History of invasive and interventional cardiology
Encyclopedia
The history of invasive and interventional cardiology is complex, with multiple groups working independently on similar technologies. Invasive and interventional cardiology
is currently closely associated with cardiologists (physician
s who treat the diseases of the heart
), though the development and most of its early research and procedures were performed by diagnostic and interventional radiologists
.
catheter
ization in 1711, when Stephen Hales placed catheters into the right
and left ventricle
s of a living horse. Variations on the technique were performed over the subsequent century, with formal study of cardiac physiology being performed by Claude Bernard in the 1840s.
Werner Forssmann
, in 1929, created an incision in one of his left antecubital
veins and inserted a catheter into his venous system. He then guided the catheter by fluoroscopy
into his right atrium. Subsequently he walked up a flight of stairs to the radiology department and documented the procedure by having a chest roentgenogram
performed. Over the next year, catheters were placed in a similar manner into the right ventricle, and measurements of pressure and cardiac output
(using the Fick principle
) were performed.
In the early 1940s, André Cournand
, in collaboration with Dickinson Richards
, performed more systematic measurements of the hemodynamics of the heart. For their work in the discovery of cardiac catheterization and hemodynamic measurements, Cournand, Forssmann, and Richards shared the Nobel Prize in Physiology or Medicine
in 1956.
, Dr. Charles Dotter began working on methods to visualize the coronary anatomy via sequential radiographic films. He invented a method known as occlusive aortography in an animal model. Occlusive aortography involved the transient occlusion of the aorta and subsequent injection of a small amount of radiographic contrast agent into the aortic root and subsequent serial x-rays to visualize the coronary arteries. This method produced impressive images of the coronary anatomy. Dotter later reported that all the animals used in the procedure survived.
Later that same year, while performing an aortic root aortography
, Mason Sones, a pediatric cardiologist at the Cleveland Clinic
, noted that the catheter had accidentally entered the patient's right coronary artery. Before the catheter could be removed, 30cc of contrast agent
had been injected. While the patient went into ventricular fibrillation
, the dangerous arrhythmia was terminated by Dr. Sones promptly performing a precordial thump
which restored sinus rhythm. This became the world's first selective coronary arteriogram. Until that time, it was believed that even a small amount of contrast agent within a coronary artery would be fatal.
Until the 1950s, placing a catheter into either the arterial or venous system involved a "cut down" procedure, in which the soft tissues were dissected out of the way until the artery or vein was directly visualized and subsequently punctured by a catheter; this was known as the Sones technique. The percutaneous approach that is widely used today was developed by Sven-Ivar Seldinger in 1953. This method was used initially for the visualization of the peripheral arteries. Percutaneous access of the artery or vein is still commonly known as the Seldinger technique
. The use of the Seldinger technique for visualizing the coronary arteries was described by Ricketts and Abrams in 1962 and Judkins in 1967.
By the late 1960s, Melvin Judkins had begun work on creating catheters that were specially shaped to reach the coronary arteries to perform selective coronary angiography. His initial work involved shaping stiff wires and comparing those shapes to radiographs of the ascending aorta to determine if the shape appeared promising. Then he would place the stiff wire inside a flexible catheter and use a heat-fixation method to permanently shape the catheter. In the first use of these catheters in humans, each catheter was specifically shaped to match the size and shape of the aorta of the subject. His work was documented in 1967, and by 1968 the Judkins catheters were manufactured in a limited number of fixed tip shapes. Catheters in these shapes carry his name and are still used to this day for selective coronary angiography.
performed the first success percutaneous transluminal coronary angioplasty (known as PTCA or percutaneous coronary intervention (PCI)) on a human on September 16, 1977 at University Hospital, Zurich. The results of the procedure were presented at the American Heart Association
meeting two months later to a stunned audience of cardiologists. In the subsequent three years, Dr. Gruentzig performed coronary angioplasties in 169 patients in Zurich, while teaching the practice of coronary angioplasty to a field of budding interventional cardiologists
. It is interesting to note that ten years later, nearly 90 percent of these individuals were still alive. By the mid 1980s, over 300,000 PTCAs were being performed on a yearly basis, equalling the number of bypass surgeries being performed for coronary artery disease.
Soon after Andreas Gruentzig began performing percutaneous interventions on individuals with stable coronary artery disease, multiple groups described the use of catheter-delivered streptokinase
for the treatment of acute myocardial infarction
(heart attack).
In the early years of coronary angioplasty, there were a number of serious complications. Abrupt vessel closure after balloon angioplasty occurred in approximately 1% of cases, often necessitating emergency bypass surgery. Vessel dissection was a frequent issue as a result of improper sizing of the balloon relative to the arterial diameter. Late restenosis occurred in as many as 30% of individuals who underwent PTCA, often causing recurrence of symptoms necessitating repeat procedures.
It was quickly realized that restenosis rates were significantly lower in individuals who received an intracoronary stent when compared to those who underwent just balloon angioplasty. A damper on the immediate use of intracoronary stents was subacute thrombosis
. Subacute thrombosis rates with intracoronary stents proved to be about 3.7 percent, higher than the rates seen after balloon angioplasty. Post-procedure bleeding was also an issue, due to the intense combination of anticoagulation
and anti-platelet agents
used to prevent stent thrombosis.
Stent technology improved rapidly, and in 1989 the Palmaz-Schatz balloon-expandable intracoronary stent was developed. Initial results with the Palmaz-Schatz stents were excellent when compared to balloon angioplasty, with a significantly lower incidence of abrupt closure and peri-procedure heart attack. Late restenosis rates with Palmaz-Schatz stents were also significantly improved when compared with balloon angioplasty. However, mortality
rates were unchanged compared to balloon angioplasty. While the rates of subacute thrombosis and bleeding complications associated with stent placement were high, by 1999 nearly 85% of all PCI procedures included intracoronary stenting.
In recognition of the focused training required by cardiologists to perform percutaneous coronary interventions and the rapid progression in the field of percutaneous coronary interventions, specialized fellowship training in the field of Interventional Cardiology was instituted in 1999.
was not required post balloon angioplasty or stent implantation, while intense anti-platelet regimens and changes in procedural technique (most importantly, making sure that the stent was well opposed to the walls of the coronary artery) improved short term and long term outcomes. Many different antiplatelet regimens were evaluated in the 1990s and the turn of the 21st century, with the optimal regimen in an individual patient still being up for debate.
One of the first products of the new focus on preventing late events (such as in stent restenosis and late thrombosis) was the heparin
coated Palmaz-Schatz stent. These coated stents were found to have a lower incidence of subacute thrombosis than bare metal stents.
At approximately the same time, Cordis
(a division of Johnson & Johnson
) was developing the Cypher stent
, a stent that would release sirolimus
(a chemotherapeutic agent) over time. The first study of these individuals revealed an incredible lack of restenosis (zero percent restenosis) at six months. This led to the approval for the stent to be used in Europe in April 2002. Further trials with the Cypher stent revealed that restenosis did occur in some individuals with high risk features (such as long areas of stenosis or a history of diabetes mellitus
), but that the restenosis rate was significantly lower than with bare metal stents (3.2 percent compared to 35.4 percent). About a year after approval in Europe, the United States FDA
approved the use of the Cypher stent as the first drug-eluting stent
for use in the general population in the United States.
With the significantly lower restenosis rates of drug eluting stents compared to bare metal stents, the interventional cardiology community began using these stents as soon as they became available. Cordis, the manufacturer of the Cypher drug eluting stent, was not able to keep up with the demand for these stents when they first entered the market. This fueled a rationing of Cypher stents; they were used on difficult anatomy and high risk individuals. At the time there was a fear by the general population that these drug eluting stents would not be used on individuals who could not afford them (as they cost significantly more than the bare metal stents of the era).
Concurrent with the development of the Cypher stent, Boston Scientific
started development of the Taxus stent. The Taxus stent was the Express2 metal stent, which was in general use for a number of years, with a copolymer coating of paclitaxel
that inhibited cell replication. As with the Cypher stent before it, the first trials of the Taxus stent revealed no evidence of in-stent restenosis at six months after the procedure, while later studies showed some restenosis, at a rate much lower than the bare metal counterpart. Based on these trials, the Taxus stent was approved for use in Europe in 2003. With further study, the FDA approved the use of the Taxus stent in the United States in March 2004.
By the end of 2004, drug eluting stents were used in nearly 80 percent of all percutaneous coronary interventions.
Trials of heparin coated stents could not match the significant decrease in restenosis rates seen with the Cypher and Taxus stents. With the increased supply in the chemotherapeutic drug eluting stents available, the use of heparin coated stents wained.
(heart attack). Even in the stable individuals, however, there are a number of subsets in which there is a mortality benefit that is attributed to PCI.
Subsequently, at the 2007 meeting of the American College of Cardiology
(ACC), data from the COURAGE trial was presented, suggested that the combination of PCI and intensive (optimal) medical therapy did not reduce the incidence of death, heart attacks, or stroke compared to intensive medical therapy alone. Critics of the trial state that the trial did not take into account the improvement in symptoms attributed to PCI. Also, the data that was presented was an intention to treat analysis
, and that there was a (possibly) significant crossover from the medical therapy arm to the PCI arm of the study. It should also be noted that the optimal medical therapy seen in the COURAGE trial is significantly more aggressive than the current guidelines of the ACC and are not commonly seen in the general cardiology clinic. As with any large clinical trial, the therapies available had changed from when the trial was designed to when the results were presented. In particular, drug eluting stents, while commonly used in practice at the time the results of the trial were presented, were used in less than 5 percent of individuals in the trial.
and clopidogrel
for 3 months when Cypher stents were used, and 9 months when Taxus stents were used, followed by aspirin indefinitely.
Soon, case reports started being published regarding late stent thrombosis. At the 2006 annual meeting of the American College of Cardiology, preliminary results of the BASKET-LATE trial were presented, which showed a slight increase in late thrombosis associated with drug eluting stents over bare metal stents. However, this increase was not statistically significant, and further data would have to be collected. Further data published over the following year had conflicting results, and it was unclear whether stent thrombosis was truly higher when compared to bare metal stents. During this time of uncertainty, many cardiologists started extending the dual antiplatelet regimen of aspirin and clopidogrel in these individuals, as some data suggested that it may prevent late thrombosis.
The FDA held an expert panel in December 2006 to go over the data presented by Cordis and Boston Scientific to determine if drug eluting stents should be considered less safe than bare metal stents. It became evident at the meeting that with all the data published there were varied definitions of late thrombosis and key differences in the types of lesions in different studies, hampering analysis of the data. It was also noted that with the advent of drug eluting stents, interventional cardiologists began performing procedures on more complex lesions, subsequently using the drug eluting stents in "off label" coronary artery lesions, which would otherwise go untreated or for bypass surgery
. The FDA advisory board reiterated the ACC guidelines that clopidogrel should be continued for 12 months after drug eluting stent placement in individuals who are at low risk for bleeding.
Cardiology
Cardiology is a medical specialty dealing with disorders of the heart . The field includes diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular heart disease and electrophysiology...
is currently closely associated with cardiologists (physician
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...
s who treat the diseases of the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
), though the development and most of its early research and procedures were performed by diagnostic and interventional radiologists
Radiology
Radiology is a medical specialty that employs the use of imaging to both diagnose and treat disease visualized within the human body. Radiologists use an array of imaging technologies to diagnose or treat diseases...
.
The birth of invasive cardiology
The history of invasive cardiology begins with the development of cardiacHeart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
catheter
Catheter
In medicine, a catheter is a tube that can be inserted into a body cavity, duct, or vessel. Catheters thereby allow drainage, administration of fluids or gases, or access by surgical instruments. The process of inserting a catheter is catheterization...
ization in 1711, when Stephen Hales placed catheters into the right
Right ventricle
The right ventricle is one of four chambers in the human heart. It receives deoxygenated blood from the right atrium via the tricuspid valve, and pumps it into the pulmonary artery via the pulmonary valve and pulmonary trunk....
and left ventricle
Left ventricle
The left ventricle is one of four chambers in the human heart. It receives oxygenated blood from the left atrium via the mitral valve, and pumps it into the aorta via the aortic valve.-Shape:...
s of a living horse. Variations on the technique were performed over the subsequent century, with formal study of cardiac physiology being performed by Claude Bernard in the 1840s.
Catheterization of humans
The technique of angiography was first developed in 1927 by the Portuguese physician Egas Moniz to provide contrasted x-ray in order to diagnose nervous diseases, such as tumors, coronary heart disease and arteriovenous malformations. He is recognized as one of the pioneers in this field.Werner Forssmann
Werner Forssmann
Werner Theodor Otto Forßmann, was a physician from Germany who shared the 1956 Nobel Prize in Medicine for developing a procedure that allowed for cardiac catheterization. In 1929, he put himself under local anesthetic and inserted a catheter into his own arm...
, in 1929, created an incision in one of his left antecubital
Cubital fossa
The cubital fossa is the triangular area on the anterior view of the elbow of a human or other hominid animal. It is colloquially known as the "elbow pit".-Boundaries:...
veins and inserted a catheter into his venous system. He then guided the catheter by fluoroscopy
Fluoroscopy
Fluoroscopy is an imaging technique commonly used by physicians to obtain real-time moving images of the internal structures of a patient through the use of a fluoroscope. In its simplest form, a fluoroscope consists of an X-ray source and fluorescent screen between which a patient is placed...
into his right atrium. Subsequently he walked up a flight of stairs to the radiology department and documented the procedure by having a chest roentgenogram
Chest X-ray
In medicine, a chest radiograph, commonly called a chest X-ray , is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures...
performed. Over the next year, catheters were placed in a similar manner into the right ventricle, and measurements of pressure and cardiac output
Cardiac output
Cardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...
(using the Fick principle
Fick principle
Developed by Adolf Eugen Fick , the Fick principle was first devised as a technique for measuring cardiac output. However, its underlying principles may be applied in a variety of clinical situations....
) were performed.
In the early 1940s, André Cournand
André Frédéric Cournand
André Frédéric Cournand was a French physician and physiologist.He was awarded the Nobel Prize in Physiology or Medicine in 1956 along with Werner Forssmann and Dickinson W. Richards for the development of cardiac catheterization.Born in Paris, Cournand emigrated to the United States in 1930 and,...
, in collaboration with Dickinson Richards
Dickinson W. Richards
Dr. Dickinson Woodruff Richards, Jr. was an American physician and physiologist. He was a co-recipient of the Nobel Prize in Physiology or Medicine in 1956 with André Cournand and Werner Forssmann for the development of cardiac catheterization and the characterisation of a number of cardiac...
, performed more systematic measurements of the hemodynamics of the heart. For their work in the discovery of cardiac catheterization and hemodynamic measurements, Cournand, Forssmann, and Richards shared the Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
in 1956.
Development of the diagnostic coronary angiogram
In 1958, Interventional RadiologistInterventional radiology
Interventional radiology is a specialty of radiology, in which image-guided procedures are used to diagnose and treat a multitude of diseases across all body systems...
, Dr. Charles Dotter began working on methods to visualize the coronary anatomy via sequential radiographic films. He invented a method known as occlusive aortography in an animal model. Occlusive aortography involved the transient occlusion of the aorta and subsequent injection of a small amount of radiographic contrast agent into the aortic root and subsequent serial x-rays to visualize the coronary arteries. This method produced impressive images of the coronary anatomy. Dotter later reported that all the animals used in the procedure survived.
Later that same year, while performing an aortic root aortography
Aortography
An aortogram involves placement of a catheter in the aorta and injection of contrast material while taking x-rays of the aorta. The procedure is known as aortography...
, Mason Sones, a pediatric cardiologist at the Cleveland Clinic
Cleveland Clinic
The Cleveland Clinic is a multispecialty academic medical center located in Cleveland, Ohio, United States. The Cleveland Clinic is currently regarded as one of the top 4 hospitals in the United States as rated by U.S. News & World Report...
, noted that the catheter had accidentally entered the patient's right coronary artery. Before the catheter could be removed, 30cc of contrast agent
Radiocontrast
Radiocontrast agents are a type of medical contrast medium used to improve the visibility of internal bodily structures in an X-ray based imaging techniques such as computed tomography or radiography...
had been injected. While the patient went into ventricular fibrillation
Ventricular fibrillation
Ventricular fibrillation is a condition in which there is uncoordinated contraction of the cardiac muscle of the ventricles in the heart, making them quiver rather than contract properly. Ventricular fibrillation is a medical emergency and most commonly identified arrythmia in cardiac arrest...
, the dangerous arrhythmia was terminated by Dr. Sones promptly performing a precordial thump
Precordial thump
The precordial thump is a medical procedure that may used by healthcare professionals, to respond to ventricular fibrillation or ventricular tachycardia under certain conditions. The procedure is outside the scope of first-aid treatment and requires, at minimum, training in advanced cardiac life...
which restored sinus rhythm. This became the world's first selective coronary arteriogram. Until that time, it was believed that even a small amount of contrast agent within a coronary artery would be fatal.
Until the 1950s, placing a catheter into either the arterial or venous system involved a "cut down" procedure, in which the soft tissues were dissected out of the way until the artery or vein was directly visualized and subsequently punctured by a catheter; this was known as the Sones technique. The percutaneous approach that is widely used today was developed by Sven-Ivar Seldinger in 1953. This method was used initially for the visualization of the peripheral arteries. Percutaneous access of the artery or vein is still commonly known as the Seldinger technique
Seldinger technique
The Seldinger technique is a medical procedure to obtain safe access to blood vessels and other hollow organs. It is named after Dr. Sven-Ivar Seldinger , a Swedish radiologist from Mora, Dalarna County, who introduced the procedure in 1953....
. The use of the Seldinger technique for visualizing the coronary arteries was described by Ricketts and Abrams in 1962 and Judkins in 1967.
By the late 1960s, Melvin Judkins had begun work on creating catheters that were specially shaped to reach the coronary arteries to perform selective coronary angiography. His initial work involved shaping stiff wires and comparing those shapes to radiographs of the ascending aorta to determine if the shape appeared promising. Then he would place the stiff wire inside a flexible catheter and use a heat-fixation method to permanently shape the catheter. In the first use of these catheters in humans, each catheter was specifically shaped to match the size and shape of the aorta of the subject. His work was documented in 1967, and by 1968 the Judkins catheters were manufactured in a limited number of fixed tip shapes. Catheters in these shapes carry his name and are still used to this day for selective coronary angiography.
Dawn of the interventional era
The use of a balloon-tipped catheter for the treatment of atherosclerotic vascular disease was first described by Charles Dotter and Melvin Judkins in 1964, when they used it to treat a case of atherosclerotic disease in the superficial femoral artery of the left leg. Building on their work and his own research involving balloon-tipped catheters, Andreas GruentzigAndreas Gruentzig
Andreas Roland Grüntzig was a German cardiologist who first developed successful balloon angioplasty for expanding lumens of narrowed arteries.-Angioplasties:...
performed the first success percutaneous transluminal coronary angioplasty (known as PTCA or percutaneous coronary intervention (PCI)) on a human on September 16, 1977 at University Hospital, Zurich. The results of the procedure were presented at the American Heart Association
American Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
meeting two months later to a stunned audience of cardiologists. In the subsequent three years, Dr. Gruentzig performed coronary angioplasties in 169 patients in Zurich, while teaching the practice of coronary angioplasty to a field of budding interventional cardiologists
Interventional cardiology
Interventional cardiology is a branch of cardiology that deals specifically with the catheter based treatment of structural heart diseases. Andreas Gruentzig is considered the father of interventional cardiology after the development of angioplasty by interventional radiologist, Dr. Charles...
. It is interesting to note that ten years later, nearly 90 percent of these individuals were still alive. By the mid 1980s, over 300,000 PTCAs were being performed on a yearly basis, equalling the number of bypass surgeries being performed for coronary artery disease.
Soon after Andreas Gruentzig began performing percutaneous interventions on individuals with stable coronary artery disease, multiple groups described the use of catheter-delivered streptokinase
Streptokinase
Streptokinase , a protein secreted by several species of streptococci can bind and activate human plasminogen. SK is used as an effective and inexpensive thrombolysis medication in some cases of myocardial infarction and pulmonary embolism...
for the treatment of acute myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
(heart attack).
In the early years of coronary angioplasty, there were a number of serious complications. Abrupt vessel closure after balloon angioplasty occurred in approximately 1% of cases, often necessitating emergency bypass surgery. Vessel dissection was a frequent issue as a result of improper sizing of the balloon relative to the arterial diameter. Late restenosis occurred in as many as 30% of individuals who underwent PTCA, often causing recurrence of symptoms necessitating repeat procedures.
Development of the intracoronary stent
From the time of the initial percutaneous balloon angioplasty, it was theorized that devices could be placed inside the arteries as scaffolds to keep them open after a successful balloon angioplasty. This did not become a reality in the cardiac realm until the first intracoronary stents were successfully deployed in coronary arteries in 1986. The first stents used were self-expanding Wallstents. The use of intracoronary stents was quickly identified as a method to treat some complications due to PTCA, and their use can decrease the incidence of emergency bypass surgery for acute complications post balloon angioplasty.It was quickly realized that restenosis rates were significantly lower in individuals who received an intracoronary stent when compared to those who underwent just balloon angioplasty. A damper on the immediate use of intracoronary stents was subacute thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
. Subacute thrombosis rates with intracoronary stents proved to be about 3.7 percent, higher than the rates seen after balloon angioplasty. Post-procedure bleeding was also an issue, due to the intense combination of anticoagulation
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
and anti-platelet agents
Antiplatelet drug
An antiplatelet drug is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation...
used to prevent stent thrombosis.
Stent technology improved rapidly, and in 1989 the Palmaz-Schatz balloon-expandable intracoronary stent was developed. Initial results with the Palmaz-Schatz stents were excellent when compared to balloon angioplasty, with a significantly lower incidence of abrupt closure and peri-procedure heart attack. Late restenosis rates with Palmaz-Schatz stents were also significantly improved when compared with balloon angioplasty. However, mortality
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
rates were unchanged compared to balloon angioplasty. While the rates of subacute thrombosis and bleeding complications associated with stent placement were high, by 1999 nearly 85% of all PCI procedures included intracoronary stenting.
In recognition of the focused training required by cardiologists to perform percutaneous coronary interventions and the rapid progression in the field of percutaneous coronary interventions, specialized fellowship training in the field of Interventional Cardiology was instituted in 1999.
Changes in post-procedure medications
Through the 1990s and beyond, various incremental improvements were made in balloon and stent technology, as well as newer devices, some of which are still in use today while many more have fallen into disuse. As important as balloon and stent technology had been, it was becoming obvious that the anticoagulation and anti-platelet regimen that individuals received post-intervention was at least as important. Trials in the late 1990s revealed that anticoagulation with warfarinWarfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
was not required post balloon angioplasty or stent implantation, while intense anti-platelet regimens and changes in procedural technique (most importantly, making sure that the stent was well opposed to the walls of the coronary artery) improved short term and long term outcomes. Many different antiplatelet regimens were evaluated in the 1990s and the turn of the 21st century, with the optimal regimen in an individual patient still being up for debate.
The drug eluting stent era
With the high use of intracoronary stents during PCI procedures, the focus of treatment changed from procedural success to prevention of recurrence of disease in the treated area (in-stent restenosis). By the late 1990s it was generally acknowledged among cardiologists that the incidence of in-stent restenosis was between 15 and 30%, and possibly higher in certain subgroups of individuals. Stent manufacturers experimented with (and continue to experiment with) a number of chemical agents to prevent the neointimal hyperplasia that is the cause of in-stent restenosis.One of the first products of the new focus on preventing late events (such as in stent restenosis and late thrombosis) was the heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
coated Palmaz-Schatz stent. These coated stents were found to have a lower incidence of subacute thrombosis than bare metal stents.
At approximately the same time, Cordis
Cordis (medical)
Cordis is a medical device company owned by Johnson & Johnson. The company was founded in Miami in 1959 and is currently headquartered in Bridgewater Township, New Jersey.Cordis' products include stents, distal protection devices, catheters, and guidewires....
(a division of Johnson & Johnson
Johnson & Johnson
Johnson & Johnson is an American multinational pharmaceutical, medical devices and consumer packaged goods manufacturer founded in 1886. Its common stock is a component of the Dow Jones Industrial Average and the company is listed among the Fortune 500....
) was developing the Cypher stent
Cypher stent
Cypher is a brand of drug-eluting coronary stent from Cordis Corporation, a Johnson & Johnson company. During a balloon angioplasty, the stent is inserted into the artery to provide a "scaffold" to open the artery...
, a stent that would release sirolimus
Sirolimus
Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
(a chemotherapeutic agent) over time. The first study of these individuals revealed an incredible lack of restenosis (zero percent restenosis) at six months. This led to the approval for the stent to be used in Europe in April 2002. Further trials with the Cypher stent revealed that restenosis did occur in some individuals with high risk features (such as long areas of stenosis or a history of diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
), but that the restenosis rate was significantly lower than with bare metal stents (3.2 percent compared to 35.4 percent). About a year after approval in Europe, the United States FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
approved the use of the Cypher stent as the first drug-eluting stent
Drug-eluting stent
A drug-eluting stent ' is a peripheral or coronary stent placed into narrowed, diseased peripheral or coronary arteries that slowly releases a drug to block cell proliferation. This prevents fibrosis that, together with clots , could otherwise block the stented artery, a process called restenosis...
for use in the general population in the United States.
With the significantly lower restenosis rates of drug eluting stents compared to bare metal stents, the interventional cardiology community began using these stents as soon as they became available. Cordis, the manufacturer of the Cypher drug eluting stent, was not able to keep up with the demand for these stents when they first entered the market. This fueled a rationing of Cypher stents; they were used on difficult anatomy and high risk individuals. At the time there was a fear by the general population that these drug eluting stents would not be used on individuals who could not afford them (as they cost significantly more than the bare metal stents of the era).
Concurrent with the development of the Cypher stent, Boston Scientific
Boston Scientific
The Boston Scientific Corporation , is a worldwide developer, manufacturer and marketer of medical devices whose products are used in a range of interventional medical specialties, including interventional cardiology, peripheral interventions, neuromodulation, neurovascular intervention,...
started development of the Taxus stent. The Taxus stent was the Express2 metal stent, which was in general use for a number of years, with a copolymer coating of paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
that inhibited cell replication. As with the Cypher stent before it, the first trials of the Taxus stent revealed no evidence of in-stent restenosis at six months after the procedure, while later studies showed some restenosis, at a rate much lower than the bare metal counterpart. Based on these trials, the Taxus stent was approved for use in Europe in 2003. With further study, the FDA approved the use of the Taxus stent in the United States in March 2004.
By the end of 2004, drug eluting stents were used in nearly 80 percent of all percutaneous coronary interventions.
Trials of heparin coated stents could not match the significant decrease in restenosis rates seen with the Cypher and Taxus stents. With the increased supply in the chemotherapeutic drug eluting stents available, the use of heparin coated stents wained.
Modern controversies in interventional cardiology
The field of interventional cardiology has had a number of controversies since its inception. In part this is because of the dawning of the randomized control trial as the marker of a successful procedure. This is worsened by the rapid changes in the field of interventional cardiology. Procedures would be used soon after they are described in the literature or at conferences, with trial data determining if the procedure improves outcomes lagging behind by years due to the strict protocols and long follow-up of patients necessary to test the procedure. By the time the trials were published, they would be considered out of date, as they did not reflect the current practice in the field. This led to the inception and use of a number of procedures and devices in the interventional realm that have fallen out of practice due to their being found to not improve outcomes after formal trials have been performed.Roles of bypass surgery and intracoronary stents for coronary artery disease
Another source of controversy in the field of interventional cardiology is the overlapping roles of PCI and coronary artery bypass surgery for individuals with coronary artery disease. This area has been studied in a number of trials since the early 1990s. Unfortunately, due to the rapid changes in technique in both bypass surgery as well as PCI, added to the better understanding of the role of intense pharmacologic therapy in individuals with coronary artery disease, questions still remain on the best form of therapy in many subgroups of patients. Multiple ongoing studies hope to tease out which individuals do better with PCI and which do better with CABG, but in general each case is individualized to the patient and the relative comfort level of the interventional cardiologist and the cardiothoracic surgeon.The role of PCI in individuals without symptoms of ischemic heart disease
In the vast majority of cases, percutaneous coronary interventions do not improve mortality when compared to optimal medical therapy in the stable individual. This is, of course, not true in the unstable individual, such as in the setting after a myocardial infarctionMyocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
(heart attack). Even in the stable individuals, however, there are a number of subsets in which there is a mortality benefit that is attributed to PCI.
Subsequently, at the 2007 meeting of the American College of Cardiology
American College of Cardiology
The American College of Cardiology is a nonprofit medical association established in 1949 to advocate for quality cardiovascular care through education, research promotion, development and application of standards and guidelines, and to influence health care policy...
(ACC), data from the COURAGE trial was presented, suggested that the combination of PCI and intensive (optimal) medical therapy did not reduce the incidence of death, heart attacks, or stroke compared to intensive medical therapy alone. Critics of the trial state that the trial did not take into account the improvement in symptoms attributed to PCI. Also, the data that was presented was an intention to treat analysis
Intention to treat analysis
In epidemiology, an intention to treat analysis is an analysis based on the initial treatment intent, not on the treatment eventually administered. ITT analysis is intended to avoid various misleading artifacts that can arise in intervention research...
, and that there was a (possibly) significant crossover from the medical therapy arm to the PCI arm of the study. It should also be noted that the optimal medical therapy seen in the COURAGE trial is significantly more aggressive than the current guidelines of the ACC and are not commonly seen in the general cardiology clinic. As with any large clinical trial, the therapies available had changed from when the trial was designed to when the results were presented. In particular, drug eluting stents, while commonly used in practice at the time the results of the trial were presented, were used in less than 5 percent of individuals in the trial.
The safety of drug-eluting stents
When the results of the first trials of drug-eluting stents were published, there was a general feeling in the interventional cardiology community that these devices would be part of the perfect revascularization regimen for coronary artery disease. With the very low restenosis rates of the RAVEL and SIRIUS trials, interventions were performed on more complex blockages in the coronary arteries, under the assumption that the results in real life would mimic the results in the trials. The antiplatelet regimens that were advised for the drug eluting stents were based on the early trials of these stents. Based on these trials, the antiplatelet regimen was a combination of aspirinAspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
and clopidogrel
Clopidogrel
Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly...
for 3 months when Cypher stents were used, and 9 months when Taxus stents were used, followed by aspirin indefinitely.
Soon, case reports started being published regarding late stent thrombosis. At the 2006 annual meeting of the American College of Cardiology, preliminary results of the BASKET-LATE trial were presented, which showed a slight increase in late thrombosis associated with drug eluting stents over bare metal stents. However, this increase was not statistically significant, and further data would have to be collected. Further data published over the following year had conflicting results, and it was unclear whether stent thrombosis was truly higher when compared to bare metal stents. During this time of uncertainty, many cardiologists started extending the dual antiplatelet regimen of aspirin and clopidogrel in these individuals, as some data suggested that it may prevent late thrombosis.
The FDA held an expert panel in December 2006 to go over the data presented by Cordis and Boston Scientific to determine if drug eluting stents should be considered less safe than bare metal stents. It became evident at the meeting that with all the data published there were varied definitions of late thrombosis and key differences in the types of lesions in different studies, hampering analysis of the data. It was also noted that with the advent of drug eluting stents, interventional cardiologists began performing procedures on more complex lesions, subsequently using the drug eluting stents in "off label" coronary artery lesions, which would otherwise go untreated or for bypass surgery
Coronary artery bypass surgery
Coronary artery bypass surgery, also coronary artery bypass graft surgery, and colloquially heart bypass or bypass surgery is a surgical procedure performed to relieve angina and reduce the risk of death from coronary artery disease...
. The FDA advisory board reiterated the ACC guidelines that clopidogrel should be continued for 12 months after drug eluting stent placement in individuals who are at low risk for bleeding.
External links
- Angioplasty.Org History Center, celebrating a decade of independent cardiology news and education