Interventional Cardiology at a Pivot Point

I was recently asked to give the Hildner Lecture at the Opening Plenary Session of the Society for Cardiac Angiography and Intervention. This prompted me to reflect upon the current and future role of interventional cardiology in the management of cardiovascular disease. It seemed to me that interventional cardiology was at an inflection point in terms of its activities and growth. While founded in the transcatheter treatment of coronary artery disease, the diagnosis and treatment of structural heart disease was emerging in prominence, and in fact had the greatest growth potential. I thought of calling this evolution a transition, but that implied a change from one thing to another. So I rather described it as a pivot point; a situation where one continues to have a strong foothold in one area while moving forcefully into another.

There is no doubt that interventional cardiology has a firmly established role in acute coronary syndromes. The data supporting this role are numerous and robust both for ST elevation and Non-ST elevation myocardial infarctions.^1,2 In fact, several studies validated a role for routine catheterization, and intervention when indicated, in acute coronary syndromes. However, the benefit of transcatheter revascularization for chronic coronary disease and stable angina has recently been called into question.

The well conducted COURAGE Trial compared percutaneous coronary revascularization (PCI) to optimal medical therapy in a goodly number of patients with stable angina.³ The investigators found that the two therapeutic approaches were similar in regard to survival, both as a sole event and when combined with subsequent acute coronary syndrome or myocardial infarction. Revascularization did provide superior relief of angina during the course of the trial. As is almost universally true, COURAGE was not a perfect trial and had some limitations. The study enrolled only about 7% of the patients screened and used only bare metal stents. The cross-over rate was 32%, and optimal medical therapy consisted of a very intense regimen with frequent patient contacts that could be challenging for a busy practice. Of perhaps greatest significance, the study did not have angina as an endpoint. Nevertheless, while imperfect, these data in conjunction with several prior studies called into question the survival benefit of intervention in chronic stable angina patients. The symptomatic relief of angina, however, continued to represent an important indication for angioplasty and stenting.

The role of transcatheter intervention to alleviate angina was just recently called into question by the OPTIMA Trial.⁴ This was the first randomized controlled trial to apply an invasive sham arm as a comparator. The study compared PCI to optimal medical therapy in patients with stable angina utilizing exercise duration as the primary endpoint for symptomatic relief. OPTIMA was a tour de force in terms of methodology, insuring that the patients as well as the investigators were completely blinded by means of sedation and earphones. Medical therapy was even more intense than in COURAGE, with medical contacts often several times per week. The surprising results of the trial showed no statistical difference in exercise time between medical and interventional therapy. Clinical class was also similar in the two groups post 6 week treatment, although a decrease in ischemia on stress testing was greater in the PCI cohort. Again, there were a number of limitations to the study. Patients had relatively infrequent angina, and trial duration was only 6 weeks. Functional testing revealed that 30% of lesions were not flow limiting, and 4 of 95 patients crossed over from medical to interventional therapy. Medical therapy was extraordinarily intense. Most importantly, the patients with single vessel disease were included in the trial.

The initial reaction to the results of OPTIMA was to consider that much of the benefit of stenting was due to a placebo effect, and this may indeed be a significant contributor. However, it occurred to me that another variable might be a major factor in the results. Specifically, PCI could relieve angina only if the symptoms were due to obstruction of an epicardial coronary artery. Therefore, if ischemia was due to some other cause, catheter intervention would not be effective in alleviating angina despite the presence of coronary obstruction.

Considerable evidence attests to the fact that there may be a discordance between ischemia (angina) and coronary obstruction. Significant coronary obstruction has been found to be absent in a number of patients with stable angina and even acute coronary syndromes. Moreover, evidence of ischemia does increase the risk of events even in the absence of obstruction. By the same token, some patients with advanced atherosclerotic luminal encroachment are free of angina, and elimination of a stenosis does not invariably lead to reduction of symptoms or events. Finally, a number of non-atherosclerotic causes have been documented to cause ischemia, including inflammation, vasospasm, and endothelial and microvascular dysfunction. The discordance between epicardial coronary obstruction and angina is perhaps best exemplified by a study from the ACC National Cardiovascular Disease Registry (NCDR) that found coronary artery disease, defined as lumen obstruction of less than 20%, was absent in 39.2% of patients undergoing angiography, regardless of risk category or nature of symptoms.⁵

The potential mechanisms for the production of angina in patients without obstructive coronary lesions was examined in a study that applied multiple modalities to study coronary physiology, including intracoronary velocity, flow, and pressure measurements and acetylcholine stimulation.⁶ The investigators found that over two-thirds of the patients had evidence of either endothelial or microvascular dysfunction. Moreover, as suggested by authorities, epicardial obstruction and microvascular dysfunction may be present in the same patient.⁷ Clearly, if coronary obstruction and microvascular dysfunction are both present and decrease myocardial blood flow, relief of the coronary obstruction cannot be expected to eliminate angina or ischemia. If this were the case in even 20% of patients, the results of both COURAGE and OPTIMA could be significantly altered.

In view of the foregoing, it would seem critical to identify patients in whom both microvascular dysfunction and coronary obstruction are present. A consensus document by the Coronary Vasodilation Disorders International Study Group (COVADIS) defined four criteria for the diagnosis of microvascular angina, one of which is the detection of abnormal microvascular function.⁸ Several invasive techniques exist by which this can be done, including the measurement of coronary velocity and blood flow reserve, quantitation of microvascular resistance, and detection of coronary spasm by intracoronary Doppler and thermodilution methods or acetylcholine injection. More techniques need to be defined. The important point is that interventional cardiologists will have to become more oriented to physiology in the future. It is likely that the future role of PCI in patients with stable angina will depend upon identifying those patients in whom ischemia and angina are due to coronary obstruction rather than some other mechanism, and that this will require detailed evaluation of coronary physiology on a level that is not typically applied at the current time. As such, this will represent a bit of pivot.

However, if interventional cardiology is to grow and flourish, it is likely that it will require targets other than coronary atherosclerosis. In this regard, I believe that a clear course can already be visualized, and it is in the realm of structural heart disease. The definition of structural heart disease has not been formalized, but includes valvular and congenital disease, as well as a variety of other disorders including left atrial thrombi, pulmonary and systemic hypertension, hypertrophic cardiomyopathy, and even many cases of heart failure. A number of therapeutic procedures have already been incorporated into clinical practice, including closure of atrial septal defects and transcatheter aortic valve replacement (TAVR). I believe that structural heart disorders will form an increasing portion of both non-invasive and invasive cardiology practices, and cardiac surgery as well.

Interventional procedures have been applied for a variety of congenital heart diseases for many years. In fact, catheter closure of atrial septal defects was the first non-invasive technique directed to the treatment of structural heart disease. A variety of devices have been developed to close atrial and ventricular septal defects as well as patent ductus arteriosus. In addition, balloon dilation of pulmonic stenosis, coarctation of the aorta, and pulmonary artery stenosis have become accepted clinical procedures. Transcatheter valves are being deployed even as technological innovation continues. It is likely that such procedures will increase in the future as patients with congenital heart disease increasingly survive into adulthood. In terms of the future, perhaps the greatest growth will be in closure of the patent foramen ovale (PFO). Three recent studies in the New England Journal of Medicine and a recent meta-analysis all attested to the value of catheter closure of a patent foramen in patients with prior cryptogenic stroke or transient ischemic attack.⁹ Since a PFO has been found to be present in approximately 20% of the population, closure of such lesions is likely to substantially increase.

The diagnosis and treatment of valvular heart disease will certainly consume greater attention from cardiologists and cardiac surgeons in the future. Considerable evidence exists that the prevalence of asymptomatic heart disease, both aortic and mitral, is considerable in the general population. In fact, one survey in Europe reported that undiagnosed moderate to severe valve disease was present in one in 20 individuals.¹⁰ Moreover, severe symptomatic valvular heart disease often goes without interventional treatment, even when it fulfills guideline recommendations for such therapy.^11,12 Often the lack of intervention is related to high risk or co-morbidities. As the population ages, the prevalence of valve disorders is sure to increase as will the need for innovative transcatheter or minimally invasive therapies.

Transcather aortic valve replacement has already been incorporated into daily clinical practice. Data currently exists indicating that TAVR yields similar results to aortic valve surgery in patients at both high and intermediate risk,¹³ and preliminary data suggests that catheter approaches may be comparable to surgery even in low-risk patients. The potential for TAVR to be an effective strategy in patients with asymptomatic aortic stenosis is intriguing and almost certainly will be evaluated. Extension of TAVR to these additional populations will clearly require that the durability of catheter valves is similar to those implanted at surgery.

Balloon dilation has been utilized to treat rheumatic mitral stenosis for many years with good results. Multiple efforts are now underway to develop catheter or minimally invasive techniques to treat mitral regurgitation. It is said that over 20 different companies are developing and/or evaluating various technologies, including mitral clip, ventricular reshaping and coronary sinus annular devices, chordal implantation approaches, and a variety of prosthetic valves capable of catheter delivery. A variety of significant challenges exist to the minimally invasive treatment of mitral regurgitation. The mitral annulus is larger than the aortic, does not afford direct access, and is not flat but saddle-shaped, creating a problem for any planar device. Importantly, it remains uncertain if correction of functional mitral regurgitation is beneficial. Nevertheless, based upon history it is likely that ingenuity and innovation is likely to overcome these challenges. Emerging data has recently focused attention upon the prevalence and prognostic significance of tricuspid regurgitation.¹⁴ This recognition has stimulated a variety of catheter-delivered devices and prosthetic valves similar to mitral ones to treat tricuspid regurgitation.¹⁵ Finally, catheter procedures have found an important place in the treatment of prosthetic valve dysfunction. Whether it involves perivalvular leaks or even valve-in-valve implantation for prosthetic deterioration, interventional procedures provide an attractive therapeutic alternative. Catheter treatment of atrioventricular valve regurgitation and prosthetic valve dysfunction is sure to create an expansion for the field of interventional cardiology.

The prevalence of atrial fibrillation is increasing as the population ages. Although anticoagulant therapy has proven effective in reducing systemic emboli associated with atrial fibrillation, bleeding complications are not uncommon and many patients have clear contraindications to anticoagulant therapy. Several approaches to catheter left atrial appendage occlusion have been introduced and been found to provide an attractive alternative to anticoagulation in these patients.¹⁶ As time goes by and experience increases it is possible that appendage occlusion devices may be found to be superior to anticoagulation in patients with a lower risk for bleeding than is currently applied. This catheter therapy for a structural heart type disorder will again extend the role of interventional cardiology.

Renal artery sympathetic denervation as a therapeutic catheter technique for the treatment of hypertension failed to be superior to medical therapy in a sham controlled clinical trial in the past. However, novel technological approaches involving both radio-frequency and ultrasonic ablation of renal sympathetic innervation have now been developed and are in clinical trials for both moderate and resistant hypertension.^17,18 Obviously, the demand for interventional services will increase should these studies yield positive results. Similar studies are underway for pulmonary artery sympathetic denervation in patients with pulmonary hypertension.¹⁹ In this regard, pulmonary artery balloon dilation has been shown to be an effective alternative to surgical thromboenarterectomy in patients with chronic thromboembolic pulmonary hypertension who are not surgical candidates. Thus, new populations with structural disease for whom interventional procedures have not previously been applied are being identified.

The area that is currently most investigational but for which interventional procedures may increase the most in the future is the treatment of heart failure. As more and more patients survive cardiac conditions that would have been fatal in the past, the number who ultimately develop heart failure increases. A variety of innovative procedures for heart failure are in early stages of development and evaluation. Several devices have been developed to achieve left atrial decompression in heart failure patients by creating left atrial to right atrial communications analogous to an interatrial septal defect.^20,21 The concept is that left atrial pressure and pulmonary congestion can be decreased without adversely impacting cardiac output, right ventricular function, or pulmonary artery pressure. Such an approach might be of particular value in patients with heart failure with preserved ejection fraction. Small early studies have been mildly encouraging. A variety of ventricular partition devices have also been created to treat patients with advanced, generally ischemic left ventricular dysfunction. Percutaneous therapy for these patients, who are high risk for cardiac surgery, would be especially valuable. Catheter procedures are also being employed more frequently to insert left ventricular support devices for cardiogenic shock and in guiding alcohol septal ablation for hypertrophic cardiomyopathy. It is almost certain that, as the number of patients afflicted with advanced heart failure increases, innovative catheter therapeutic procedures for such patients will continue to appear.

Inherent in the concept of an impending increase in transcatheter or minimally invasive interventional procedures for structural heart disease is the need for a proportional growth in the entire heart team. More patient candidates and potential procedures for valvular and congenital diseases and heart failure will entail a need for more imagers, anesthesiologists, surgeons, and specialized nurses and technologists. The entire interventional enterprise will be on an augmented trajectory and be part of the pivot that is taking place toward structural heart disease. Just as the interventionalists themselves will require additional specialized training, the same will almost certainly be true for the rest of the team.

Interventional cardiology was born and grew through adolescence to maturity based upon coronary artery procedures. While the role of interventional cardiology in acute coronary syndromes is fully established for nearly all patients and will always exist, transcatheter procedures will likely be more selective in patients with chronic stable angina. A more scientific and quantitative assessment of coronary physiology will be required of interventionalists to select the stable angina patients who are most likely to benefit from PCI. While the number of procedures devoted to coronary disease may plateau, there will be enormous growth in diagnostic and therapeutic approaches for the increasing number of patients with structural heart disease. There is no question in my mind that this pivot to structural disease, while keeping one foot firmly in the coronary space, will lead to an extremely bright future for interventional cardiology.