The Road to Conquering Complexity in CAD Despite the Unknowns

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 - The Diamondback 360
The Diamondback 360 Coronary Orbital Atherectomy System.
Source: Cardiovascular Systems

For physicians who treat patients with coronary artery disease (CAD), the complex has become more and more commonplace. CAD patients with comorbidities, challenging anatomical features and sometimes a combination of the two now have options beyond medical management. But what they often lack is data from randomized, controlled clinical trials, making some treatment decisions a challenge.

No simple definition

Many physicians agree about the basic factors that constitute complexity in patients with CAD. They include comorbidities such as heart failure, high blood pressure, diabetes, chronic kidney disease and obesity that ramp up risk as well as anatomical and physiological features such as multivessel disease, bifurcations, severely calcified lesions and chronic total occlusions (CTOs). Like a Jackson Pollack drip painting, these factors can exist as a fairly straightforward solo splatter on a bare canvas or as a tangle of intermingling conditions and situations piled thickly atop each other. Based on trend lines, interventional cardiologists, cardiothoracic surgeons and other physicians should anticipate more intermingling in coming years.

“There is no question that in North America the prevalence of diabetes, hypertension, hypertriglyceridemia and metabolic syndrome has increased tremendously,” says Roxana Mehran, MD, director of interventional cardiovascular research and clinical trials at Mount Sinai Hospital in New York City. “We are right in the middle of an epidemic of high burden of atherosclerotic disease.”

According to the Centers for Disease Control and Prevention (CDC), the prevalence of coronary heart disease has edged down slightly in the U.S. but still remains high at 6 percent. At the same time, the number of adults in the U.S. with diagnosed diabetes tripled between 1980 and 2011, from 5.5 million to 19.5 million. Almost 17 percent of children and 35 percent of adults were obese in 2012. While overall prevalence has remained mostly stable since 2003, the morbidly obese posted steep gains through 2010.  

Complexity doesn’t end with comorbidities and vessels. Age, left ventricular function, valvular disease and severity of disease can come into play as well. “When I think of a com plex patient, I think of someone with many comorbidities who is on multiple medications that would require many different specialists in consultation while he or she is in house recovering from any procedure,” says Terry Shih, MD, a surgeon at the University of Michigan in Ann Arbor. “I also think of patients who have extreme severity of disease, those patients who go into severe heart failure after a heart attack, who have to be on a balloon pump or need a lot of intensive care even before moving toward CABG.”

Changes in clinical practice also can contribute to the growing pool of complex patients. When the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) found no benefit to PCI in addition to medical management in patients with stable CAD, some cardiologists began to defer elective PCIs and CABGs, notes Ajay Kirtane, MD, SM, director of the cardiac catheterization laboratories at NewYork-Presbyterian Hospital/Columbia University Medical Center in New York City. One analysis of practices before and after COURAGE found a steep drop in PCIs in patients with stable angina and 16 percent decline in the overall use of PCIs (Circ Cardiovasc Qual Outcomes 2011; 4[3]:300-305).

“What this means is that we typically are seeing patients with more advanced stages at their presentation,” Kirtane says. “In our experience at a tertiary center where we get lots of referrals, the complexity has definitely increased, which is probably a good thing as long as you are not underdiagnosing. If you are not underdiagnosing, the patients you can help most are those who are more complex as opposed to those with single-vessel disease, who might be fine with medical therapy.”

Excluded but in need

How to optimally treat complex patients sometimes boils down to clinical judgment rather than top-notch evidence, though. Complex patients often are not invited to the party when recruiters seek out patients for randomized clinical trials. By design, some trials exclude complex patients for ethical reasons or to ensure feasibility. Other trials may include patients with comorbidities or other factors that make them more complex but in too few numbers to be statistically significant.

Researchers can turn to registry data that captures what happens to a spectrum of patients in clinical practice, but the studies are observational and vulnerable to biases. They can pool data from various studies and do propensity matching to evaluate an underrepresented patient population but even with standardized methodologies and definitions, “it still is not the same as having 10,000 complex patients randomized to X vs. Y,” Mehran says. “This is the best we can do.”

While not the gold standard, these kinds of analyses can inform cardiologists in their day-to-day practice when faced with a complex patient. Almost one quarter of the adults in the U.S. with a diagnosis of diabetes in 2012 also had coronary heart disease, by the CDC’s count. Compared with patients without diabetes, they are more likely to die of cardiovascular disease and more likely to be hospitalized for an MI or stroke.

Diabetes in and of itself doesn’t mean anatomic complexity, Kirtane points out. “Picture in your mind the typical, poorly treated diabetic,” he says. “Those patients often are complex with multivessel disease.”

Kirtane, Mehran and other researchers plumbed data from the ACUITY study (Acute Catheterization and Early Intervention Triage Strategy) in an effort to determine the best revascularization approach for patients with non-ST-segment elevation acute coronary syndrome and diabetes mellitus (Circ Cardiovasc Interv online June 8, 2015). The almost 1,772 patients they assessed had diabetes and multivessel disease that involved the left anterior descending artery, a group often excluded in randomized trials. They found comparable MI and death rates for patients treated with PCI or CABG at 30 days and one year.

Kirtane underscores the limitations, including treatment choice being at the physician’s discretion, but he calls the findings reassuring. “What the study does show is that among patients who physicians select appropriately, these therapies are associated with pretty good outcomes, especially the hard clinical outcomes at 30 days and a year.” 

Mehran and colleagues tapped ACUITY and 17 other databases from randomized trials maintained at the Cardiovascular Research Foundation, where Mehran is the chief scientific officer of its clinical trials center (J Am Coll Cardiol 2014;63:2111-2118). Their goal was to assess lesion complexity and outcomes in patients with diabetes implanted with drug-eluting stents, using the American College of Cardiology and American Heart Association classification for lesion severity. Almost 19 percent of the 18,441 patients in the pooled data had diabetes.

Diabetes was an independent predictor of revascularization, cardiac death and MI at one year. But the burden rested most heavily on the sickest. The target lesion revascularization rate for patients with diabetes and complex lesions reached 8 percent while the rate for patients with no diabetes and complex lesions and both diabetic and nondiabetic patients with simple lesions hovered between 4.8 percent and 4.5 percent. The group with diabetes and complex lesions also posted the highest target vessel revascularization rate.

Extremes in obesity

Obesity offers another conundrum for cardiologists. Obesity is an independent risk factor for coronary heart disease and is associated with advanced atherosclerosis (Circulation 2006;113:898-918). Childhood obesity has been on an upward slope, paving the way for atherosclerosis earlier in life. Among adults, extreme obesity has been outpacing other categories. Moderate obesity may have stabilized or reached a plateau, according to one study (Int J Obese 2013;37[6]:889-891). But severe and morbid obesity, defined as a body mass index (BMI) of 40 and 50 and above, posted increases of 100 percent and 120 percent, respectively, between 2000 and 2010.

Patients who undergo PCIs are not only getting bigger, but the biggest present at a younger age, according to Michael E. Buschur, MD, an interventional cardiologist at Mount Carmel Columbus Cardiology Consultants in Columbus, Ohio. “We are catching disease in patients who obviously have other comorbidities but are getting younger as well,” he says. “Not only does it make the procedure itself more complicated and have higher risk for the patient, but then it makes managing the patient and following the patient chronically more challenging because we need to impress upon the patient the lifestyle changes he or she needs to do.”

Buschur and colleagues used a consortium-based registry in Michigan to review data on 277,044 PCIs performed in the state between 1998 and 2009 (J Am Coll Cardiol 2013;62:685-691). They categorized patients by BMI, from lean to morbidly obese, which they defined as a BMI of 40 and higher. The percentage of morbidly obese patients increased over the decade, from 4.4 percent to 8.4 percent. The proportion of submorbidly obese (BMI of 30 to less than 40) also ticked up, from 33.6 percent to 38 percent.

Overall, 7.4 percent of the patients were morbidly obese with a mean age of 59.2 years. In contrast, overweight patients (a BMI of 25 to less than 30) had a mean age of 64.9 years. The morbidly obese were less likely to be smokers but were more likely to have diabetes and hypertension. Despite being younger, the morbidly obese had an increased risk of death as well as an increased risk for contrast-induced nephropathy, nephropathy requiring dialysis and vascular complications.

“There are aspects that make them more challenging,” Buschur adds. For instance, total contrast volume was highest in the morbidly obese group, which may have contributed to the higher incidence rates for nephropathy. Vascular closure can be difficult with femoral access if girth is an impediment. Preprocedural planning and awareness may help operators reduce these risks. 

“Looking at radial access as opposed to femoral access is potential way to reduce vascular complications,” Buschur suggests. “A lot of times it is being aware of the contrast dose and radiation you are using because we do quickly use more contrast and radiation on these patients.”

Advancements in technology may help, at least in the right hands. A high-efficiency SPECT system using multiple pinhole collimation with cadmium-zinc-telluride semiconductor detectors has shown promise, even in the extremely obese (J Nucl Cardiol 2015;22[2]:266-257). A study that included 60 patients who were morbidly obese achieved high imaging quality in all obesity groups, but the researchers cautioned that the interpreters used quantitative and visual assessments and were experienced with the system. Still, they proposed that centers that stick to a quantitative assessment could achieve success with this approach.

Tackling calcification

Improvements in stents, atherectomy and ablative devices, wires and other technologies have opened doors for challenging cases such as bifurcations, CTOs and severely calcified lesions. “There is no question that those types of patients are more and more being referred to interventional practices,” Mehran notes.

One reason may be a greater understanding of the pervasiveness and consequences of these conditions. Mehran and colleagues combined data from COURAGE and HORIZON-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) for insights on another group often excluded in PCI trials: those with severely calcified lesions (J Am Coll Cardiol 2014;63:1845-1854). Of the 6,855 patients with acute coronary syndrome assessed in the analysis, 5.9 percent had severely calcified lesions and 26.1 percent had moderate calcification. Patients with severe or moderate calcification had significantly higher rates of death, definite stent thrombosis, target lesion revascularization and major cardiovascular adverse events (MACE) at one year than those with no or mild calcification.

“Arterial calcium is increasing,” says Jeffrey W. Chambers, MD, director of the cardiac catheterization laboratory at Mercy Hospital in Minneapolis. “Our population is aging, which is one of the risk factors. Diabetes is epidemic right now and that leads to renal failure,” which may contribute to calcification. “That is an expanding problem and it has been difficult to treat.”

Chambers was part of a research team to evaluate outcomes with the Diamondback 360 Coronary Orbital Atherectomy System (Cardiovascular Systems) as a treatment for severely calcified lesions. The device received FDA approval for coronary arteries in 2013. At two years, the 443 patients in the pivotal ORBIT II trial (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions) had a cardiac death rate of 4.3 percent, a target lesion/target vessel revascularization rate of 8.1 percent and a MACE rate of 19.4 percent. In diabetic patients, the rates were 5.3 percent, 8.7 percent and 20.6 percent, respectively.

ORBIT II, which was funded by Cardiovascular Systems, required that the length of calcium equal or exceed 15 mm and with calcium present in at least 270 degrees of a cross-section as assessed by intravascular ultrasound. The FDA had asked for the definition, Chambers says, which is more stringent than cutoffs used in some other studies. “They wanted to know we were treating the really severe,” he says.

In a cost-effectiveness analysis that used ACUITY and HORIZON-AMI data as a comparator, Orbital treatment totaled $11,895 per life-year gained, which generally is considered a reasonable value. Chambers presented the two-year and economic results at the 2015 Society of Cardiovascular Angiography and Interventions conference.

Critics may argue that as a single-arm, nonrandomized trial, ORBIT II falls short of the gold standard. “The acute and long-term outcomes were better than anything we could find with apples-to-apples historic controls and durable, long-term results,” Chambers counters. “In my mind, we have changed the outcomes but that ultimately will have to be tested in head-to-head trials. … This has refocused attention on calcium and I think it is helping patients, which at the end of the day is what it is all about.”

Progress with CTOs

Complexity applies not only to the patient but also to skills of the physicians and institutes involved in a procedure, Kirtane adds. “If you ask an interventionalist or a surgeon if he or she treats complex patients, everybody says yes, but the complex for one might be routine for somebody else. Similarly, what is complex for the most experienced operators might be unapproachable for many other operators.”

Bradley M. Strauss, MD, PhD, of the Schulich Heart Center at the Sunnybrook Health Sciences Centre in Toronto, agrees that in the context of CTOs, the most challenging cases should be performed by an elite subset of experienced cardiologists for optimal outcomes. But given the prevalence of CTOs, training another tier of cardiologists to handle less complex cases may benefit patients and the healthcare system, he argues.

Using registry data, Strauss and colleagues calculated that 18.4 percent of patients with CAD who were referred for coronary angiography had CTOs (J Am Coll Cardiol 2012;59:991-997). About a quarter of those patients underwent CABG and attempts to treat the CTO artery by PCI occurred in only 10 percent of the CTO patients.

“We have kind of ignored these lesions even though they are very common,” Strauss says. “We just write them off as being the same as other stable but nonoccluded blockages.”

Some cardiologists may be skeptical or ambivalent about the benefit of revascularizing CTOs without results from randomized trials. In a review of the existing data, Strauss and his colleagues pointed to recent evidence showing that many CTOs are ischemic, with revascularization alleviating symptoms such as angina and improving quality of life (J Am Coll Cardiol 2014;64:1281-1289). Learning curve issues may have influenced early results as well.

“Techniques are improving and operators are improving, so I think we are getting closer to the day when we can reliably open these chronic total occlusions and see whether there are definite clinical advantages to doing it,” he says.

Several randomized trials now are in progress. In the meantime, Strauss and other cardiologists are exploring another option to assist operators as they navigate CTOs. They completed a safety study of a formulation designed to degrade collagen in CTOs and make guide wire crossing easier in PCIs (Circulation 2012;125:522-528). Matrizyme Pharma, which Strauss founded, manufactured the formulation. 

The need to treat the growing number of complex patients facilitated by progress in techniques and technologies has another lasting legacy for cardiology community, according to Mehran. Patients with complex disease benefit from a heart team approach, she says. “Previously, everyone worked in their own silo and now there is so much more of an interdisciplinary approach of treating and finding strategies to treat complex patients and complex patients with complex disease,” she says. “That is a huge stride forward.”

Payment Schemes: What Bundling Misses

The shift in healthcare from volume to value may prove to be a two-edged sword for hospitals that treat complex patients. Reimbursement systems such as bundled payments that are designed to reward a continuum of care nudge physicians into working as teams in a collaborative effort to achieve optimal outcomes at the lowest cost. But those reforms may not adequately account for complexity.

“When you think about bundled payments in general, they are meant to streamline some of the costs of what we think of as commodity services, what physicians do routinely,” says Brahmajee K. Nallamothu, MD, MPH, an interventional cardiologist at the University of Michigan’s cardiovascular center in Ann Arbor and a researcher in the Center for Healthcare Outcomes and Policy (CHOP). PCI and CABG stand out as likely candidates. “The challenges are: when does PCI or CABG go from being a commodity to a high-end service? Because there are some types of patient factors or anatomic factors that suddenly change everything.”

In a review of the advantages and disadvantages of bundled payments for cardiac care, Nallamothu and CHOP colleague Terry Shih, MD, placed bundled payments at the midpoint between fee-for-service and global payment reimbursement models (Circulation 2015;2151-2158). Theoretically, bundled payments for complex patients should lead to more integrated care and more efficient use of resources.

“If you tell a hospital system that we will give you only so much money to take care of this patient’s problems or this episode of care, then all the different teams are forced to work together to figure out what is the most appropriate plan,” Shih says. “In our current and more traditional system, everybody is ordering different tests and different care. We are paid for all these different things but no one is talking to one another.”  

Complexity likely adds to near-term costs, though. The price of a device to treat severely calcified lesions for PCIs reached almost $3,795 in one analysis. Treating a chronic total occlusion requires additional wires and more time in the catheterization lab. Patients with comorbidities need multiple specialists consulting to ensure they coordinate care.

Bundled payments also potentially could have unintended consequences. They might compel hospitals to cherry-pick patients, selecting only cases that are straightforward and low cost. Hospitals might try to game the system by upcoding or delay coding for postprocedural complications until the bundling period expires.

Results from the Geisinger Health’s ProvenCare bundled payment demonstration for elective CABG procedures underscore another challenges. The program led to a 5 percent reduction in hospital charges and raised adherence to best-practice measures from 59 percent to 100 percent. But over one year, only 117 patients received elective CABGs while 290 nonelective CABGs were excluded.

“Less than half the patients who underwent CABG were not able to participate in the plan because they were just different; they were more complex,” Nallamothu says.

Bundled payments potentially can be modified to account for severity of disease, multiple comorbidities and other factors, they agree. The process of identifying subgroups and assigning supplemental payments for them may be difficult, but worth the effort over the long term.

“Oftentimes it is the complex patients who are the ones who have the greatest health benefits from some of these procedures,” Nallamothu says.