organs) and the measuring methods, as well as the type of intervention.[47,48] In patients with documented CAD, typical anginal and ischemic electrocardiographic changes can be triggered during dobutamine infusion. Dynamic PET examinations during induced ischemia reveal increased and decreased regional CBF.[48] During SCS, increased and decreased regional CBF can also be observed with and without stimulation in patients with refractory angina.[49] In these two different patient groups, there are correlations within the following regions: increased CBF in the hypothalamus, and in the periaqueductal grey area and bilaterally in the thalamus, and decreased CBF in the posterior insular cortex, an area that modulates sympathetic effects.[48,49] The well supported effects of SCS are possibly attained by influencing central structures within the area of pain perception and processing. The thalamus may act as a filter for afferent pain signals.[48,50]

Effect on Coronary Blood Flow. SCS has repeatedly demonstrated an anti-anginal effect by reducing angina pectoris and the use of short-acting nitrates, increasing exercise tolerance, and decreasing ST-segment depression on the electrocardiogram.[51-55] Discussion about the effect of SCS on myocardial blood flow is ongoing.

SCS has been demonstrated to reduce catecholamine levels.[56] A direct sympatholytic effect is under discussion. Stimulating the dorsal paths in the spinal cord leads in turn to stimulation of segmental reflex paths and an inhibition of tonic activity in the sympathetic nervous system.[57] Vasodilatation of the microvessels leads to improved myocardial perfusion. Even in patients with refractory angina pectoris, coronary reserve is not completely eliminated.[47] One study was able to demonstrate a significant increase in cardiac index and a decrease in pressure frequency product as an indirect indicator for a reduction in myocardial oxygen consumption.[46]

Changes in myocardial perfusion can be directly visualized by intracoronary pressure and flow measurements. Non-invasive methods, such as stress echocardiography and nuclear medical techniques like myocardial scintigraphy and PET, indirectly illustrate myocardial perfusion by measuring contractility of the left ventricle (wall motion analyses) and differences in activity of enriched nucleotides in the myocardial cells.

Not even the use of different methods to evaluate myocardial perfusion, with varying study designs and clear results, have been able to explain the key issue of the anti-ischemic effect of SCS.

In 15 patients, stress echocardiography with adenosine led to a slight decrease in pumping function during SCS, in comparison to baseline without stimulation.[58] This may be interpreted as an indirect indication of improved myocardial perfusion.

For direct measurement of blood flow in a coronary artery, a catheter or wire has to be introduced. This can contribute to a reduction in flow within the vessel, depending on the diameter of the catheter. The different studies employ a variety of systems and conditions. Chauhan et al.[57] examined 34 patients with syndrome X (endothelial dysfunction) and 15 patients with CAD. Measurements were taken using an 8-French catheter in a presumed healthy vessel - left coronary artery without significant stenoses - at rest, with and without neurostimulation (TENS). An increase in flow velocity was ascertained. The authors concluded that the site of action was at the microcirculatory level, and that the effects may be mediated by neural mechanisms.

Norrsell et al.[59] examined eight patients with advanced CAD and four patients with syndrome X. A Doppler guidewire was placed in the vessel, corresponding to the ischemic area on a prior myocardial scintigram. Perfusion at rest and with right-ventricular stimulation, with and without SCS, was examined. The result was negative. There were no significant changes in coronary flow velocity during maximum pacing frequency when stimulation was introduced.

In a prospective study in 31 patients with advanced CAD, Diedrichs et al.[60] demonstrated an improvement in myocardial perfusion with sestamibi-single-photon emission computed tomography (MIBI-SPECT) scintigraphy after 12 months, but not after 3 months. Thus the reduction in ischemia does not seem to be a direct effect of neurostimulation, but might be due to an increased exercise tolerance of the patients with improved cardiac blood flow because of a better collateralization.

PET examinations of myocardial perfusion with SCS have also revealed different results. In eight patients undergoing SCS, De Landsheere et al.[61] found no increase in regional myocardial perfusion in ischemic regions when stimulated. Hautvast et al.[62] postulated a homogenization of myocardial blood flow. In nine patients with CAD, no significant difference in coronary blood flow due to SCS was revealed during dipyridamole stress testing after 6 weeks of SCS. Total resting blood flow remained unchanged, but flow reserve decreased. In a pilot study, we examined six patients with advanced CAD.[63] Perfusion at rest and during the maximum hemodynamic effect of intravenous adenosine was studied by ammonia PET at baseline and 13 ± 0.5 months after SCS. We found a significant increase in myocardial blood flow and a reduction in minimal coronary resistance after 1 year.[63] Figure 1 shows increased myocardial perfusion in the basal posterior wall of a 62-year-old man undergoing SCS. His history is typical for patients with refractory angina pectoris: severely restricted left-ventricular function in conjunction with advanced coronary triple vessel disease, two myocardial infarctions, two operative myocardial revascularizations, three catheter interventions, all therapeutic options exhausted, and angina upon slight physical exercise. In all patients, additional 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET) was performed at baseline to distinguish vital myocardial regions from non-vital regions (figure 2). Fifty patients are included in an ongoing prospective study of the same design.[64]

Figure 1. Improvement in myocardial blood flow in the inferior wall of the heart in a 65-year-old man after 1 year of spinal cord stimulation. (a) Baseline examination; and (b) 1-year follow-up.

Figure 2. Assessment of viability by positron emission tomography (PET) imaging. Baseline examination: (a) discrimination between vital and non-vital myocardium using 18 F-fluorodeoxyglucose positron emission ( 18 F-FDG-PET). Detection of ischemia by ammonia PET at (b) rest and (c) stress.

The results pertaining to improved myocardial perfusion following SCS are not uniform. The number of patients included in studies is small, and follow-up intervals differ. A direct effect of neuromodulation on myocardial perfusion is not conclusive, even with a positive result. The discussion addresses a relative redistribution of myocardial perfusion from non-ischemic to ischemic myocardial areas when stimulated. Since the differences are slight and the reduction in myocardial perfusion in the non-ischemic areas presumes a significantly higher level than the increase to be achieved in the ischemic areas, ischemia is not to be expected in the non-ischemic areas. In the ischemic areas, however, a significant increase in perfusion is to be expected. This explains the symptomatic improvement, which may be explained by a direct effect due to vasodilatation, in particular, of the microvessels, with a reduction in minimum coronary resistance, and an indirect effect due to an improved collateralization (development of collateral vessels).

Improvement in myocardial perfusion through an indirect improvement in endothelial function can be explained by the presumed increase in exercise tolerance and quality of life when angina pectoris is reduced.[27] Whether or not the anti-anginal and anti-ischemic effects of SCS are mediated by an increase in coronary flow velocity is a discussion still ongoing. The effect is derived through decreased myocardial oxygen consumption.[11]

Clinical Experience with SCS in Angina Pectoris

Angina pectoris is a projected pain that is caused by insufficient perfusion of the myocardium due to significant coronary stenoses or reduced vasodilatatory capacity, particularly of the microcirculation. CAD is frequently accompanied by endothelial dysfunction. In the majority of patients with significant coronary stenoses and exercise-induced ischemia, pain relief can be achieved following revascularization and/or through risk factor modulation with improvement in endothelial function (Table I). TENS and SCS are recognized therapies in patients with refractory angina pectoris.[2] In many clinical studies, the effectiveness of these therapies have been demonstrated in patients (approximately 2500) with CAD and endothelial dysfunction:[2,21,54,55,59,65-70] fewer angina pectoris episodes and less short-acting nitroglycerin (glyceryl trinitrate) or mononitrate intake per time period; increase in exercise tolerance, time to angina, and the appearance of ST-segment depression; extended walking distance in the 6-minute walk test before onset of angina; improvement in quality of life; and fewer stays in hospital as well as visits to the physician due to cardiac-related symptoms.

Table I. Steps in Optimizing Medication and Management in Patients With Chronic Refractory Angina.

Despite these well known symptomatic improvements, SCS is still not recognized by many cardiologists. Its acceptance in European countries is low and varies (countries employing SCS in descending order of frequency are: Sweden, Italy, Germany, and Denmark). Since to date there are no systematic investigations regarding the distribution of SCS in patients with refractory angina pectoris, statistics come from manufacturers only (total 400-500 patients/year; in Germany, a total of 225 patients since 1998).

In a randomized, prospective study, the effectiveness of SCS was compared with that of operative myocardial revascularization (ACB).[18] SCS (n = 53, 41 males) and ACB (n = 51, 42 males) scored equally in subjective symptomatic improvement. Compared with the SCS group, after 6 months of follow-up, the ACB group had an increased exercise tolerance, as well as less ST-segment depression on maximum and comparable workloads. The maximum workload capacity was lower in the SCS group, and the ST-segment depression on maximum workload was higher than that in the ACB group. The mortality rate was lower in the SCS group (one SCS patient vs seven ACB patients). After 5 years, survival and quality of life were comparable between the two groups.[19] Secondary prevention was poor in both groups (SCS/ACB): aspirin (acetylsalicylic acid) 42%/33%, β-adrenoceptor antagonists 43%/24%, lipid-lowering drugs 6%/3% and ACE inhibitors 7%/8%.

Since patients experience retrosternal prickling during active SCS, a blind, placebo-controlled SCS study in patients with refractory angina pectoris is not an option. Eddicks and coworkers[54] have examined the therapeutic effects of subthreshold SCS. Twelve responders to SCS were randomized into four consecutive treatment arms, each for 4 weeks, with various stimulation timing and output parameters. One group was defined as a control-subthreshold stimulation (0.1 V) without retrosternal prickling. Walking distance, angina pectoris, short-acting nitroglyerin intake, and quality of life only improved in the groups sensing stimulation. This study showed for the first time that a placebo effect in conjunction with SCS is unlikely. The option of using subthreshold stimulation in active yet blind patient treatment is an attractive concept for further studies.

Safety Aspects

SCS is a safe, recognized, and effective therapy for patients with refractory angina pectoris.[2,70-73] Critics of SCS object that patients no longer receive warning signals (angina pectoris) and thus endanger themselves as their exercise levels increase.[74] Angina pectoris is the cardinal symptom of acute myocardial ischemia including infarction, and it is possible that effective pain relief through SCS may conceal such an infarction.[75] In many studies, it has been shown, however, that angina pectoris could be significantly reduced with SCS. Quality of life improves and cardiovascular event rates are significantly lower.[12,70,76,77] Of course, myocardial infarctions cannot be prevented through SCS: advancing CAD, plaque ruptures, or bypass closures can still be responsible for these.

In a prospective study, Andersen and coworkers[74] investigated the possibility that SCS used for pain relief might conceal acute myocardial infarction. During the observation period of up to 37 months (108.6 patient-years), ten out of 50 patients experienced a myocardial infarction. Nine of these ten patients with acute infarction recognized that the precordial pain was clearly different and definitely more severe than their usual angina. Angina was not influenced by SCS. The mean number of admissions for chest pain, angina, or observation, in case of acute myocardial infarction, was not significantly different in the ten patients with acute myocardial infarction compared with patients without infarction during the 3-year period before SCS treatment or during SCS treatment.

SCS is used in patients with advanced CAD. Patients with CAD can also experience disorders that necessitate the use of permanent pacemaker (PPM) treatment for bradyarrhythmias or an implantable cardioverter defibrillator (ICD) for ventricular tachycardias.

The experiences of various groups confirm the safety of SCS in patients with PPM.[78-84] SCS does not interact with pacemakers, provided that strict bipolar right-ventricular sensing is used. Unipolar SCS has been reported to cause PPM inhibition, and should not be considered.[7,81] The amplitudes of the stimulator noise are often seen on the intracardiac electrogram (figure 3). There were no interactions between the two systems during T-wave sensing with unipolar PPM. Individual testing is mandatory to assess safety in each patient.

Figure 3. Intracardiac electrograms showing stimulator noise amplitudes in patients with permanent pacemakers undergoing spinal cord stimulation (SCS): no noise interference.

In the future, more patients with refractory angina will have pacemakers (including left-ventricular stimulation) and ICDs. An increase in patients with ICDs has already been observed over the past decade. In line with current information, many patients included in ESBY (Electrical Stimulation versus Bypass Surgery in Severe Angina Pectoris) study have an indication for ICD therapy due to severely impaired left-ventricular function. Thus, the treatment of one condition must be compatible with the treatment of the others.

The literature only contains case studies of combined SCS and ICD therapy.[85] Problems can arise, on the one hand, from a false detection of SCS spikes with consecutive antitachycardia therapy and, on the other hand, from the suppression of therapy in conjunction with a threat of arrhythmia, since spikes are often still falsely interpreted as 'rhythm' below the intervention threshold.

Many ICD systems use an automated gain-control during bipolar sensing. According to our experience, ICD-SCS combination therapy may be safely performed.[86,87] Differentiated testing is unavoidable. In a prospective study in five patients within a follow-up of 12.2 ± 10.5 (2-40) months, no interaction between SCS and ICD therapy was documented.[87] We evaluated possible interactions under general anesthesia with the highest SCS amplitude (10.5 V/450 ms) and the most sensitive bipolar sensing during induced ventricular fibrillation (twice) [figure 4].

Figure 4. Spinal cord stimulation (SCS) and implantable cardioverter defibrillator therapy: no interaction by induction (a) and termination (b) of ventricular fibrillation (highest sensitivity).

TENS therapy should not be performed in patients in conjunction with SCS, PPM, cardiac resynchronization therapy (CRT), or ICD since inhibitions cannot be excluded. The general recommendations regarding minimization of interactions and infections should be observed for SCS as for other stimulation therapies. MRI and diathermia should not be performed due to possible warming of the leads.

Stress tolerance in patients with SCS is not limited by the wearing of the system, but by progressive CAD, restricted left-ventricular function, and possible concomitant diseases.

Cameron[55] has summarized direct SCS-related complications from the literature over the last 20 years, covering a total of 2753 patients: lead migration 13.2%, lead breakage 9.1%, and infection 3.4%. Through optimization of implantation technique and perioperative management, these complications can be reduced.[80,81] In the German Angina Register[76,88] including 101 patients, the frequency of these complications is as follows: lead migration 5%, lead breakage 5%, and infection 3%. In the 1-year follow-up, 8% died: sudden cardiac death occurred in 3%, heart failure in 2%, and malignoma in 3%. One patient experienced a myocardial infarction and one patient underwent PCI.

SCS shows a long-term beneficial effect, even in patients with unstable angina.[51] The target values of concomitant risk factors must be reduced prior to commencing SCS and then be aligned long-term through interventions (Table I, figure 5).

Table I. Steps in Optimizing Medication and Management in Patients With Chronic Refractory Angina.

Figure 5. Therapeutic options in the cardiovascular continuum for patients with unstable angina. ACB = aortocoronary bypass; CRT = cardiac resynchronization therapy; ICD = implantable cardioverter defibrillator; PCI = percutaneous coronary intervention; PPM = permanent pacemaker; SCS = spinal cord stimulation.

Conclusion

Refractory angina pectoris during end-stage CAD and with endothelial dysfunction is a specific coronary syndrome that is chiefly caused by microcirculatory disturbances. Already receiving the best use of evidence-based therapies and with no interventional options, these patients can benefit from SCS. SCS is safe and effective for treating refractory angina pectoris - reducing both the number of anginal episodes and the intensity of the angina pectoris. With SCS the dosage of short-term effective nitrates per time period is reduced. The work period during exercise tests is significantly prolonged. SCS leads to a significant reduction in hospital admission for cardiac causes, without masking myocardial ischemias or myocardial infarction. The implantation costs are balanced out by savings in aftercare (fewer consultations and hospital stays).

SCS is an excellent alternative for patients at an increased risk of requiring operative revascularization. For patients with refractory angina who are waiting for heart transplantation, SCS is also a good bridging option.

In small studies, an improvement in myocardial blood flow in vital ischemic myocardial areas has also been proved. It has yet to be investigated whether SCS, in addition to a proven improvement in symptoms, also reduces mortality.

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Authors

Siegfried Eckert and Dieter Horstkotte, Department of Cardiology, Heart and Diabetes Center North Rhine-Westphalia, Ruhr-University Bochum, Bad Oeynhausen, Germany

Technorati Tags: coronary heart disease,coronary,angina pectoris,spinal cord stimulation,anasthesia

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