The Future of Cardiovascular Medicine: Big Data
Now, if it could just get more meaningful
(We’ll help with some of the meanings)

The term “big data” refers to volume, volume, and more volume. Even turning it up to an 11 isn’t enough. It is measured not in bytes or kilobytes, but rather megabytes, gigabytes (GB), terabytes (TB), petabytes (PB), exabytes (which equals 109 GB), and zettabytes. A zettabyte can also be expressed as 1021 or 1 sextillion bytes. One zettabyte is approximately equal to a thousand exabytes or a billion TBs. (There is something beyond zettabytes: yottabytes. After a Star Wars character, it is named.) Yottabytes are more theoretical than actual: it is one septillion bytes, but to save all those bytes you would need a data center as big as the states of Delaware and Rhode Island—and need $100 trillion to pay for it.

How to put this in perspective? Well, James E. Tcheng, MD, FACC, a professor at Duke University, Durham, NC, notes that with the conversion to electronic health records (EHRs), a typical tertiary care hospital generates about 100 TBs of data per year. By comparison, he said, the Library of Congress is estimated to contain only about 10 TB of text data. That’s right: “Your health care institutions each generate more data per month than the entire Library of Congress,” he said.

Oh, and to get the idea of a petabyte in mind, Google processes 24 PB of data per day (including our search to figure out how to explain all of this to you).

Health Hyperefficiency (But Still Falling Short)

It’s been called health hyperefficiency: Innovations in computers, software, and mobile technology are helping to make health and medical care more efficient, safe, and effective for all patients. Moreover, big data and powerful computers will help facilitate cost-effective clinical trials. In some cases, patients soon will use social media to find one another, prep for trial participation, and maybe even recruit scientists to conduct the research. Caveat: As more data are collected, hard questions are arising regarding the ethics and privacy of these new tools.

Still, Dr. Tcheng said, “We are falling short of achieving meaningful use of health information technology. During a presentation on big data at ACC.15, he said, “We are focused on administrative click-off boxes, but data is now being used to help identify which patients we need to engage, and this is a paradigm shift. I think big data will become a big part of what cardiovascular care will look like in the future.”

What’s needed so we stop falling well short of achieving “meaningful” use of big data in health care? Currently, he said, EHR certification demands are stifling innovation. He said we must move from closed systems to open software architectures that enable big data analytics—not just “document transport.”

Dr. Tcheng added, “Big data is really a vision of an interoperable health data infrastructure, and it will be a big driver in the future for research and how we provide care in the future.”

As we noted just last month in ACCEL, by now, everyone in medicine is familiar with the concept of big data, where important knowledge can be gleaned from an analysis of the clinical experience of millions of patients. Then there is the explosion of molecular data, where one report by Ashley et al. presented the results of a single patient and an analysis of 2.6 million single nucleotide polymorphisms.¹ This suggests large—even humongous —untapped opportunities to use data to improve health outcomes.

In discussing his ACC presentation—“So, Just What is “Big Data?”—Dr. Tcheng recently said in a communication from the Duke Clinical Research Institute: “Cardiology is perhaps the most data-rich environment in all of medicine. A prerequisite of good big data is good data inputs. Since cardiology has both the opportunity for good data and has a diverse and deep basis of science driving guidelines, best practices, and health policies, cardiology is poised to take advantage of what big data can provide. Big data can take us well beyond our classical constructs of medicine by incorporating patient-reported information, genomics, and social media-derived data, into creating a more accurate and composite picture of both individual patients and populations of patients.”

Tweet That/Analyze This

Even social media may be a rich source of data for analysis. Dr. Tcheng used this example from 2015.

Hostility and chronic stress are known risk factors for heart disease, but are costly to assess on a large scale. Investigators used language expressed on Twitter to characterize community-level psychological correlates of age-adjusted mortality from atherosclerotic heart disease. They started with 826 million Tweets, 146 million of which were geo-located across 1,300 U.S. counties. Language patterns reflecting negative social relationships, disengagement, and negative emotions—especially anger—emerged as risk factors for CHD; positive emotions and psychological engagement emerged as protective factors.

That’s not surprising, of course, but this was: a cross-sectional regression model based only on Twitter language predicted heart disease mortality significantly better than did a model of 10 classic demographic, socioeconomic, and health risk factors, including smoking, diabetes, hypertension, and obesity. The authors concluded that capturing community psychological characteristics through social media is feasible, and these characteristics are strong markers of cardiovascular mortality at the community level.

Big Data Begins at Home

Bringing the topic down to a more personal level, in the September 15 issue of JACC,³ Richard J. Kovacs, FACC, clinical director of the Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, noted what the Institute of Medicine calls the virtuous cycle of an evidence-based practice that in turn generates practice-based evidence of patient outcomes. He noted that clinicians need more opportunities to look at their own practice-based evidence, reflect on the evidence, and improve care. “This is the essence of the learning health care system,” wrote Dr. Kovacs. “Electronic medical records and other sources of ‘big data’ now allow for the analysis of such practice-level data, including outcomes of patients treated according to different pathways.”

Data, like that collected by the ACC’s PINNACLE Registry®, hold promise to not only confirm guideline adherence in real-world care, but also identify gaps in care and generate new hypotheses for testing in randomized trials. The sheer volume of practice-based evidence that can be accumulated automatically should allow for a rapid cycle of improvement in care and the acquisition of new knowledge. Dr. Kovacs believes the practice of medicine and the pursuit of new knowledge will merge in ways not possible prior to EHRs and big data.

He was specifically responding to a paper by Ogedegbe et al.,⁴ who conducted an analysis of real-world clinical data on the treatment of hypertensive black patients served by New York City’s Health and Hospital Corporation. More than 43,000 patient records were analyzed to answer a crucial question: Did black hypertensive patients receiving angiotensin-converting enzyme (ACE) inhibitors in this health care system fare worse than white hypertensive patients receiving ACE inhibitors?

They determined that ACE inhibitor use in blacks was associated with poorer outcomes: more strokes, MIs, and HF. Dr. Kovacs noted that comparing the effectiveness and safety of antihypertensive drugs in real-world practice empowers a large system of care to make changes that will prevent adverse events, adding, “The opportunity to improve outcomes is staggering.”

References

1. Ashley EA, Butte AJ, Wheeler MT, et al. Lancet. 2010;375:1525-35.
2. Eichstaedt JC, Schwartz HA, Kern ML, et al. Psychol Sci. 2015;26:159-69.
3. Kovacs RJ. U. J Am Coll Cardiol. 2015;66(11):1234-5.
4. Ogedegbe G, Shah NR, Philips C, et al. J Am Coll Cardiol. 2015;66:1224-33.

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A BRIDGE Too Far?
What to do when indications for anticoagulation interruption are unclear

More than 35 million prescriptions for oral anticoagulation (OAC) are written each year in the United States for a variety of conditions, including atrial fibrillation, mechanical heart valves, venous or arterial thromboembolism (TE), and ventricular assist devices. In any given year, 15% to 20% of these patients will undergo an invasive procedure or surgery that interrupts their chronic OAC, putting them at increased risk for TE, hemorrhage, and death.

What to do is not entirely clear. Current guidelines recommend anticoagulant prophylaxis in all but the lowest risk AF patients. Until recently, VKAs, such as warfarin, were the only option for stroke prevention in such patients. Now, the situation has changed abruptly with the introduction of several non-VKA OACs (NOACs), which target thrombin or factor Xa.

With a more predictable anticoagulant response and shorter half-lives (range: 8 to 17 hours) than warfarin (mean: ~40 hours), NOACs have the potential to streamline peri-procedural management in AF patients undergoing surgical procedures. However, data with NOACs are limited, and at times contradictory, which complicates their integration into routine practice.

In advising the surgeon who is going to do a nonurgent procedure, it is first necessary to determine the bleeding risk of the planned procedure (TABLE). If bleeding risk is low, there may be no need to stop anticoagulant therapy. As risk of bleeding increases, there is a need to determine what is best for the patient.

These agents also have different degrees of renal excretion; the one with the greatest renal clearance is dabigatran, meaning it may be important to know whether a patient taking dabigatran has chronic kidney disease; the poorer the creatinine clearance the longer the half-life, meaning the longer you may have to delay the surgery. Of the new Factor Xa inhibitors, like rivaroxaban and apixaban, only a small portion is renally cleared.

Expert Recommendations

The management of anticoagulation has become a “team sport” involving multiple specialties in multiple sites of care. The ACC, through the College’s Anticoagulation Initiative, recently published the results of a roundtable of experts from multiple specialties who were brought together to discuss topics important to the management of patients requiring anticoagulation and to make expert recommendations on issues such as the initiation and interruption of anticoagulation.

The document was published as a State-of-the-Art review in the April 7, 2015, issue of JACC.¹ The authors note that bridging with a parenteral agent (e.g., unfractionated heparin or low-molecular-weight heparin) is common, but the data on prevention of embolic events are limited, and the rate of bleeding is significantly increased. Thus, the decision to bridge must balance the risk of an embolic event against the risk of bleeding.

But that’s about all the authors wrote on this specific topic. More recent advice comes from the September 22, 2015, issue of JACC, in which Stephen J. Rechenmacher, MD, and James C. Fang, MD, FACC, presented a review on the topic.² They noted that the evidence to inform decision making is limited, “making current guidelines equivocal and imprecise.” Moreover, they wrote, indications for anticoagulation interruption may be unclear.

Recent observational studies and one large randomized trial3 have noted significant perioperative or peri-procedural bleeding rates without reduction in TE when bridging is employed. Such bleeding may also increase morbidity and mortality. In light of these findings, Rechenmacher and Fang noted that “physician preferences for routine bridging anticoagulation during chronic anticoagulation interruptions may be too aggressive.”

Areas of Agreement

Current guidelines from the ACC, AHA, Heart Rhythm Society, and American College of Chest Physicians have yet to incorporate the findings of this trial and remain based upon observational studies and expert opinion. Yet, Rechenmacher and Fang note that the guidelines do largely agree upon three important principles:

OAC should not be interrupted for procedures with low bleeding risk.

Patients at highest risk for TE without excessive bleeding risk should consider bridging. Conversely, those at low risk for TE should not be bridged.

Intermediate-risk cases should be managed by individually considering patient- and procedure-specific risks for bleeding and TE.

Patients at low risk for TE should not create a clinical dilemma. Yet, they note, physician surveys of peri-procedural bridging preferences demonstrate that approximately 30% of physicians choose to bridge patients at low risk for TE due to overestimation of thrombosis risk. There is even greater heterogeneity of practice in those patients with intermediate or unclear risks of bleeding or TE.

Current evidence, including the recently reported (August 2015) BRIDGE trial (Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery),³ suggests that peri-procedural bleeding rates are significantly higher than thrombosis rates in this group.

Although bridging anticoagulation may be necessary for those patients at highest risk for TE, for most patients it produces excessive bleeding, longer length of hospital stay, and other significant morbidities, while providing no clear prevention of TE. Unfortunately, contemporary clinical practice, as noted in physician surveys, continues to favor interruption of OAC and the use of bridging anticoagulation. While awaiting the results of additional randomized trials, Rechenmacher and Fang suggest that physicians carefully reconsider the practice of routine bridging and whether peri-procedural anticoagulation interruption is even necessary.

Patients should be educated, too, about the importance of continuing their therapy. Some dentists will advise patients to stop anticoagulant therapy prior to simple dental procedures. This can be a dangerous practice and patients should be told to alert their physician whenever they are told to stop therapy so that a discussion can help determine whether or not this is appropriate.

Jeffrey I. Weitz, MD, FACC, a professor of medicine and biochemistry at McMaster University Ontario, Canada, who now focuses his clinical work in the area of thrombosis, recently wrote about the topic in patients undergoing AF ablation.⁴ Overall, he thinks peri-procedural management of NOACs is straightforward and simpler than that required for warfarin. He agrees: many patients do not need to discontinue NOACs.

He also recommends an internet site that can help clinical decision-making: Thrombosis Canada™. The organization is a registered non-profit organization with no commercial interests. The site includes a downloadable app that can be used to estimate the risk level of an individual patient about to undergo a specific procedure. There is also information relating on whether it is necessary to stop NOAC therapy and, if so, when and how to re-initiate therapy.

References:  

1. Kovacs RJ, Flaker GC, Saxonhouse SJ, et al. J Am Coll Cardiol. 2015;65:1340-60.
2. Rechenmacher SJ, Fang JC. J Am Coll Cardiol. 2015;66:1392-403.
3. Douketis JD, Spyropoulos AC, Kaatz S, et al. N Engl J Med. 2015;373:823-33.
4. Weitz JI, Healey JS, Skanes AC, et al. Circulation. 2014;129:1688-94.

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Beware of Stable Angina and No Obstructive CAD
Out of sight but certainly not out of mind

Non-obstructive coronary disease is more common than once appreciated, although the prevalence has varied across studies.

1. In the Coronary Artery Surgery Study Registry of 25,000 subjects undergoing angiography for angina, 39% of women and 11% of men had normal coronaries.¹
2. NCDR (National Cardiovascular Data Registry) identified 51% of women and 32% of men with stable angina who had nonobstructive disease on angiography.²
3. Similarly, 20% of women and 10% of men presenting for ACS in the NCDR had nonobstructive disease.³
4. An analysis of ACS trials revealed that, on average, 23% of women and 13% of men had nonobstructive CAD.⁴
5. There is also plenty of evidence indicating ethnic differences in the prevalence of nonobstructive CAD.²

What are we specifically talking about? Karin Humphries, MBA, DSc, is an associate professor of medicine at the University of British Columbia and scientific director for the Centre for Improved Cardiovascular Health there. She noted the current definitions of nonobstructive CAD:

1. Angina suggestive of ischemic disease, with or without evidence of myocardial ischemia; and
2. Coronary angiography that identifies either:
   • Normal or near normal (diffuse vessel irregularities or discrete mild stenosis < 20% in all epicardial vessels
   • Nonobstructive coronary disease based on < 50% stenosis in all epicardial vessels.

Nonobstructive disease would seemingly bode well for the patient. In fact, until recently, the prognosis was thought to be benign and many of these patients were offered little more than reassurance that they do not have serious heart disease.

Not a Good Sign

However, nonobstructive CAD really is not benign. As one paper recently noted, stable angina pectoris with no obstructive CAD is associated with increased risks of major adverse cardiac events (MACE).⁴ Specifically, in a pooled analysis of 11,223 patients, the risk of MACE increased with increasing degrees of CAD, with multivariable-adjusted hazard ratios (HRs) of 1.52 (95% CI: 1.27 to 1.83) for patients with normal coronary arteries and 1.85 (95% CI: 1.51 to 2.28) for patients with diffuse nonobstructive CAD compared with a 6,233 people in a reference population. (The asymptomatic reference population was comprised of individuals in the fourth Copenhagen City Heart Study.) For all-cause mortality, normal coronary arteries and diffuse nonobstructive CAD were associated with HRs of 1.29 (95% CI: 1.07 to 1.56) and 1.52 (95% CI: 1.24 to 1.88), respectively.

Dr. Humphries and her colleagues looked specifically at sex-based differences in a retrospective cohort study using prospectively collected angiographic and clinical data on all patients in British Columbia, presenting for their first cardiac catheterization with suspected ischemic heart disease but angiographically normal coronaries. Among 32,856 patients, 7.1% of men versus 23.3% of women were angiographically normal (p < 0.001). Among angiographically normal patients, women were older and more likely to present with hypertension, prior stroke, chronic obstructive pulmonary disease, and peripheral vascular disease than men, but Canadian Cardiovascular Society class of angina did not vary by sex.

Within 1 year, 1.0% died, (19 women, 18 men; p = 0.27) and 0.6% had a stroke (13 women, nine men; p = 0.91), which is reassuring. However, readmission to hospital for ACS or chest pain requiring catheterization was significantly higher in women compared to men (adjusted odds ratio: 4.06; 95% CI: 1.15 to 14.31). So, in this population-based cohort presenting for cardiac catheterization for ACS or stable angina, women were three times more likely to show angiographically normal arteries compared to men and, among patients with angiographically normal coronaries, women were more than four times more likely to be readmitted for ACS or chest pain with repeat cardiac catheterization.

More recently, Humphries and her team studied all patients ≥ 20 years with stable angina, undergoing coronary angiography in British Columbia from July 1999, to December 2002 (n = 13,695) with maximum follow-up to 3 years. No CAD, nonobstructive CAD, and obstructive CAD were defined as 0%, 1% to 49%, and ≥ 50% luminal narrowing in any epicardial coronary artery, respectively.

Freedom from MACE (the combined endpoints of all-cause mortality, nonfatal acute MI, nonfatal stroke, and HF admissions) was estimated. Within the first year, women with nonobstructive CAD had a higher risk of MACE than men with nonobstructive CAD (Table) and these women had a higher risk of MACE than women with no CAD (95% CI: 1.33 to 4.88). In contrast, men with nonobstructive CAD had a similar risk as men with no CAD (adjusted HR: 0.61; 95% CI: 0.26 to 1.45).

At ACC.15, investigators with the WISE (Women’s Ischemia Syndrome Evaluation) study, who were among the first to report this problem, women with signs and symptoms of ischemia and no obstructive CAD had a 5.8% prevalence of myocardial scar detected by cardiac magnetic resonance imaging. This suggests that these women can develop irreversible myocardial injury, which may be clinically underdiagnosed.

In another WISE analysis, investigators found that anti-anginal therapy does improve quality-of-life measures, although a majority of women continued to have angina.

In looking at independent predictors of adverse outcome, Dr. Humphries saw only two when assessing patients with normal or near normal angiography results (diffuse vessel irregularities or discrete mild stenosis < 20% in all epicardial vessels). Only female sex and prior MI predicted adverse outcomes. In looking across a variety of studies, with a less restrictive definition of nonobstructive disease (up to 50% stenosis), Dr. Humphries reported a number of independent predictors of adverse outcomes:

• female sex;
• cardiovascular risk factors (diabetes, smoking);
• persistent chest pain (WISE);
• low coronary blood flow (coronary flow reserve, TIMI frame counts);
• acute presentation; and
• extent of plaque/plaque burden.

Clearly, there is a need for research on the value of further risk stratification and better treatment strategies for patients with stable chest pain associated with no obstructive CAD.

References:

1. Kemp HG, Kronmal RA, Vlietstra RE, et al. J Am Coll Cardiol. 1986;7:479-83.
2. Shaw LJ, Shaw RE, Merz CN, et al. Circulation. 2008;117:1787-801.
3. Anderson RD, Pepine CJ. Circulation. 2007;115:823-26.
4. Jespersen L, Hvelplund A, Abildstrøm SZ, et al. Eur Heart J. 2012;33:734-44,
5. Humphries KH, Pu A, Gao M, Carere RG, et al. Heart J. 2008;155:375-81.
6. Sedlak TL, Lee M, Izadnegahdar M, et al. Am Heart J. 2013;166:38-44.

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Academic Medical Centers:
The Future of Cardiovascular Medicine

Academic medical centers (AMCs) graduate nearly 17,000 MDs every year, provide more than 40% of charity care, and account for 20% of all hospital admissions, surgical operations, and outpatient visits.¹

Given the dramatic changes in the U.S. health care system, the outlook for AMCs is unclear. They could be well-positioned for the future—or not so much. According to Marvin A. Konstam, MD, FACC, a professor and chief physician executive for the CardioVascular Center at Tufts University School of Medicine in Boston, MA, the pro and con arguments look like this:

PROS: AMCs are well-positioned:

• They already have greater physician-hospital integration.
• Often they have high stature in the community.
• Their training programs provide a natural pipeline of community relationships.
• Academic leadership provides early access to new drugs and technologies.

CONS: AMCs are poorly positioned:

• Academic departments are barriers to programmatic structure.
• Medical schools may hamper the AMC’s competitiveness.
• A town-gown mentality may impair community relationships.
• Academic culture and processes may impair right-minded leadership and personnel decision making.

“What we have to do,” said Dr. Konstam, “is leverage our strengths and fix our problems.”

The survival of AMCs is threatened by a combination of economic, cultural, and demographic factors that are part and parcel to the most dramatic reordering ever of the nation’s health care system. Historically, academic medical centers have been bound by a “social contract” to provide excellent medical care, advance new knowledge, and train future physicians on behalf of society. However, this has become economically difficult to sustain, with repeated reductions in government funding.

Back in 2009, Arthur M. Feldman, MD, PhD, FACC, executive dean of Temple University School of Medicine, Philadelphia, PA, published Pursuing Excellence in Healthcare: Preserving America’s Academic Medical Centers. In that book, Dr. Feldman noted, “If AMCs are to survive, they must adopt a new philosophy, challenging assumptions and providing the shift in perspectives that a resolution of this crisis requires.”

The fundamental message of the book, he said, “is that by pursuing excellence, we can preserve America’s academic medical centers and see to it that Americans of all ethnic, racial, and socioeconomic backgrounds will be able to count on AMCs to provide them with the best possible care.”

Challenges Abound

There are a number of critical needs for AMCs. Like every other medical center, they need to augment revenues, increase market share, and respond to increasing competition from nontraditional health care practitioners and sources of education and research. In terms of innovation, they need more inventive products, care processes, personalized health management systems, and population management covering both the indigent and what is referred to as “the paying sophisticated.”

At ACC.15, Dr. Konstam discussed efficient, cost-effective, coordinated cardiovascular care in the academic setting. In short, he said each AMC will need to reinvent itself in order to survive and thrive and carry on its academic mission. That is, providing clinical care that makes sense.

It’s a difficult time. Funding sources are changing, research costs continue to rise faster than sources of funding, and AMCs are perceived to be “high-cost” providers in an accountable care environment focused on lowering costs.² Cuts in research support has been accompanied by decreased funding for graduate medical education, both having an outsized impact on AMCs.

Additionally, up to 10% of traditional AMC revenue could be at risk due to external funding threats. With slim operating margins that average approximately 5%, many AMC profit margins could disappear.²

At the same time, AMCs are facing the same challenges as the medical community in general. As the prevalence of CVD continues to grow, there have been double-digit decreases in hospitalization rates in recent years for cardiology in general and interventional cardiology in particular. Said Dr. Konstam, “Right in front of our eyes, we’re seeing the beginning of what may well be a continuous decline in inpatient utilization.”

It’s being driven, mechanistically, by a number of things, one of which is the shift from inpatient care to observational care. Payers are not accepting that many of the patients being seen for a short period of time are truly inpatients, so they are coding them as observational and paying one tenth or less of the reimbursement. At his own center, Dr. Konstam noted that from fiscal year 2011, to fiscal year 2014, the number of observational cases rose by about 50%, representing a large shift from inpatient to observational care (and greatly diminished reimbursement). “We are going to have to reinvent ourselves,” he said, and that includes restructuring the academic medical center.

It will require an effort to integrate and align incentives, including compensation, across CV disciplines and between hospital and physician organizations. It will be necessary to “measure, measure, measure everything we can think of that’s important,” he said and incentivize, particularly those things deemed important. And, on both an enterprise-wide and program-specific basis, those things will drive financial performance, quality, and patient satisfaction. All the while, making efforts to preserve the academic mission.

Also, Dr. Konstam said, prepare for a shift to population management, with system integration and alignment in order to deliver truly cost effective care.

Even with all these changes, will AMCs survive? Dr. Feldman remains optimistic. Going back to his book from a few years ago, he noted that while the stresses placed on today’s AMCs by the current health care environment are unprecedented in size and scope, AMCs have met great challenges over the past century, including two world wars that drew many of the finest physician groups from major AMCs to battle fronts in Europe and the Pacific, a Great Depression, the entrance of managed care more than 3 decades ago, and recent crises in the financial markets. Despite everything, he noted, “AMCs have stepped forward and continued to assure that their patients were cared for, that students and graduates were trained, and that new forms of care continued to be developed.”

References:

1. [No authors listed] 2011 Association of American Medical Colleges (AAMC) Databook: How Do Teaching Hospitals Serve America’s Communities? AAMC.
2. [No authors listed] The future of the academic medical center: Strategies to avoid a margin meltdown. Health Research institute, 2012.

Keywords: CardioSource WorldNews, Angina Pectoris, Angina, Stable, Angiography, Anticoagulants, Atrial Fibrillation, Coronary Disease, Coronary Vessels, Factor Xa, Heart Valves, Heart-Assist Devices, Hemorrhage, Stroke, Thrombin, Thromboembolism, Warfarin

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