Cover Story

New knowledge, technologies yield drastic changes in cardiology over 20 years

Since Cardiology Today was launched 20 years ago in 1997, not only has the prognosis for patients with heart disease vastly changed, but so has the practice of cardiology.

Back then, cardiologist involvement occurred mainly when patients were seriously ill, often if they needed CABG or other heart surgery, if they needed PCI with or without bare-metal stenting, or if they had MI, or cardiac arrest. Another difference between then and now was that stroke was often the focus of only neurologists. The prognosis for most patients with HF was grim. Fewer people visited cardiologists for diagnostic testing or preventive strategies.

“The focus in the late ’90s when we launched the Cardiology Today print publication was totally dominated by acute MI, principally STEMI,” Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, eminent scholar emeritus and professor in the division of cardiovascular medicine at University of Florida, Gainesville, said in an interview. “Now, due to advances, patients with STEMI are in a far minority, and I would say that the field is dominated by HF. I like to think that’s a result of our success: We have kept people from dying of heart disease, so now they’re living with heart disease.”

Over the course of 20 years, CVD and CV mortality rates have declined in the United States and many other countries, minimally invasive technologies have enabled more patients to be treated for heart problems successfully, new drugs and better understanding of old drugs have enabled patients to live longer before an intervention is required, and physicians and patients have a stronger knowledge of what it means to be heart-healthy.

Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, reflects on cardiology advances and challenges during the past 2 decades.
Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, reflects on cardiology advances and challenges during the past 2 decades.

Source: David Braun Photography

A common thread among all the changes is “an increasing reliance on doing something rather than watchful waiting,” Eduardo Marbán, MD, PhD, director of the Cedars-Sinai Heart Institute, told Cardiology Today.

The landscape in 1997

One major difference between then and now, Pepine said, is that cardiology did not have nearly as many subspecialties. One could specialize in electrophysiology/arrhythmias or intervention, but many of today’s other subspecialties within cardiology were embryonic or nonexistent.

“Back then, I was an interventionalist and we were concerned mostly with ... diagnostics and early intervention: plain old balloon angioplasty and BMS,” Pepine said. “By the late ’90s and early 2000s, that all changed. We didn’t have a HF subspecialty at the time, but we’ve since had an explosion of HF specialists and an American Board of Internal Medicine certification in advanced HF and transplant cardiology. Now there are specialists with focus in topics such as cardio-oncology, cardiometabolic and cardio-renal.”

The catheter laboratory then doubled as the physiology laboratory, but that is no longer the case, as the latter has generally shifted to the echocardiography, MR and nuclear labs, he said.

For diagnostics, “we had conventional stress testing, such as echocardiography and nuclear testing, and invasive angiography,” Pamela S. Douglas, MD, who holds the Ursula Geller professorship for research in cardiovascular diseases at Duke Clinical Research Institute, Duke University School of Medicine, told Cardiology Today. “We had no noninvasive angiography or calcium scoring. CT was nonexistent as a cardiac test.”

Nanette K. Wenger, MD, FAHA, MACC
Nanette K. Wenger

Moreover, there was not nearly the intensity of focus on evidence-based medicine that is seen today, Nanette K. Wenger, MD, FAHA, MACC, emeritus professor of medicine in the division of cardiology at Emory University School of Medicine, consultant at Emory Heart and Vascular Center, and director of the Cardiac Clinics at Grady Memorial Hospital, Atlanta, said in an interview.

“In general, there was more consensus and less evidence base,” Wenger, a member of the Cardiology Today Editorial Board, said. “We were just beginning to get into the very careful exploration of evidence, at a point of transition between consensus — people sitting around a table and making recommendations — and a very precise exploration of the data.”

Peter Libby, MD, the Mallinckrodt Professor of Medicine at Harvard Medical School, cardiovascular medicine specialist at Brigham and Women’s Hospital and section editor of the Vascular Medicine section of the Cardiology Today Editorial Board, agreed.

“One of the distinctive directions of evolution of cardiology in the last 20 years is a reinforcement of the evidence base,” he said. “So many other subspecialties or domains in medicine rely on observational data. And the trials in most other areas are much smaller and less ambitious than the cardiology community expects.”

Another change, Wenger said, is that “we have seen particular attention paid to previously ignored subpopulations: women, the elderly and minorities. The clinical community recognized that there were clinical differences in recognition of symptoms and management of outcomes. The emphasis that the 40-year-old male is the prototype of how we study disease has totally changed. I think that is stunning.”

Major advances in drug therapy

In 1997, patients with severe dyslipidemia had their lipids managed, often by lipidologists, but many other individuals did not, other than receiving dietary recommendations.

The first statin, lovastatin (Mevacor, Merck), was approved in 1987. In 1997, statins were just beginning to catch on and the concept of preventive cardiology was still fairly novel, experts said (see Timeline for list of key approvals).

Pamela S. Douglas, MD
Pamela S. Douglas

“By and large, we were not addressing lipids [20 years ago],” Douglas said. “Statins weren’t very common, and doctors were using agents like gemfibrozil and niacin” to control lipids.

At first, Pepine said, statin use “was restricted to people with very severe hypercholesterolemia, perhaps due to concern about serious side effects.”

That would start to change early on in Cardiology Today’s history. The Scandinavian Simvastatin Survival Study (4S), the first study to demonstrate that LDL lowering via statin therapy led to reduced risk for CV events and mortality, was published in 1994. In 1996, atorvastatin (Lipitor, Warner-Lambert, later Pfizer), was approved and soon caught on, becoming the best-selling pharmaceutical product in the United States by 2003.

“It was around the mid-’90s when we started to use [statins] more,” Pepine said. “Then we evolved to the point where we were asking if we should start putting them in drinking water.”

For BP and HF management in the past 20 years, change came not so much in what was used, but rather how it was used.

The first ACE inhibitor, captopril (Capoten, Squibb, now Bristol-Myers Squibb), was approved in 1981, and beta-blockers have been around since the 1960s for angina, but their use has changed dramatically between 1997 and now, Pepine said.

“ACE inhibitors were initially approved for hypertension, but weren’t that effective in hypertension when used alone,” he said. “Their beneficial effects in HF started to be known in the late ’80s and early ’90s. Beta-blockers were approved for chronic angina and then acute ischemia, and now their greatest use is in HF. That represents a huge change. In fact, many people argue they don’t play much of a role in adult hypertension and are only useful in younger people, and if it’s not ACS, their use in chronic ischemic heart disease has also been limited.”

Use of “blood thinners” has also been transformed since 1997. Before then, the main choices for oral therapy were aspirin or warfarin. The first P2Y12 inhibitor, ticlopidine (Ticlid, Roche), was approved in 1991, but it “was associated with serious hematologic side effects so we didn’t like to use it,” Pepine said.

That changed in 1997, when clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi) was approved. “Right around the time [Cardiology Today] got started, in the CAPRI trial, clopidogrel was proven superior to aspirin, but more importantly, safe,” Pepine said. “That was really the first P2Y12 inhibitor that we were comfortable using, and it made a big difference in stent thrombosis rates. Now, stent thrombosis rates are very low, and usually always associated with an interruption of the antiplatelet regimen, a deployment of the stent in a vessel that was too small or a failure to metabolize clopidogrel to its active drug.” Now, patients who do not benefit from clopidogrel can be recognized by genotyping and clinicians can prescribe them an alternative P2Y12 inhibitor.

Click the image for a larger image.
Source: www.fda.gov. We put our best effort into making a representative list and regret any omissions. Appearance does not constitute any endorsement by Cardiology Today, its editors, publisher or editorial board.

Patients requiring an oral anticoagulant for stroke prevention in 1997 had only one choice: warfarin, which requires continuous monitoring and dietary changes. Since 2010, four non-vitamin K oral anticoagulants have emerged as alternatives.

Wenger said perhaps the most stunning pharmacological developments have been recent ones: PCSK9 inhibitors alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen), which dramatically lower LDL; and sacubitril/valsartan (Entresto, Novartis), which reduces risk for CV death and HF-related hospitalization compared with enalapril in patients with HF with reduced ejection fraction.

“Those have been the game changers,” she said.

Structural heart disease transformed

Experts told Cardiology Today that arguably the greatest change of the past 20 years in cardiology is the ability to treat structural heart disease.

“Among the greatest accomplishments have been the replacement of surgical approaches by percutaneous methods for almost all types of structural heart disease,” Marbán said in an interview.

“The whole [specialty] of structural and valvular heart disease didn’t exist at all,” Douglas said. “We were doing surgeries, but you had to be pretty sick to have an aortic valve replacement or an [atrial septal defect] closure. There certainly weren’t any [patent foramen ovale] closures.”

The most prominent change in structural heart disease is the advent of transcatheter aortic valve replacement; the first system (Sapien, Edwards Lifesciences) was approved by the FDA in 2011.

“For valvular disease, we couldn’t do much except for balloon valvuloplasty,” Pepine said. “TAVR revolutionized treatment of aortic stenosis, particularly in the elderly, which is where most aortic stenosis lies.”

The technology has enabled people with severe aortic stenosis whose only options were life-threatening surgery or death to survive with enhanced quality of life. Similarly, patients with severe mitral insufficiency can undergo a much less risky procedure in transcatheter mitral valve repair (MitraClip, Abbott Vascular).

“Perhaps the most dramatic development [since 1997] has been the rapid growth of percutaneous valve repair and replacement since the first TAVR [procedure] in 2002,” Timothy D. Henry, MD, director of the cardiology division at Cedars-Sinai Heart Institute and a member of the Cardiology Today Editorial Board, said.

Eduardo Marbán, MD, PhD
Eduardo Marbán
Timothy D. Henry, MD
Timothy D. Henry

Changes in MI, CAD management

Today, except in the worst cases of STEMI, MI is generally considered a manageable problem because of all the treatments that are readily available for it, and all the protocols that have been proven to work over time.

This was not true in 1997, Marbán said.

“The difference in best practices is ‘night and day,’” he said. “Use of interventional approaches to urgently open the occluded coronary artery in [MI] had still not gained broad acceptance. Now it is the cornerstone of MI care. As a result, morbidity and mortality have fallen greatly.”

Henry said the improvement is due not only to primary PCI becoming the chief method of reperfusion for patients with STEMI, but also to the establishment of regional STEMI systems.

“The number of eligible but untreated patients with STEMI is now less than 5%, and more than 80% of patients with STEMI receive primary PCI, with significant improvement in treatment times,” he said. “This has resulted in a remarkable reduction in morbidity and mortality, which has transformed the natural history of STEMI. The benefit of regional STEMI systems has also extended to other acute CV emergencies, including out-of-hospital cardiac arrest and stroke.”

Over time, fewer patients with MI have needed to be treated in the coronary care unit and instead go right to the cath lab, Libby said.

“What we take care of now in the cardiology ICU are much more complex, challenging patients, either with severe complications of ischemic heart disease or with advanced HF, and patients with multi-organ system problems, often requiring circulatory assist or other kinds of life support,” he said. “This has really changed the specialty over the last several dozen years. The [coronary care unit] doesn’t have garden-variety [MIs] anymore.”

While PCI with BMS was an option for patients with CAD in 1997, sometimes the treatment caused as many problems as it solved. The effects of angioplasty were often temporary, and BMS were prone to in-stent restenosis. Six years into Cardiology Today’s history, drug-eluting stents came along, and PCI has produced increasingly better outcomes since then.

“Approval of the sirolimus-eluting stent (Cypher, Cordis) in the United States in 2003 markedly decreased the vexing problem of in-stent restenosis,” Henry said. “The excellent outcomes of new-generation DES have transformed PCI to expand the indications to more complex patients with increasingly low event rates. The treatment of STEMI and improvement in PCI have dramatically changed the outcome of patients with [CAD].”

The cardiology community is waiting to see if stents and scaffolds that can be absorbed by the body will usher in a change of similar impact; the first fully bioresorbable scaffold (Absorb, Abbott Vascular) was approved in 2016, a year after the first DES with a bioabsorbable polymer (Synergy, Boston Scientific) received approval.

Device development

By 1997, pacemakers had been around for decades and implantable cardioverter defibrillators for 12 years. The first ventricular assist device had been approved 3 years before. All such implantable technologies have been markedly improved since then.

Most people with a diagnosis of advanced HF were not expected to live long unless they received a transplant, Douglas said.

“There was no such thing as a bridge or a destination VAD,” she said.

VADs have become smaller and safer, and have improved to the point where many cardiologists see them as permanent solutions for advanced HF, while cardiac resynchronization devices, introduced in the early 2000s, have been a boon to people with HF who require a pacemaker or ICD.

Pacemakers and ICDs have evolved to become much safer, with far less risk for inappropriate shocks and complications, and the development of leadless pacemakers and subcutaneous ICDs has enabled clinicians and patients to choose an option with no possibility for lead-related complications, experts said.

“The broad acceptance of ICDs as lifesaving prophylactic devices” has been a major development of the past 20 years, Marbán said.

Patients with atrial fibrillation have benefited from advances in device-based therapies such as catheter ablation and left atrial appendage occlusion for stroke prevention.

Patient attitudes

Since 1997, CV care has become more patient-centered, and patients have become proactive about their own heart health, experts said.

“The way we approach cardiology has changed,” Wenger said. “Twenty years ago, it was very much an authoritarian approach for many physicians. The provider-patient partnership was not there. My approach to the teaching and training of young doctors is to tell them to present the information, tell the patient of their personal risks and benefits and give them your recommendations, and then ask what they want to do. I think good doctors have always provided patient-centered care.”

The change has come not only because the practice of cardiology has evolved, but because patients have access to more information, Douglas said.

“There is more patient education through TV, the internet, magazines and newspapers, but also it’s the case that there’s more that patients can do now,” she said. “It’s not that they couldn’t diet and exercise before, but it’s clear that there’s more cardiac rehab and other counseling than there used to be. Part of it is having better and less invasive treatments. By having more tools, we’ve made it clear that heart disease is more manageable and preventable. Some people have become more engaged with that.”

Peter Libby, MD
Peter Libby

The challenge, however, is to help patients distinguish between good information and bad, Libby said.

“We live now in an era where a lot of people get their information from non-peer reviewed publications, notably ... on the internet,” he said. “And the information is often unfiltered and is of wide and varying quality, a lot of it poor. That makes our job of applying the evidence base much harder because we have to confront ... the less reliable information which inundates our patients and which is so readily accessible at the click of a mouse.”

Patients now understand the notion of “false news,” so it’s much easier to discuss these issues, Pepine said.

Perhaps the most dramatic difference in patient behavior is the reduction in smoking and the disappearance of it from many public places, Douglas said.

“Twenty years ago, we still had smoking in restaurants, bars, workplaces and other public areas,” she said. “It’s a public health intervention as opposed to a medical intervention, but it’s made things dramatically different, and it affects cardiology.”

Further, Libby said, “we must remain ever-vigilant to ensure that we put advancing a healthy environment as an ongoing priority, not only in the United States but worldwide. This doesn’t include only obesity and inactivity, but it also includes air pollution and access to clean water.”

Challenges remain

Despite all the advances that have happened in the past 20 years, there are still gaps in knowledge and management that need to be overcome, experts said.

“The one thing we’re all baffled about is the concept of therapeutic angiogenesis, which has tremendous relevance for all kinds of vascular disease,” Pepine said. “Despite novel approaches such as gene therapy, cell-based therapies, ultrasound, etc, we haven’t hit a homer in the ability to create new blood vessels. The same is true for cardiac muscle regeneration.”

Another challenge, he said, is sudden cardiac death.

“Although coronary disease death rates have diminished, we still have a problem of sudden deaths due to ischemic and nonischemic heart disease,” Pepine said. “We’ve identified some genetic syndromes associated with potentially lethal arrhythmias. But we have generally not succeeded in preventing them.”

The transplantation field has not advanced much, with rates not much different from what they were in 1997, because of “lack of availability of donors and lack of states wanting to move to an opt-out situation,” in which people would be considered donors unless they actively opted out, instead of being considered non-donors unless they actively opted in, Pepine said.

“Nothing is going to change the heart transplant field unless we deal with the donor issue or find ways to preserve hearts and make them usable,” he said.

Research in genetics and genomics has shown promise at times, but it has yet to translate into improvement in practice, Wenger said.

“I think we may begin to have a better genetics/genomics approach, but I’ve not seen much of that come into fruition yet,” she said. “So far, it’s been almost unfulfilled expectation. We’re still looking.”

New frontiers

In the coming years, cardiologists may well need to become familiar with glucose management, as CV outcome trials have unexpectedly shown that some diabetes drugs confer CV benefit.

“Cardiologists have backed away from managing glucose, but endocrinologists, who have been trained to manage it, are among the most scarce subspecialty; it’s almost impossible to get an endocrine consult,” Pepine said. “That’s been defaulted to primary care, and I don’t think they do a very good job of it. A natural group to fill the void is the CV specialist.”

It is also likely that cardiologists will be treating prediabetes and prehypertension more than they do now, he said.

Genetic and other forms of advanced research have begun to pay off, with PCSK9 inhibitors being the most notable example.

“The PSCK9 story is a wonderful story of how a genetic defect was identified, how a solution to it was manufactured, how it was shown to be safe, and how it appears to have remarkable efficacy,” Pepine said. “Now that is spinning off into new ways to address PCSK9 inhibition for a much longer duration.”

Similar research is ongoing with other lipid fractions. A technology being developed by Ionis Pharmaceuticals can reduce the level of lipoprotein(a) to zero, Pepine said.

As prevention, diagnoses and treatments improve and patients live longer, cardiologists will have to become more involved with their patients’ end-of-life decisions, Wenger said.

“We’re doing so well at treating CV diseases that we now have a very large population with end-stage disease with devices and multiple therapies,” she said. “We have to listen very carefully to the patient who now says, ‘Enough. I want comfort and reasonable function, but I don’t want anything invasive, aggressive or intensive.’ We will have to learn when to begin to focus first on palliative care and then finally hospice care. And we will have to learn to be very comfortable with this. As we see our older and sicker patients, these discussions will have to happen on an ambulatory basis, not when the patient is in an ICU.”

Cardiologists will also have to adapt to new ways of designing and conducting studies, Libby said.

“The way in which we do clinical trials is going to have to shift as we learn how to use big data and as we design ever-smarter kinds of clinical trials so we don’t have the huge trials with 25,000 people with pretty broad entry criteria. We’re going to need to begin to target our trials in a more focused way in order to keep going with CV therapeutics. We have become the victims of our own success in that our standard of care has driven event rates so low that we need to have these incredibly large trials. The enterprise is probably unsustainable unless we get clever about how to move forward in clinical trial design.”

Evolution will continue

While there is no consensus on what exactly the practice of cardiology will look like 10 or 20 years from now, there is agreement that the transformation of the focus of the discipline from reacting to disease to taking action to prevent disease will continue.

Libby said a priority “as a profession and as a society is to address the fundamental risk factors before they get to a stage that we need to give people drugs. In terms of preventive cardiology ... the battle is joined but we haven’t won the war.”

Wenger said the biggest challenge may be to find a way to emphasize primary and secondary disease prevention as much as end-stage disease management.

“I expect we’re going to see almost every cardiologist become a preventive cardiologist,” she said. “If not in general, then in his or her specific areas of interest.” – by Katie Kalvaitis and Erik Swain

Disclosures: Douglas reports receiving research grants from GE and HeartFlow. Henry, Libby, Marbán, Pepine and Wenger report no relevant financial disclosures.

Since Cardiology Today was launched 20 years ago in 1997, not only has the prognosis for patients with heart disease vastly changed, but so has the practice of cardiology.

Back then, cardiologist involvement occurred mainly when patients were seriously ill, often if they needed CABG or other heart surgery, if they needed PCI with or without bare-metal stenting, or if they had MI, or cardiac arrest. Another difference between then and now was that stroke was often the focus of only neurologists. The prognosis for most patients with HF was grim. Fewer people visited cardiologists for diagnostic testing or preventive strategies.

“The focus in the late ’90s when we launched the Cardiology Today print publication was totally dominated by acute MI, principally STEMI,” Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, eminent scholar emeritus and professor in the division of cardiovascular medicine at University of Florida, Gainesville, said in an interview. “Now, due to advances, patients with STEMI are in a far minority, and I would say that the field is dominated by HF. I like to think that’s a result of our success: We have kept people from dying of heart disease, so now they’re living with heart disease.”

Over the course of 20 years, CVD and CV mortality rates have declined in the United States and many other countries, minimally invasive technologies have enabled more patients to be treated for heart problems successfully, new drugs and better understanding of old drugs have enabled patients to live longer before an intervention is required, and physicians and patients have a stronger knowledge of what it means to be heart-healthy.

Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, reflects on cardiology advances and challenges during the past 2 decades.
Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, reflects on cardiology advances and challenges during the past 2 decades.

Source: David Braun Photography

A common thread among all the changes is “an increasing reliance on doing something rather than watchful waiting,” Eduardo Marbán, MD, PhD, director of the Cedars-Sinai Heart Institute, told Cardiology Today.

The landscape in 1997

One major difference between then and now, Pepine said, is that cardiology did not have nearly as many subspecialties. One could specialize in electrophysiology/arrhythmias or intervention, but many of today’s other subspecialties within cardiology were embryonic or nonexistent.

“Back then, I was an interventionalist and we were concerned mostly with ... diagnostics and early intervention: plain old balloon angioplasty and BMS,” Pepine said. “By the late ’90s and early 2000s, that all changed. We didn’t have a HF subspecialty at the time, but we’ve since had an explosion of HF specialists and an American Board of Internal Medicine certification in advanced HF and transplant cardiology. Now there are specialists with focus in topics such as cardio-oncology, cardiometabolic and cardio-renal.”

The catheter laboratory then doubled as the physiology laboratory, but that is no longer the case, as the latter has generally shifted to the echocardiography, MR and nuclear labs, he said.

For diagnostics, “we had conventional stress testing, such as echocardiography and nuclear testing, and invasive angiography,” Pamela S. Douglas, MD, who holds the Ursula Geller professorship for research in cardiovascular diseases at Duke Clinical Research Institute, Duke University School of Medicine, told Cardiology Today. “We had no noninvasive angiography or calcium scoring. CT was nonexistent as a cardiac test.”

Nanette K. Wenger, MD, FAHA, MACC
Nanette K. Wenger

Moreover, there was not nearly the intensity of focus on evidence-based medicine that is seen today, Nanette K. Wenger, MD, FAHA, MACC, emeritus professor of medicine in the division of cardiology at Emory University School of Medicine, consultant at Emory Heart and Vascular Center, and director of the Cardiac Clinics at Grady Memorial Hospital, Atlanta, said in an interview.

“In general, there was more consensus and less evidence base,” Wenger, a member of the Cardiology Today Editorial Board, said. “We were just beginning to get into the very careful exploration of evidence, at a point of transition between consensus — people sitting around a table and making recommendations — and a very precise exploration of the data.”

Peter Libby, MD, the Mallinckrodt Professor of Medicine at Harvard Medical School, cardiovascular medicine specialist at Brigham and Women’s Hospital and section editor of the Vascular Medicine section of the Cardiology Today Editorial Board, agreed.

PAGE BREAK

“One of the distinctive directions of evolution of cardiology in the last 20 years is a reinforcement of the evidence base,” he said. “So many other subspecialties or domains in medicine rely on observational data. And the trials in most other areas are much smaller and less ambitious than the cardiology community expects.”

Another change, Wenger said, is that “we have seen particular attention paid to previously ignored subpopulations: women, the elderly and minorities. The clinical community recognized that there were clinical differences in recognition of symptoms and management of outcomes. The emphasis that the 40-year-old male is the prototype of how we study disease has totally changed. I think that is stunning.”

Major advances in drug therapy

In 1997, patients with severe dyslipidemia had their lipids managed, often by lipidologists, but many other individuals did not, other than receiving dietary recommendations.

The first statin, lovastatin (Mevacor, Merck), was approved in 1987. In 1997, statins were just beginning to catch on and the concept of preventive cardiology was still fairly novel, experts said (see Timeline for list of key approvals).

Pamela S. Douglas, MD
Pamela S. Douglas

“By and large, we were not addressing lipids [20 years ago],” Douglas said. “Statins weren’t very common, and doctors were using agents like gemfibrozil and niacin” to control lipids.

At first, Pepine said, statin use “was restricted to people with very severe hypercholesterolemia, perhaps due to concern about serious side effects.”

That would start to change early on in Cardiology Today’s history. The Scandinavian Simvastatin Survival Study (4S), the first study to demonstrate that LDL lowering via statin therapy led to reduced risk for CV events and mortality, was published in 1994. In 1996, atorvastatin (Lipitor, Warner-Lambert, later Pfizer), was approved and soon caught on, becoming the best-selling pharmaceutical product in the United States by 2003.

“It was around the mid-’90s when we started to use [statins] more,” Pepine said. “Then we evolved to the point where we were asking if we should start putting them in drinking water.”

For BP and HF management in the past 20 years, change came not so much in what was used, but rather how it was used.

The first ACE inhibitor, captopril (Capoten, Squibb, now Bristol-Myers Squibb), was approved in 1981, and beta-blockers have been around since the 1960s for angina, but their use has changed dramatically between 1997 and now, Pepine said.

“ACE inhibitors were initially approved for hypertension, but weren’t that effective in hypertension when used alone,” he said. “Their beneficial effects in HF started to be known in the late ’80s and early ’90s. Beta-blockers were approved for chronic angina and then acute ischemia, and now their greatest use is in HF. That represents a huge change. In fact, many people argue they don’t play much of a role in adult hypertension and are only useful in younger people, and if it’s not ACS, their use in chronic ischemic heart disease has also been limited.”

Use of “blood thinners” has also been transformed since 1997. Before then, the main choices for oral therapy were aspirin or warfarin. The first P2Y12 inhibitor, ticlopidine (Ticlid, Roche), was approved in 1991, but it “was associated with serious hematologic side effects so we didn’t like to use it,” Pepine said.

That changed in 1997, when clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi) was approved. “Right around the time [Cardiology Today] got started, in the CAPRI trial, clopidogrel was proven superior to aspirin, but more importantly, safe,” Pepine said. “That was really the first P2Y12 inhibitor that we were comfortable using, and it made a big difference in stent thrombosis rates. Now, stent thrombosis rates are very low, and usually always associated with an interruption of the antiplatelet regimen, a deployment of the stent in a vessel that was too small or a failure to metabolize clopidogrel to its active drug.” Now, patients who do not benefit from clopidogrel can be recognized by genotyping and clinicians can prescribe them an alternative P2Y12 inhibitor.

Click the image for a larger image.
Source: www.fda.gov. We put our best effort into making a representative list and regret any omissions. Appearance does not constitute any endorsement by Cardiology Today, its editors, publisher or editorial board.

Patients requiring an oral anticoagulant for stroke prevention in 1997 had only one choice: warfarin, which requires continuous monitoring and dietary changes. Since 2010, four non-vitamin K oral anticoagulants have emerged as alternatives.

Wenger said perhaps the most stunning pharmacological developments have been recent ones: PCSK9 inhibitors alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen), which dramatically lower LDL; and sacubitril/valsartan (Entresto, Novartis), which reduces risk for CV death and HF-related hospitalization compared with enalapril in patients with HF with reduced ejection fraction.

“Those have been the game changers,” she said.

PAGE BREAK

Structural heart disease transformed

Experts told Cardiology Today that arguably the greatest change of the past 20 years in cardiology is the ability to treat structural heart disease.

“Among the greatest accomplishments have been the replacement of surgical approaches by percutaneous methods for almost all types of structural heart disease,” Marbán said in an interview.

“The whole [specialty] of structural and valvular heart disease didn’t exist at all,” Douglas said. “We were doing surgeries, but you had to be pretty sick to have an aortic valve replacement or an [atrial septal defect] closure. There certainly weren’t any [patent foramen ovale] closures.”

The most prominent change in structural heart disease is the advent of transcatheter aortic valve replacement; the first system (Sapien, Edwards Lifesciences) was approved by the FDA in 2011.

“For valvular disease, we couldn’t do much except for balloon valvuloplasty,” Pepine said. “TAVR revolutionized treatment of aortic stenosis, particularly in the elderly, which is where most aortic stenosis lies.”

The technology has enabled people with severe aortic stenosis whose only options were life-threatening surgery or death to survive with enhanced quality of life. Similarly, patients with severe mitral insufficiency can undergo a much less risky procedure in transcatheter mitral valve repair (MitraClip, Abbott Vascular).

“Perhaps the most dramatic development [since 1997] has been the rapid growth of percutaneous valve repair and replacement since the first TAVR [procedure] in 2002,” Timothy D. Henry, MD, director of the cardiology division at Cedars-Sinai Heart Institute and a member of the Cardiology Today Editorial Board, said.

Eduardo Marbán, MD, PhD
Eduardo Marbán
Timothy D. Henry, MD
Timothy D. Henry

Changes in MI, CAD management

Today, except in the worst cases of STEMI, MI is generally considered a manageable problem because of all the treatments that are readily available for it, and all the protocols that have been proven to work over time.

This was not true in 1997, Marbán said.

“The difference in best practices is ‘night and day,’” he said. “Use of interventional approaches to urgently open the occluded coronary artery in [MI] had still not gained broad acceptance. Now it is the cornerstone of MI care. As a result, morbidity and mortality have fallen greatly.”

Henry said the improvement is due not only to primary PCI becoming the chief method of reperfusion for patients with STEMI, but also to the establishment of regional STEMI systems.

“The number of eligible but untreated patients with STEMI is now less than 5%, and more than 80% of patients with STEMI receive primary PCI, with significant improvement in treatment times,” he said. “This has resulted in a remarkable reduction in morbidity and mortality, which has transformed the natural history of STEMI. The benefit of regional STEMI systems has also extended to other acute CV emergencies, including out-of-hospital cardiac arrest and stroke.”

Over time, fewer patients with MI have needed to be treated in the coronary care unit and instead go right to the cath lab, Libby said.

“What we take care of now in the cardiology ICU are much more complex, challenging patients, either with severe complications of ischemic heart disease or with advanced HF, and patients with multi-organ system problems, often requiring circulatory assist or other kinds of life support,” he said. “This has really changed the specialty over the last several dozen years. The [coronary care unit] doesn’t have garden-variety [MIs] anymore.”

While PCI with BMS was an option for patients with CAD in 1997, sometimes the treatment caused as many problems as it solved. The effects of angioplasty were often temporary, and BMS were prone to in-stent restenosis. Six years into Cardiology Today’s history, drug-eluting stents came along, and PCI has produced increasingly better outcomes since then.

“Approval of the sirolimus-eluting stent (Cypher, Cordis) in the United States in 2003 markedly decreased the vexing problem of in-stent restenosis,” Henry said. “The excellent outcomes of new-generation DES have transformed PCI to expand the indications to more complex patients with increasingly low event rates. The treatment of STEMI and improvement in PCI have dramatically changed the outcome of patients with [CAD].”

The cardiology community is waiting to see if stents and scaffolds that can be absorbed by the body will usher in a change of similar impact; the first fully bioresorbable scaffold (Absorb, Abbott Vascular) was approved in 2016, a year after the first DES with a bioabsorbable polymer (Synergy, Boston Scientific) received approval.

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Device development

By 1997, pacemakers had been around for decades and implantable cardioverter defibrillators for 12 years. The first ventricular assist device had been approved 3 years before. All such implantable technologies have been markedly improved since then.

Most people with a diagnosis of advanced HF were not expected to live long unless they received a transplant, Douglas said.

“There was no such thing as a bridge or a destination VAD,” she said.

VADs have become smaller and safer, and have improved to the point where many cardiologists see them as permanent solutions for advanced HF, while cardiac resynchronization devices, introduced in the early 2000s, have been a boon to people with HF who require a pacemaker or ICD.

Pacemakers and ICDs have evolved to become much safer, with far less risk for inappropriate shocks and complications, and the development of leadless pacemakers and subcutaneous ICDs has enabled clinicians and patients to choose an option with no possibility for lead-related complications, experts said.

“The broad acceptance of ICDs as lifesaving prophylactic devices” has been a major development of the past 20 years, Marbán said.

Patients with atrial fibrillation have benefited from advances in device-based therapies such as catheter ablation and left atrial appendage occlusion for stroke prevention.

Patient attitudes

Since 1997, CV care has become more patient-centered, and patients have become proactive about their own heart health, experts said.

“The way we approach cardiology has changed,” Wenger said. “Twenty years ago, it was very much an authoritarian approach for many physicians. The provider-patient partnership was not there. My approach to the teaching and training of young doctors is to tell them to present the information, tell the patient of their personal risks and benefits and give them your recommendations, and then ask what they want to do. I think good doctors have always provided patient-centered care.”

The change has come not only because the practice of cardiology has evolved, but because patients have access to more information, Douglas said.

“There is more patient education through TV, the internet, magazines and newspapers, but also it’s the case that there’s more that patients can do now,” she said. “It’s not that they couldn’t diet and exercise before, but it’s clear that there’s more cardiac rehab and other counseling than there used to be. Part of it is having better and less invasive treatments. By having more tools, we’ve made it clear that heart disease is more manageable and preventable. Some people have become more engaged with that.”

Peter Libby, MD
Peter Libby

The challenge, however, is to help patients distinguish between good information and bad, Libby said.

“We live now in an era where a lot of people get their information from non-peer reviewed publications, notably ... on the internet,” he said. “And the information is often unfiltered and is of wide and varying quality, a lot of it poor. That makes our job of applying the evidence base much harder because we have to confront ... the less reliable information which inundates our patients and which is so readily accessible at the click of a mouse.”

Patients now understand the notion of “false news,” so it’s much easier to discuss these issues, Pepine said.

Perhaps the most dramatic difference in patient behavior is the reduction in smoking and the disappearance of it from many public places, Douglas said.

“Twenty years ago, we still had smoking in restaurants, bars, workplaces and other public areas,” she said. “It’s a public health intervention as opposed to a medical intervention, but it’s made things dramatically different, and it affects cardiology.”

Further, Libby said, “we must remain ever-vigilant to ensure that we put advancing a healthy environment as an ongoing priority, not only in the United States but worldwide. This doesn’t include only obesity and inactivity, but it also includes air pollution and access to clean water.”

Challenges remain

Despite all the advances that have happened in the past 20 years, there are still gaps in knowledge and management that need to be overcome, experts said.

“The one thing we’re all baffled about is the concept of therapeutic angiogenesis, which has tremendous relevance for all kinds of vascular disease,” Pepine said. “Despite novel approaches such as gene therapy, cell-based therapies, ultrasound, etc, we haven’t hit a homer in the ability to create new blood vessels. The same is true for cardiac muscle regeneration.”

Another challenge, he said, is sudden cardiac death.

“Although coronary disease death rates have diminished, we still have a problem of sudden deaths due to ischemic and nonischemic heart disease,” Pepine said. “We’ve identified some genetic syndromes associated with potentially lethal arrhythmias. But we have generally not succeeded in preventing them.”

The transplantation field has not advanced much, with rates not much different from what they were in 1997, because of “lack of availability of donors and lack of states wanting to move to an opt-out situation,” in which people would be considered donors unless they actively opted out, instead of being considered non-donors unless they actively opted in, Pepine said.

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“Nothing is going to change the heart transplant field unless we deal with the donor issue or find ways to preserve hearts and make them usable,” he said.

Research in genetics and genomics has shown promise at times, but it has yet to translate into improvement in practice, Wenger said.

“I think we may begin to have a better genetics/genomics approach, but I’ve not seen much of that come into fruition yet,” she said. “So far, it’s been almost unfulfilled expectation. We’re still looking.”

New frontiers

In the coming years, cardiologists may well need to become familiar with glucose management, as CV outcome trials have unexpectedly shown that some diabetes drugs confer CV benefit.

“Cardiologists have backed away from managing glucose, but endocrinologists, who have been trained to manage it, are among the most scarce subspecialty; it’s almost impossible to get an endocrine consult,” Pepine said. “That’s been defaulted to primary care, and I don’t think they do a very good job of it. A natural group to fill the void is the CV specialist.”

It is also likely that cardiologists will be treating prediabetes and prehypertension more than they do now, he said.

Genetic and other forms of advanced research have begun to pay off, with PCSK9 inhibitors being the most notable example.

“The PSCK9 story is a wonderful story of how a genetic defect was identified, how a solution to it was manufactured, how it was shown to be safe, and how it appears to have remarkable efficacy,” Pepine said. “Now that is spinning off into new ways to address PCSK9 inhibition for a much longer duration.”

Similar research is ongoing with other lipid fractions. A technology being developed by Ionis Pharmaceuticals can reduce the level of lipoprotein(a) to zero, Pepine said.

As prevention, diagnoses and treatments improve and patients live longer, cardiologists will have to become more involved with their patients’ end-of-life decisions, Wenger said.

“We’re doing so well at treating CV diseases that we now have a very large population with end-stage disease with devices and multiple therapies,” she said. “We have to listen very carefully to the patient who now says, ‘Enough. I want comfort and reasonable function, but I don’t want anything invasive, aggressive or intensive.’ We will have to learn when to begin to focus first on palliative care and then finally hospice care. And we will have to learn to be very comfortable with this. As we see our older and sicker patients, these discussions will have to happen on an ambulatory basis, not when the patient is in an ICU.”

Cardiologists will also have to adapt to new ways of designing and conducting studies, Libby said.

“The way in which we do clinical trials is going to have to shift as we learn how to use big data and as we design ever-smarter kinds of clinical trials so we don’t have the huge trials with 25,000 people with pretty broad entry criteria. We’re going to need to begin to target our trials in a more focused way in order to keep going with CV therapeutics. We have become the victims of our own success in that our standard of care has driven event rates so low that we need to have these incredibly large trials. The enterprise is probably unsustainable unless we get clever about how to move forward in clinical trial design.”

Evolution will continue

While there is no consensus on what exactly the practice of cardiology will look like 10 or 20 years from now, there is agreement that the transformation of the focus of the discipline from reacting to disease to taking action to prevent disease will continue.

Libby said a priority “as a profession and as a society is to address the fundamental risk factors before they get to a stage that we need to give people drugs. In terms of preventive cardiology ... the battle is joined but we haven’t won the war.”

Wenger said the biggest challenge may be to find a way to emphasize primary and secondary disease prevention as much as end-stage disease management.

“I expect we’re going to see almost every cardiologist become a preventive cardiologist,” she said. “If not in general, then in his or her specific areas of interest.” – by Katie Kalvaitis and Erik Swain

Disclosures: Douglas reports receiving research grants from GE and HeartFlow. Henry, Libby, Marbán, Pepine and Wenger report no relevant financial disclosures.

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