10
Until now, I have focused primarily on advances in controlling risk factors to prevent adverse cardiovascular events, rather than on advances in treating these events. The priority of prevention reflects the fact that there is a ceiling on how much good one can do by treating heart attacks after they happen, since a substantial portion of heart attack victims die suddenly without surviving long enough to receive medical care. Still, spurred by spectacular advances in technology in the past half-century, we have witnessed a sea change in the treatment of heart attack since the 1970s, a change that is all the more remarkable because our initial therapeutic approach—i.e., to direct our attention to the arterial segments with the largest plaques and the most severe obstruction to blood flow—was based on a fundamental misconception of how heart attacks happen.
When I began my NHLBI career in 1977, atherosclerosis in the coronary arteries and elsewhere was viewed fundamentally as a plumbing problem. In this conceptualization (as applied to the heart), cholesterol and cellular debris accumulate as plaques in the walls of the coronary arteries, gradually narrowing their lumen (interior channel) until the circulation to a segment of heart muscle is cut off—usually by a blood clot—and an infarction (death of a segment of functioning heart muscle and its eventual replacement by a fibrous scar) or even arrhythmia and sudden death ensue. This theory did not tell us why plaques occur in some places but not others or what acute factors caused an occlusive clot to form in a particular place at a particular time. We did know that persons with large obstructive coronary plaques suffer a characteristic form of exertional chest pain called angina pectoris (or just angina, for short), which can be relieved by placement of a nitroglycerine tablet under the tongue, and that this syndrome is often a harbinger of the characteristic crushing chest pain of a full-blown heart attack. So we directed our efforts toward finding ways to open or bypass the most severe blockages, thereby reducing angina and hopefully the risk of heart attacks. Only much later did we learn that the stability rather than the size of plaques is the critical factor in infarction, and that the sudden rupture of a small but unstable plaque, which reduces blood flow through the affected artery from nearly 100% to zero in a matter of seconds, is far likelier to kill than a larger but stable plaque that has been gradually choking off blood flow and causing angina for years.
The History of Coronary Revascularization
During the past 50 years, procedures to “revascularize” the heart either by bypassing or dilating local blockages due to atherosclerosis have grown from nearly nothing to among the commonest and safest procedures in cardiovascular medicine. In the early 1970s, when our prototypical patient A.L. was hospitalized for a heart attack (Chapter 1), the treatments deployed were relatively low-tech—bed rest, intravenous medications for pain relief and arrhythmia, and an electronic monitor to alert nurses to changes in the pulse rate, BP, and electrocardiogram. Coronary artery bypass surgery (CABG) was first performed in the 1960s but carried a >10% mortality rate and was used only in patients with chronic intractable angina. Percutaneous coronary interventions (PCI) like coronary balloon angioplasty and stent placement, by which coronary blockages are opened via placement of an arterial catheter without opening the chest, did not even exist. By contrast, 337,444 CABG surgeries and 777,780 PCI procedures were performed in the U.S. in 2003.1 Although these numbers fell to 201,840 CABG surgeries and 440,505 PCI procedures in 2016 (for reasons we will address later), they remain the bread and butter of cardiothoracic surgeons and interventional cardiologists—a medical subspecialty that did not yet exist in 1970. This exponential growth could not have happened without technological advances in diagnostic radiology, surgical techniques, and medical device development that date back as far as the late 19th century but converged in the 1970s and 1980s.
Since one cannot begin to “fix” coronary plaques with knowing where they are, let us begin with diagnostic radiology. To orient you, I have provided a diagram of the coronary circulation in Figure 10.1.
Anatomy of the coronary arteries. Drawing by Debra L. Roney. A = aortic trunk, C = circumflex coronary artery, LAD = left anterior descending coronary artery, LM = left main coronary artery, PA = pulmonary artery, R = right coronary artery, SVC = superior vena cava.
The left and right coronary arteries are the first arteries to branch off from the aorta above the valve that governs the exit of oxygenated blood from the left ventricle of the heart. The left coronary artery is responsible for most of the blood supply to the hard-working left ventricle, which pumps oxygenated blood at high pressure to every organ (including the heart itself) except for the lungs. After a short distance, the proximal segment of the left coronary artery (commonly called the left main coronary artery) divides into two large branches, the left anterior descending branch (also called the anterior intraventricular branch, which supplies blood to the front-facing portion of the left ventricle) and the circumflex branch (which circles behind the left ventricle). The right coronary artery is responsible mainly for the blood supply to the less hard-working right ventricle, which pumps de-oxygenated blood at low pressure only to the lungs, where it can take up oxygen. There are of course many additional branches downstream, but these four large coronary conduits—the left main, the left anterior descending, the circumflex, and the right—are where most fatal heart attacks originate and are the major targets for intervention. Blockages in the left main coronary artery—often called “the widow maker”—are especially dangerous.
The science of diagnostic radiology dates back to 1895, when Wilhelm Röntgen took X-ray photos of his wife’s hand; his discovery won him the 1901 Nobel Prize in Physics.2 Although the injection of radio-opaque dyes to enhance contrast soon followed, the heart was considered off limits until a 25-year-old German surgical trainee, Werner Forssman, passed a venous catheter into his own right atrium in 1929.3 Once practitioners recovered from their shock at what Forssman had dared to do, cardiac catheterization quickly became an important tool for diagnosing congenital heart malformations and cardiac valvular disease. However, well into the 1950s, selective injection of dye into the coronary arteries was considered too dangerous and likely to induce a fatal arrhythmia or to stop the heart entirely (asystole). The first injection of dye into the coronary arteries by Dr. F. Mason Sones of the Cleveland Clinic on October 30, 1958, happened by accident during a cardiac catheterization in a young man with rheumatic mitral valve disease, when a heartbeat displaced the catheter into the coronary root as dye was being injected.4 When the man’s heart beat normally after a cough or two, the taboo was broken, and Dr. Sones began to perform coronary angiography intentionally. Over the next decade, this procedure became a staple of the diagnosis and treatment of coronary artery disease.
Even after identifying and locating critical obstructions in the coronary circulation, performing delicate corrective surgical procedures on the heart represents a considerable challenge, since the heart is a constantly moving target that won’t hold still voluntarily while a delicate surgery is performed. Cardiac surgeon John Gibbon’s invention of the cardiopulmonary bypass machine, which was first used in human patients in 1953, allowed surgeons to operate on a still heart, while Dr. Gibbon’s machine took over the heart’s function of oxygenating blood and pumping it to the brain and other vital organs.5 By the time the first CABG surgery was performed, cardiopulmonary bypass was already a staple of cardiothoracic surgery for many congenital heart defects, rheumatic valvular disease, and other conditions that had once been extremely risky or impossible to correct surgically.
Although animal experimentation on coronary bypass grafting dates back to 1910, the first CABG surgery in humans was performed in 1960 by Dr. Robert Goetz at the Albert Einstein Bronx Municipal Hospital Center in a man with a blocked right coronary artery by joining the right internal thoracic artery to the coronary artery downstream from the blockage.6 The operation (which foreshadowed modern minimally invasive techniques) was done without cardiopulmonary bypass, and the grafting took only 17 seconds. The patient survived for 13 months and his graft remained open at autopsy. However, other attempts over the next five years to perform similar operations brought discouraging results. CABG surgery did not really catch on until 1967–68 at the Cleveland Clinic, when surgeons began using pieces of saphenous (leg) veins as conduits for bypassing obstructed segments of the coronary arteries. Although these vein grafts tended to be less durable than the bypasses constructed by joining the left internal thoracic artery to the left anterior descending coronary artery (the most common form of “arterial anastomosis” in current use), they have the important practical advantage of being able to provide multiple grafts for patients with multiple obstructions, while the arterial grafts can bypass only a single obstruction. Today, both types of graft are often used in conjunction in patients with multiple blockages. The early CABG surgeries carried a relatively high immediate mortality rate (up to 10%) and considerable long-term neurological morbidity (ranging from subtle cognitive changes to stroke) due to the formation of tiny air bubbles and clots during cardiopulmonary bypass. There have been many procedural advances in CABG surgery since 1970, which have shortened the time on cardiopulmonary bypass and reduced morbidity and mortality. A detailed exposition of these technical changes is beyond the scope of this chapter. However, the recent advent of minimally invasive CABG surgery, which is now used in about 25% of cases, is noteworthy. By using a thoracotomy (cutting through the ribcage) rather than a sternotomy (cutting through the breastbone) to access the heart and eschewing cardiopulmonary bypass, this procedure has shortened recuperation time and reduced neurological complications of conventional CABG surgery.7 Currently, the operative mortality rate of CABG surgery is typically less than 3% in the non-emergency setting.
But in the 1970s, CABG surgery was still an ordeal, and there was a demand for kinder and gentler approaches to angina relief. This relief would take the form of coronary balloon angioplasty, a procedure in which a small catheter with an inflatable cuff is inserted via the femoral artery in the groin and guided under radiologic monitoring through the aorta to the coronary arteries and then to the targeted partially obstructed coronary arterial segment.8 When the catheter reaches its destination, the cuff is inflated briefly to crush the obstructing plaque, then deflated and withdrawn, leaving behind an open channel. The first angioplasty (like the first coronary angiogram) was performed by accident in 1964 when Charles Dotter inadvertently recanalized an occluded right iliac artery as he was trying to pass a catheter for an aortic angiogram.9 Andres Grüntzig performed the first deliberate femoral balloon angioplasty in 1974 and brought his technique to the coronary arteries in 1977. This achievement brought Dotter and Grüntzig the 1978 Nobel Prize in Medicine. Later, as techniques improved, angioplasty could be combined with diagnostic coronary angiography, and multiple obstructive lesions could be addressed during a single catheterization procedure. However, balloon angioplasty is not risk-free. The most serious potential complication is acute vessel closure, usually within 24 hours of the procedure, due to a combination of damage to the artery wall and clot formation. In the early days, this potentially lethal complication—the equivalent to an acute heart attack—occurred in 3–5% of cases. A more frequent and less dangerous complication was the gradual restenosis of the dilated coronary vessel over months due to fibrous scarring, which often left patients alive but no better off than they had been before the procedure.
The next major advance came in 1986 with the development of elastic wire mesh devices called stents, which could be put in place at the site of a balloon angioplasty to keep the newly dilated channel from narrowing or closing off.10 Stents were actually invented by a 19th-century dentist named Charles Thomas Stent, who used them as an adjunct to root canal surgery.11 In the first half of the 20th century, stent-like devices were frequently used in urological and biliary surgery to maintain the patency of ureters and bile ducts until they healed, although the term “stent” did not become standard for these devices until 1972. The cardiovascular application of stents began with their use in peripheral artery disease in the late 1970s, before they were adapted for coronary arteries. In any case, stent placement greatly improved the effectiveness and durability of angioplasty. However, stent thrombosis (clot formation) remained a significant and potentially life-threatening medium- and long-term risk. So in general, anti-platelet drugs, like clopidogrel (Plavix) and later variants, are prescribed in combination with aspirin for 1–2 years to stent recipients, which in turn raise the risk of serious bleeds. In the 1990s, the displacement of “bare metal” stents by new and improved drug-eluting stents, which are coated with drugs that inhibit the proliferation of the cells that form fibrous scars as they are slowly released in the artery wall. In a meta-analysis of 26.616 stent recipients, this and other improvements in stent design were shown effective in lowering rates of long-term stent thrombosis to about 1%.12
Randomized Trials of Revascularization to Prevent Heart Attacks in Stable Patients
So far, we have seen how technical advances in radiology, surgery, and medical technology have enabled surgeons and interventional cardiologists to make “plumbing repairs” that restore the coronary arterial circulation and mitigate angina pectoris for more than a million Americans every year. But the larger question, especially for the purpose of this book, is whether these plumbing repairs actually prevent heart attacks or prolong life. Although it seems logical to believe that this is the case, you must realize by now that what seems “logical” in medicine is not always true. After all, the application of leeches seemed logical to George Washington’s physicians in 1799.
So let us begin with the clinical trials of CABG surgery and/or PCI in patients with stable coronary artery disease. Three largish, randomized trials were initiated in the 1970s to address this question—with lukewarm results:
• In 1982, the European Coronary Surgery Study (ECSS) reported a significant reduction in mortality after five to eight years of follow-up in 768 men with mild to moderate angina and > 50% stenosis in at least two coronary arteries.13
• In 1984, the Coronary Artery Surgery Study (CASS) reported a small reduction in mortality but no difference in the combined incidence of heart attack and death after five years of follow-up in 780 patients with stable ischemic heart disease.14 A small reduction in mortality was offset by an equal increase in nonfatal heart attack.
• In 1992, the Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery, reported a small early reduction in mortality in 686 patients with stable angina and angiographically indicated coronary artery disease, but that reduction was reversed by the end of the planned 11-year follow-up.15 The reversal was attributed to the rapid development of obstructive atherosclerotic plaques in the saphenous vein grafts.
However, despite these underwhelming results, a great deal of emphasis was placed on the subgroup results which showed favorable results in the highest risk subgroups—i.e., those with left main coronary obstruction and those who had three or more significantly obstructed coronary artery segments and left ventricular dysfunction.16 Presumably, this reflected the relative infrequency of heart attacks and deaths in the low-risk subgroups and the consequent lack of statistical power to detect small differences between medically and surgically treated patients. Despite the limited usefulness of P-values when applied to subgroups identified after the fact, CABG surgery came to be recognized as the treatment of choice for the highest-risk subgroups of chronic coronary artery disease, and its primacy for treating left main coronary artery disease has rarely been challenged.
The government database ClinicalTrials.gov listed 665 completed clinical trials of stents in coronary artery disease as of July 2020.17 That is probably an underestimate. I do not wish to overwhelm my readers—or myself, for that matter—with a detailed review of these trials. In general, the vast majority are trials sponsored by stent manufacturers to prove that their devices are at least as good as previously approved stents with regard to safety and short-term outcomes and may offer some advantage in reducing late stenosis. They focus mainly on patients with one- or two-vessel coronary artery disease and cede superiority of CABG surgery in patients with left main or more complex coronary artery disease. None of these studies really address the topic of interest here, namely long-term cardiac mortality. So, in 1999, the official ACC/AHA guidelines for intervention in chronic stable angina recommended CABG for patients with significant left main coronary disease and for most patients with 3-vessel or complicated 2-vessel disease (very strong evidence) and PCI for most other patients with significant angina (moderate evidence).18 In my opinion, while these recommendations were not unreasonable given what was known at the time, the strength of the evidence supporting them was considerably overstated.
Let us now look at the results of more recent long-term outcome trials of coronary revascularization in chronic coronary artery disease. In 1988, the NHLBI initiated the Bypass Angioplasty Revascularization Investigation (BARI) trial, the first randomized trial to compare PCI and CABG head-to-head.19 This trial, which began before stents were widely used, randomized 1819 patients who could be reasonably viewed as candidates for either procedure to receive either CABG surgery or angioplasty. Patients with left main coronary disease or complex triple vessel disease were excluded as inappropriate candidates for angioplasty, while patients with single-vessel disease were excluded as inappropriate candidates for CABG. After 5.4 years mean follow-up, overall survival and survival free of a heart attack were similar in patients who received angioplasty versus CABG. However, in a subgroup analysis of survival, diabetic patents did significantly better with CABG than angioplasty. The investigators drew the appropriate inference, not that CABG is preferable to angioplasty in diabetic patients, but that this finding was of sufficient interest to generate a new trial, which they called BARI-2D (where the D stands for diabetes).20
The new BARI 2D trial, which was sponsored by the NHLBI, with contributions from the NIDDK and Glaxo-Smith-Kline, included 2368 patients with type 2 diabetes and ran from 2000 to 2009. It differed from BARI in several respects:
• It did not compare CABG and PCI head to head but compared both to optimal medical care, which by this time included far more stringent control of BP and cholesterol than was practiced in BARI.
• The use of stents in PCI (including drug-eluting stents) was far more prevalent in BARI 2D than in BARI.
• BARI 2D also included a factorial component comparing insulin-providing and insulin-sensitizing strategies in type 2 diabetes (see Chapter 7).
After 5 years mean follow-up, BARI 2D patients who were randomized to revascularization plus optimal medical care fared neither better nor worse than patients randomized to optimal medical care alone with regard to the primary composite cardiovascular outcome or to heart attack or overall mortality. Since BARI 2D (like BARI) excluded high-risk patients with left main coronary and/or complex multivessel disease, it did not address the value of CABG in these patients. Still, the results gave pause to advocates of PCI and CABG in diabetic patients with chronic stable coronary artery disease.
Starting in 1999, while the BARI 2D trial was just getting underway, the Veterans Affairs Cooperative Study Group and the Canadian Institutes of Health Research co-sponsored the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial in 2287 patients with stable coronary artery (but not left main coronary artery) disease.21 It was narrower than BAR 2D in that it addressed only PCI and not CABG, but also broader in that it included patients with and without diabetes. As in BARI 2D, there was no difference in adverse cardiovascular outcomes between patients randomized to PCI plus optimal medical care versus optimal medical care alone.
In 2005, Boston Scientific Corporation broke new ground by finally testing its TAXUS drug-eluting stent against CABG head-to-head in high-risk patients with left main coronary and triple-vessel disease, who had been considered the exclusive province of the surgeons.22 The SYNTAX trial randomized 1800 patients with severe coronary artery disease to receive either CABG or PCI with the TAXUS paclitaxel-eluting coated stent.23 SYNTAX was designed as a “non-inferiority trial”—that is, its objective was to prove not that the stent was superior to CABG, but that it was no worse than CABG. This made sense clinically since most patients would prefer the less invasive procedure (PCI), other things being equal. (Also, a conventional superiority trial would have required many more patients and would have cost far more.) The inclusion of repeat revascularization in the primary outcome (along with death, heart attack, and stroke) was unwise, since CABG, in which long coronary artery segments are bypassed, has long been known to produce a more complete and lasting result than PCI, in which only the most severe blockages are fixed. The results confirmed this obvious and predictable fact, showing a significant advantage of CABG over PCI with respect to repeat revascularizations (5.9% versus 13.5%) and in the composite primary outcome (12.4% versus 17.8%) after one year of follow-up., However, there was virtually no difference between PCI and CABG for deaths, heart attacks, and strokes. A subgroup analysis suggested that CABG was superior to PCI in the subgroup with the highest “SYNTAX score,” a risk score relating baseline coronary anatomy and function to adverse cardiovascular outcomes in the accompanying 1275-person SYNTAX registry. However, SYNTAX did not address whether either PCI or CABG was better than modern purely medical management.
The 2012–14 update to the ACC/AHA Guidelines, reflecting the results of COURAGE, SYNTAX and the two BARI trials, did not substantially change its recommendations, except for incorporating the SYNTAX score and diabetes in the decision tree of who should receive CABG versus PCI.24 However, they were appropriately more circumspect in stating the strength of the evidence supporting their recommendations. After all, the only clinical trial evidence supporting the proposition that any form of revascularization intervention improved long-term outcomes relative to medical management dated back to subgroup analyses of randomized trials initiated in the 1970s, when CABG was performed mainly using saphenous vein grafts, coronary stents did not exist, and medical management did not include aggressive cholesterol and BP control. More recent trials showed that both CABG and PCI provided symptomatic relief of angina pectoris and that CABG was superior to stenting under some circumstances, but not that either reduced cardiovascular risk or prolonged life.
Even after the COURAGE, BARI 2D, and SYNTAX results were in, some continued to suggest that clinical trials were not a fair test of the long-term benefit of coronary revascularization since they excluded de facto many of the patients with the most clear-cut indications for the procedure, because their cardiologists simply went ahead and performed PCI as a continuation of their coronary angiography procedure, rather than stop to enroll them in a clinical trial. Thus, they argued, only the difficult or questionable cases were randomized into clinical trials. The NHLBI initiated the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) in 2011 to address this criticism.25 Rather than randomize patients after their coronary angiographic evaluation, which allows the angiographer/interventionist to immediately siphon off the “cleanest” cases for immediate PCI or referral to a surgeon for CABG, ISCHEMIA moved the randomization upstream to the identification of patients with cardiac ischemia (the medical term, derived from Greek, meaning inadequate blood supply), as determined by non-invasive diagnostic tests, before angiography. Thus, patients were randomized not to revascularization versus no revascularization, as in COURAGE or BARI 2D, but to either an invasive strategy beginning with coronary angiography or to a conservative strategy involving only optimal medical management (i.e., statins, BP control, aspirin, etc.) The downside to this design is that some patients who are randomized to the invasive strategy will turn out to have no treatable coronary blockages and thus receive no revascularization, and that some patients who are randomized to the conservative strategy will eventually require PCI or CABG due to worsening angina. Therefore, ISCHEMIA required a larger sample size to accommodate higher expected “crossover” rates.
The primary outcome results from ISCHEMIA (cardiovascular deaths, heart attacks, unstable angina hospitalizations, heart failure, and resuscitated cardiac arrest) are shown in Figure 10.2.26
Primary composite outcome of ISCHEMIA trial, Invasive versus Conservative strategy. Data are from ISCHEMIA primary results paper, N Engl J Med 2020; 382:1395–1407.
Patients randomized to the conservative strategy did slightly better in the first two years, while patients randomized to the invasive strategy did slightly better thereafter. The overall difference between the two curves was not even close to statistically significant. The early increase reflected an increase in “procedural myocardial infarctions”—that is, damage sustained by a segment of heart muscle during the PCI procedure itself. Contrary to the general wisdom, there were no significant differences among subgroups; specifically, patients with more severe and widespread coronary artery disease benefited no more from the invasive approach than patients with one or two blockages. Unsurprisingly, patients with angina who were randomized to the invasive strategy had significant symptomatic improvement and required fewer anti-angina medications than patients randomized to the conservative strategy. No significant differences were seen in any secondary outcomes, including mortality.
So, at the end of the day, I draw the following conclusions about the use of revascularization in chronic coronary artery disease:
• Revascularization definitely offers symptomatic relief and improved quality of life to patients with significant angina, albeit at the cost of some short-term morbidity from the procedure.
• Based on early trial results, CABG probably improves long-term outcomes in patients with partial blockages of the left main coronary artery. Joining the left internal thoracic artery to the left main coronary artery achieves a more durable result than saphenous vein grafts. Ideally, one would like to see more robust clinical trial evidence on this point, but trials in which patients with known significant left main coronary artery disease can be randomized to conservative care have become ethically untenable.
• There is no good evidence that CABG or PCI offer any long-term survival advantage in patients without left main coronary disease. CABG offers more complete revascularization than PCI and is probably superior in patients with more severe disease, but PCI is a more benign procedure and is probably good enough in patients with lesser disease. New minimally invasive approaches to CABG may represent a good compromise. A recently funded follow-up to the ISCHEMIA trial may provide more answers.
Restoring Coronary Circulation in Acute Coronary Syndrome
The use of revascularization—particularly PCI—in the setting of an acute developing heart attack is a completely different story. When an unstable coronary plaque ruptures, its contents spill into the arterial channel (or lumen) and attract platelets, which form a clot (thrombosis) that partially or completely obstructs blood flow, abruptly depriving the downstream segment of heart muscle of oxygen-carrying blood. The ability of the heart to carry on pumping blood for a period of time depends on the location and degree of obstruction. If the obstruction is complete and cuts off the blood supply to a large and/or critical area of the heart, death may be virtually instantaneous, especially if the artery had not been significantly obstructed before the rupture. (Often, when obstructive plaques build up gradually over many years, collateral blood channels develop to augment blood circulation to the affected area.) Since the left main coronary artery supplies virtually the entire left ventricle (see Figure 10.1), plaque ruptures in this “widow maker” artery tend to be more lethal than similar ruptures downstream or in the right coronary artery. But even a small infarct in the wrong place can cause a fatal arrhythmia.
Let me pause here to make my terminology more specific than the familiar but imprecise term “heart attack,” which I have tried to use (for simplicity) throughout the first nine chapters. The acute onset of persistent coronary pain is called acute coronary syndrome (ACS); this syndrome (which is also sometimes called “unstable angina”) often signifies an impending or evolving myocardial infarction (or MI). When obstruction is severe, there is a window of perhaps three hours before the heart muscle downstream is irreversibly damaged and eventually replaced by scar tissue, which impairs its function of pumping blood. When a patient presents in the emergency room with ACS, the first step is to perform an electrocardiogram (ECG) and to draw blood to determine whether characteristic enzymes from heart muscle cells have leaked into the blood. An elevation of the ST-segment of the ECG and/or significantly elevated blood levels of cardiac enzymes (which have spilled out of damaged heart muscle cells into the bloodstream) are indicative of acute heart muscle damage or MI. For the purpose of this discussion, I will use the term MI to describe ACS patients who present with evidence of acute heart muscle damage, whether or not it is reversible. The acronym STEMI is often used to identify the subset of MI patients with ST elevation on their ECG; generally, they have sustained more widespread acute damage and have a worse prognosis than patients presenting with non–STEMI. The term “heart attack” may refer to any or all of these clinical situations.
Thrombolysis
Survival—or at least mitigation of the damages—of an acute MI requires urgent medical attention. The means of effectively treating these acute blockages and thus the sense of urgency in providing medical attention did not exist in the 1960s and early 1970s, when palliative treatments like bed rest and morphine were the order of the day. However, all this changed in the 1980s, with the development of “clot-busting” (thrombolytic) drugs, which could be administered intravenously at virtually any hospital.
The first thrombolytic drug used to re-open blocked arteries was streptokinase. Its medical use dates back to 1933 when William Smith Tillett noticed serendipitously that streptococcus bacteria made a substance that could digest fibrin, the essential structural protein of blood clots.27 Streptokinase was used in a variety of medical conditions for several decades before being tried in acute coronary thrombosis. Several small trials in the early 1980s suggested that streptokinase improved survival in ACS if it was administered within six hours of onset of symptoms.28 The results of the Italian megatrial Gruppo Italiano per la Sperimentazione della Streptchinasi nell’Infarto Miocardico (GISSI) trial, nailed it down.29 Starting in February 1984, GISSI randomized 11,806 patients with the acute onset (< 12 hours) of MI symptoms in 176 coronary care units over a period of 17 months to receive an intravenous infusion of either streptokinase or a placebo. Patients receiving streptokinase had significantly improved in-hospital survival; mortality rate reductions were 26% for patients treated within three hours of onset of symptoms and 20% for patients treated within 3–6 hours of onset of symptoms. Longer delays in treatment resulted in no significant improvement. These survival differences persisted after one year of follow-up despite the occurrence of more re-infarctions in the streptokinase group.30
Several other randomized trials in 1985–92 built on the results of GISSI—the 290-patient NHLBI-sponsored Thrombolysis in Myocardial Infarction (TIMI) trial and two international megatrials, GISSI-2 (12,490 patients) and the 3rd International Study of Infarct Survival (ISIS-3, 41,299 patients).31 These trials established the clear superiority of a newer synthetic thrombolytic drug called recombinant tissue plasminogen activator (tPA) to streptokinase in successfully restoring coronary blood flow. The benefits depended on rapid delivery of thrombolytic treatment, i.e., within six hours of symptom onset. In 1993, a third international trial called GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), which randomized 41,021 patients in 15 countries and 1081 hospitals, found that tPA, when given in an accelerated fashion (1.5 hours rather than 3 hours) with intravenous heparin significantly reduced 30-day mortality (6.9%) versus 7.8% in the streptokinase groups.32 Thus, it had become clear that the timely delivery of thrombolytic therapy offered significant benefit to acute MI patients with regard to successfully restoring blood flow in clogged coronary arteries, re-establishing perfusion of the heart muscle, reducing rates of MI and improving survival. This major breakthrough in the treatment of patients experiencing acute MI symptoms began to blur the definition of a myocardial infarction, since thrombolytic treatment when delivered early enough could potentially prevent any lasting damage to the heart muscle, as if there had never been a heart attack at all.
Angioplasty, Stenting, and Surgery in the Acute Setting
By the late 1980s, coronary angioplasty and CABG had already come of age. However, unlike intravenous thrombolytic therapy, which could be administered at any hospital, these procedures were still available only at academic and major referral centers, with sophisticated coronary catheterization facilities and teams of interventional cardiologists and surgeons. A few early trials in the 1980s (before stents) comparing the efficacy of angioplasty versus thrombolysis in acute myocardial infarction found no difference.33 However, the tide began to turn in the mid–1990s. In a 1995 review by Michaels and Yusuf of seven trials of primary angioplasty versus thrombolysis, angioplasty significantly reduced short-term (6 weeks) infarction and mortality by more than 40%.34 These benefits were sustained after one year of follow-up. However, in 16 trials testing the efficacy of angioplasty after thrombolysis, mortality was not significantly reduced. In 1997, GUSTO IIb, a substudy of GUSTO, in which 1138 acute MI patients were randomized to primary coronary angioplasty versus tPA, showed a moderate short-term benefit of angioplasty as the initial treatment of acute MI.35 In 1999, an NHLBI randomized trial called SHOCK (Should We Emergently Revascularize Occluded Coronary Arteries for Cardiogenic Shock) in 1492 patients with acute MI complicated by cardiogenic shock (inability of the damaged heart to sustain an adequate blood pressure), found no significant immediate benefit of emergency revascularization versus an initial strategy of medical stabilization, but a significant reduction in mortality after six months.36 By 2003, Keeley, Boura, and Grines were able to incorporate 23 trials of primary angioplasty versus thrombolysis in a new meta-analysis, which demonstrated clear superiority of angioplasty over thrombolysis as the initial line of therapy in acute MI at hospitals where both were available.37
The sharp dichotomy between angioplasty in the acute versus chronic setting is illustrated by the results of the 2006 Occluded Artery Trial (OAT).38 In this NHLBI-sponsored trial, 2166 stable patients who had had a recent (within the preceding 3–28 days) MI that left them with persistent occlusion of the infarct artery were randomized to receive either PCI to open the blocked coronary artery or conservative (medical only) treatment. This was one of those trials that many practitioners considered unethical because they already “knew” that of course opening the blocked artery would improve cardiovascular outcomes. In fact, it did not. The incidence of the primary composite outcome of death, reinfarction, or heart failure was actually slightly higher in the PCI group (17.2%) than in the conservatively treated control group (15.6%). Revascularization clearly offered no survival advantage, even as few as three days after an infarction.
Since 2003, there have been many improvements in PCI, both in the technique itself (incorporation of stents, improvements in stent design) and in the expanding availability of antithrombotic and antiplatelet drugs (aspirin, heparin, clopidogrel, GPIIb/IIIa inhibitors, etc.) to minimize the rate of stent thrombosis. Two of these drugs, clopidogrel and aspirin, ranked as the 40th and 42nd most prescribed drugs in 2017, with 19.4 million and 17.3 million scripts, respectively.39 A detailed review of the dizzying array of currently available options and the evidence supporting their use is beyond my scope here. The 2013 ACCF/AHA guidelines for the management of acute MI strongly recommend urgent revascularization (PCI, where feasible) as the first line of treatment.40 In settings where the timely delivery of PCI is impossible, such as rural areas without rapid access to a tertiary medical center, thrombolysis is a viable alternative. And of course, proven risk factor management treatments like statins and antihypertensive drugs should be instated or re-instated as soon as the patient’s condition has stabilized after the acute intervention.
Perhaps the most important change since 2003 is the increase in public awareness of the symptoms of acute MI and of the necessity of seeking immediate medical attention at their first onset and in the rapidity of the response once a patient arrives at the hospital. In 2011, Krumholz et al. report a marked improvement in door-to-balloon time (i.e., the time from arrival at the hospital to the angioplasty procedure) for U.S. hospitals between 2005 and 2010, based on a sampling of hospitals reporting to the Centers for Medicare and Medicaid Services, including roughly 50,000 cases per year.41 During this period, the median door-to-balloon time decreased by one-third from 96 minutes in 2005 to 64 minutes in 2010. The percentage of patients with door-to-balloon time < 90 minutes (the maximal acceptable time) increased from under 45% in 2005 to over 90% in 2010. Since the efficacy of PCI or thrombolysis in acute MI depends on delivery within 3–6 hours after onset of symptoms, time is of the essence.
Impact of Revascularization on the Decline in Heart Attack Mortality
So, at the end of the day, how did these spectacular technological advances, which have enabled us to intervene directly and decisively to restore blood flow in clogged coronary arteries, affect mortality from heart attacks in the U.S. since 1980? The answer is complicated. In their 2007 IMPACT model, Ford et al. attributed 5.5% of the decline in cardiac mortality between 1980 and 2000 to revascularization of patients with chronic stable angina (4.2% for CABG and 1.3% for angioplasty) and an additional 3.2% of this decline to revascularization and thrombolysis in the acute setting (acute coronary syndrome or MI).42 I believe that both of these estimates are seriously flawed. The estimate for chronic stable angina assumes that CABG and angioplasty reduced mortality by 36% and 13%, respectively, in this setting. Neither of these figures is even remotely accurate. Recent clinical trials through ISCHEMIA (which exclude patients with left main coronary artery disease) suggest that CABG and PCI have little or no effect on CHD mortality in this setting.43 While CABG may be helpful in patients with significant left main coronary disease, this condition is relatively uncommon; representing only 3.6% of patients in a recent report of a series of 13,228 consecutive coronary angiograms.44 Similarly, 5.1% (434/8518) of patients screened by the ISCHEMIA trial were excluded due to left main coronary artery disease.45 Thus, even if we grant that this subset of chronic patients receiving CABG enjoyed a 36% reduction in mortality, CABG in this setting can account for no more than 0.2% (5.1% times 4.2%) of the decline in heart attack mortality between 1980 and 2000. There is little evidence that angioplasty (with or without stents) accounts for any of this decline.
The real impact of revascularization on the CHD mortality has been in the acute setting, and nearly all of it has happened after 2000. This impact has almost certainly been driven by the growing use of PCI procedures (angioplasty plus stents), which have now largely superseded thrombolytic therapy and plain angioplasty and are far more commonly performed than CABG in the acute setting. Technological advances in the use and composition of stents, expanding PCI capability to many more hospitals, the increasingly sophisticated use of antiplatelet and other drugs to prevent stent thrombosis, and decreases in door-to-balloon time have brought about a sea change in the first decade of the 21st century—a period during which (not coincidentally) the most rapid decline in heart attack mortality has taken place (see Figure 1.2). So while the published IMPACT model results assumed that angioplasty reduced cardiac mortality by only a 7% in acute MI, a 2020 meta-analysis of recent PCI trials reports an overall 31% reduction in cardiac deaths in the acute scenario.46 Furthermore, while Ford et al. also assumed that only 30% of unstable angina patients and 21% of acute MI patients received a PCI, a 2016 analysis of four national registries reported that more than 90% of STEMI patients who were brought directly to participating centers received a PCI within 90 minutes of arrival.47 Also, Ford et al. incorrectly assumed a case-fatality rate of 9.4% in 2000 as the baseline case-fatality rate for acute MI, a figure that was already reduced by the use of thrombolysis and PCI. The actual in-hospital mortality rate for acute MI was 15% in 1980.48
Give all these flawed or outdated assumptions, I performed my own analysis of the contribution of improved treatment of acute MI (and acute coronary syndrome) based on the most current comprehensive data I could find, which covers the years 1970–2009 but does not include patents under age 45.49 My calculation (the details of which are laid out in Table A.6 of the appendix) is based on the improvement of short term (in-hospital) survival of acute MI and does not try to dissect the separate contributions of PCI and the antiplatelet and other therapies that are initiated more or less simultaneously. The calculation is complicated by the fact that hospitalizations for MI have decreased because of our success in primary prevention (treatment of hypertension and high LDL cholesterol and smoking cessation). This decrease has been partially offset by the increased sensitivity of modern diagnostic criteria for acute MI (specifically the displacement of creatine phosphokinase by high-sensitivity troponin as the key diagnostic cardiac enzyme assay) and the greater proportion of MI patients reaching the hospital alive.50 The consequent inclusion of milder cases has tended to artificially lower in-hospital case fatality rates. Thus, the profound drop in the in-hospital case fatality rate for acute MI from 23.9% in 1970 to 4.0% in 2009 reflects inflation of the proportion of milder cases, as well as actual improvements in treatment. For example, in a 2010 analysis of 46,086 Kaiser-Permanente patients hospitalized for acute MI between 1999 and 2008, the proportion of MI with ST segment elevation (STEMI), which have a worse prognosis than non–STEMI, decreased from 48% (133/274) in 1999 to 24% (50/208) in 2008.51 However, when one multiplies case fatality rates by the number of incident cases to obtain the number of in-hospital deaths per 100,000 population-wide, this artificial inflationary effect washes out.
Taking all these factors into account, I have estimated that improvements in the treatment of acute MI, especially the rapid deployment of PCI, account for an estimated decrease of 45.2 in-hospital deaths per 100,000 annually after adjustment for the impact of primary prevention, which represents 13.7 % of the total decline in heart attack deaths between 1970 and 2009 (see Table A.5 in the appendix). I believe that this figure represents a far more current and accurate estimate of the contribution of acute MI interventions to the decline in CHD mortality than the IMPACT model’s combined 2.8% estimate for thrombolysis, angioplasty, and CABG in the acute setting for 1980–2000. The impact of acute MI interventions has probably increased since 2009, due to continuing technological improvements and efficiency in delivering timely intervention.
1. M Alkhouli, F Alqahtini, A Kalra, S Gafoor, M Alhajii, M Alreshidan, DR Holmes, A Leman. Trends in characteristics and outcomes of hospital inpatients undergoing coronary revascularization in the United States, 2003–2016. JAMA Network Open 2020; 3(2):e1921326. doi:10.1001/jamanetworkopen.2019.21326. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2760898.
2. W Röntgen. Ueber eine neue Art von Strahlen. Vorläufige Mitteilung. Aus den Sitzungsberichten der Würzburger Physik.-medic. Gesellschaft Würzburg, pp. 137–147, 1895.
3. A Meyer. Werner Forssmann and the catheterization of the heart, 1929. Ann Thorac Surg 1990:49:497–499.
4. TJ Ryan. The coronary angiogram and its seminal contributions to cardiovascular medicine over five decades. Circulation 2002; 106:752-756.
5. RJ Morris. The history of cardiopulmonary bypass: medical advances. American College of Cardiology, June 19, 2019. https://www.acc.org/latest-in-cardiology/articles/2019/06/19/06/46/the-history-of-cardiopulmonary-bypass.
American College of Cardiology Expert Analysis. The history of cardiopulmonary bypass: medical advances. https://www.acc.org/latest-in-cardiology/articles/2019/06/19/06/46/the-history-of-cardiopulmonary-bypass.
6. L Melly, G Torregrossa, T Lee, JL Jansens, JD Puskas. Fifty years of coronary bypass grafting. J Thoracic Dis 2018; 1960–1967. Doi: 10.21037/jtd2018.02.43.
7. AL Hawkes, M Nowak, B Bidstrup, R Speare. Outcomes of coronary artery bypass graft surgery. Vascular Health and Risk Management 2006; 2:477–484.
8. ED Grech. Percutaneous coronary intervention. I. History and Development. BMJ 2003; 326:1080–1082.
9. M Barton, J Grüntzig, M Huisman, J Rüsch. Balloon angioplasty—the legacy of Andreas Grüntzig, M.D. (1939–1985). Frontiers in Cardiovascular Medicine 2014; 1(15):1–25. Doi: 10.3389/fcvm.2014.00015.
10. ED Grech.
11. A Roguin. Stent: The man and word behind the coronary metal prosthesis. Circulation: Cardiovascular Interventions 2011; 4:206–209. https://doi.org/10.1161/CIRCINTERVENTIONS.110.960872.
12. R Piccolo, KH Bonaa, O Efthimiou, O Varenne, A Baldo, P Urban, C Kaiser, W Remkes, L Raber, A de Belder, AWJ van’t Hof, G Stankovic, PA Lemos, T Wilsgaard, J Reifart, AE Rodriguez, EE Ribeiro, PWJC Serruys, A Abizaid, M Sabate, RA Byrne, JMT Hernandez, W Wijns, P Juni, S Windecker, M Valgimigli, on behalf of the Coronary Stents Trialists’ Collaboration. Lancet 2019; 393: 2503–2510. DOI: https://doi.org/10.1016/S0140-6736(19)30474-X.
LO Jansen and EH Christensen. Are drug-eluting stents safer than bare metal stents? Lancet 2019; 393:2472–2474. DOI: https://doi.org/10.1016/S0140-6736(19)31000-1.
13. European Coronary Surgery Study Group. Long-term results of prospective randomized study of coronary artery bypass surgery in stable angina patients. Lancet 1992; 320:1173–1180. DOI: https://doi.org/10.1016/S0140-6736(82)91200-4.
14. CASS Principal Investigators and Their Associates. Myocardial infarction and mortality in the Coronary Artery Surgery Study (CASS) randomized trial. N Engl J Med 1984; 310:750–758. DOI: 10.1056/NEJM198403223101204.
15. The VA Coronary Artery Bypass Surgery Cooperative Study Group. Eighteen-year follow-up in the Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery for Stable Angina. Circulation 1992; 86:121–130.
16. T Takaro, P Peduzzi, KM Detre, HN Hultgren, ML Murphy, J van der Bel-Kahn, J Thomsen, WR Meadows. Survival in subgroups of patients with left main coronary artery disease. Veterans Affairs Cooperative Study of Surgery for Coronary Arterial Occlusive Disease. Circulation 1982; 66:14–22.
17. ClinicalTrials.gov. Completed interventional trials of stents in coronary artery disease. Accessed July 5, 2020, https://clinicaltrials.gov/ct2/results?term=stents&cond=Coronary+Artery+Disease&recrs=e&age_v=&gndr=&type=Intr&rslt=&Search=Apply#.
18. RJ Gibbons, K Chatterjee, J Daley, JS Douglas, SD Fihn, JM Gardin, MA Grunwald, D Levy, BW Lytle, RA O’Rourke, WP Schafer, SV Williams, JL Ritchie, MD Cheitlin, KA Eagle, TJ Gardner, A Garson, RO Russell, TJ Ryan, SC Smith. ACC/AHA/ACP—ASIM Guidelines for the Management of Patients with Chronic Stable Angina: Executive Summary and Recommendations. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on Management of Patients with Chronic Stable Angina). Circulation 1999; 99:2829–2848. https://doi.org/10.1161/01.CIR.99.21.2829.
19. The Bypass Angioplasty Revascularization (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996; 335:217–225.
20. The BARI-2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009; 360:2503–2515.
21. WE Boden, RA O’Rourke, KK Teo, PM Hartigan, DJ Maron, WJ Kostuk, M Knudtson, M Dada, P Casperson, CL Harris, BR Chaitman, L Shaw, G Gosselin, S Nawaz, LM Title, G Gau, AS Blaustein, DC Booth, ER Bates, JA Spertus, DS Berman, J Mancini, WS Weintraub, for the COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007; 356:1503–1516.
22. CinicalTrials.gov. SYNTAX Study: TAXUS drug-eluting stent versus coronary artery bypass surgery for the treatment of narrowed arteries (SYNTAX). https://clinicaltrials.gov/ct2/show/NCT00114972?term=SYNTAX+Trial&draw=2&rank=2.
23. PW Serruys, MC Morice, AP Kappetein, A Columbo, DR Holmes, MJ Mack, E Stahle, TE Feldman, M van den Brand, EJ Bass, N Van Duck, K leadley, KD Dawkins, FW Mohr, for the SYNTAX Investigators. P ercutaneous coronary intervention versus coronary-artery bypass grafting for sever coronary artery disease. N Engl J Med 2009; 360:961–972.
24. SD Fihn, JM Gardin, J Abrams, K Berra, JC Blankenship, AP Dallas, PS Douglas, JM Foody, TC Gerber, AL Hinderliter, SB King, PD Kligfield, HM Krumholz, RYK Kwong, MJ Lim, JA Linderbaum, MJ Mack, MA Munger, RL Prager, JF Sabik, LJ Shaw, JD Sikkema, CR Smith, SC Smith, JA Spertus, SV Williams. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Intervention, and Society of Thoracic Surgeons. Circulation 2012; 126:e354-e471. DOI: 10.1161/CIR.0b013e318277d6a0.
25. DJ Maron, JS Hochman, HR Reynolds, S Bangalore, SM O’Brien, WE Boden, BR Chaitman, R Senior, J López-Sendón, KP Alexander, RD Lopes, LJ Shaw, JS Berger, JD Newman, MS Sidhu, SG Goodman, W Ruzyllo, G Gosselin, AP Maggioni, HD White, B Bhargava, JK Min, GBJ Mancini, DS Berman, MH Picard, RY Kwong, ZA Ali, DB Mark, JA Spertus, MN Krishnan, A Elghamaz, N Moorthy, WA Hueb, M Demkow, K Mavromatis, O Bockeria, J Peteiro, TD Miller, H Szwed, R Doerr, M Keltai, JB Selvanayagam, PG Steg, C Held, S Kohsaka, S Mavromichalis, R Kirby, NO Jeffries, FE Harrell, FW Rockhold, S Broderick, TB Ferguson, DO Williams, RA Harrington, GW Stone, Y Rosenberg, ISCHEMIA Research Group. I nitial invasive or conservative strategy for stable coronary disease. N Engl J Med 2020; 382:1395–1407. doi: 10.1056/NEJMoa191592.
26. Maron, et al., Table 2.
27. N Sikri, A Bardia. A history of streptokinase use in acute myocardial infarction. Texas Heart Inst J 2007; 34:318–327.
28. JW Kennedy. Streptokinase for the treatment of acute myocardial infarction: a brief review of randomized trials. J Am Coll Cardiol 1987; 10:28B-32B.
29. GISSI. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1:397·402.
30. F Rovelli, C De Vita, GA Feruglio, A Lotto, A Selvini, G Tognoni and GISSI Investigators. GISSI Trial: early results and late follow-up. J Am Coll Cardiol 1987; 10:33B-39B.
31. E Braunwald, MS Sabatine. The Thrombolysis in Myocardial Infarction (TIMI) group experience. J Thorac Cardiovasc Surg 2012; 144:762–770.
The TIMI Study Group. The Thrombolysis in Myocardial Infarction Trial—Phase I Findings. N Engl J Med 1985; 312:932–936. DOI: 10.1056/NEJM19850404.
JH Chesebro, G Knatterud, R Roberts, J Borer, LS Cohen, J Dalen, HT Dodge, CK Francis, D Hillis, P Ludbrook, JE Markis, H Mueller, ER Passamani, ER Powers, AK Rao, T Robertson, A Ross, TJ Ryan, BE Sobel, J Willerson, DO Williams, BL Zaret, E Braunwald. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987; 76:142–154.
Gruppo Italiano per la Sperimentazione della Streptchinasi nell’Infarto Miocardico. GISSI-2: a factorial randomized trial of altepase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Lancet 1990; 8797:65–71.
ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomized comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin versus aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 1992; 8976:753–770. DOI: https://doi.org/10.1016/0140-6736(92)91893-D.
32. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329:673–672.
33. EJ Topol. Coronary angioplasty for acute myocardial infarction. Ann Intern Med 1988; 109:970–980.
34. KB Michels, S Yusuf. Does PTCA in acute myocardial infarction affect mortality and reinfarction rates? A quantitative overview (meta-analysis) of the randomized clinical trials. Circulation 1995; 91:476–485. https://doi.org/10.1161/01.CIR.91.2.476.
35. The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. A clinical trial comparing primary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1997; 336:1621–1628.
36. JS Hochman, LA Sleeper, JG Webb, TA Sanborn, HD White, JD Talley, CE Buller, AK Jacobs, JN Slater, J Col, SM McKinlay, TH LeMetel, for the SHOCK Investigators. N Engl J Med 1999; 341:625–634.
37. EC Keeley, JA Boura, CL Grines. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomized trials. Lancet 2003; 361:13–20.
38. JS Hochman, GA Lamas, CE Buller, V Dzavik, HR Reynolds, SJ Abramsky, S Forman, W Ruzyllo, AP Maggione, H White, Z Sadowski, AC Carvalho, JM Rankin, JP Renkin, PG Steg, AM Mascette, G Sopko, ME Pfisterer, J Leor, V Fridrich, DB Mark, GL Knatterud, for the Occluded Artery Trial Investigators. Coronary intervention for persistent occlusion after myocardial infarction. N Engl J Med 2006; 355:2395–2407.
39. ClinCalc DrugStats Database. The top 200 drugs of 2020. https://clincalc.com/DrugStats/Top200Drugs.aspx.
40. P O’Gara, FD Kushner, DD Ascheim, DE Casey, MK Chung, JA de Lemos, SM Ettinger, JC Fang, FM Fesmire, BA Franklin, CB Granger, HM Krumholz, JA Linderbaum, DA Morrow, LK Newby, JP Ornato, N Ou, MJ Radford, JE Tamis-Holland, CL Tommaso, CM Tracy, YJ Woo, DX Zhao. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. JACC 2013; e78-e140.
EA Amsterdam, NK Wenger, RG Brindis, DE Casey, TG Ganiats, DR Holmes, AS Jaffe, H Jneid, RF Kelly, MC Kontos, GN Levine, PR Liebson, D Mukherjee, ED Peterson, MS Sabatine, RW Smalling, SJ Zieman. 2014 AHA/ACC Guidelines for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. JACC 2014; 64:e139-e228.
41. HM Krumholz, J Herrin, LE Miller, EE Drye, SM Ling, LF Han, MT Rapp, EH Bradley, BK Nallamothu, W Nsa, DW Bratzler, JP Curtis. Improvements in door-to-balloon time in the United States, 2005–2010. Circulation 2011; 124:1038–1045. doi:10.1161/CIRCULATIONAHA.111.044107.
42. ES Ford, UA Ajani, JB Croft, JA Critchley, DR Labarth, TE Kottke, WH Giles, S Capewell. Explaining the Decrease in U.S. Deaths from Coronary Disease, 1980–2000. N Engl J Med 2007; 356:2388–2398. DOI: 10.1056/NEJMsa053935.
43. L Chacko, JP Howard, C Rajkumar, AN Nowbar, C Kane, D Mahdi, M Foley, M Shun-Shin, G Cole, S Sen, A Al-Lamee, DP Francis, Y Ahmad. Effects of percutaneous coronary intervention on death and myocardial infarction stratified by stable and unstable coronary artery disease. A meta-analysis of randomized controlled trials. Circ Cardiovasc Qual Outcomes Feb. 2020; 13:e006363. DOI: 10.1161/CIRCOUTCOMES.119.006363. https://www.ahajournals.org/doi/pdf/10.1161/CIRCOUTCOMES.119.006363.
44. M Ragosta, S Dee, IJ Sarembock, LC Lipson, LW Gimple, ER Powers. Prevalence of unfavorable angiographic characteristics for percutaneous intervention in patients with unprotected left main coronary artery disease. Catheter Cardiovasc Interv 2007; 68:357–362. doi: 10.1002/ccd.20709.
45. D Maron, et al.
46. L Chacko, et al.
47. FA Masoudi, A Ponikaris, JA de Lemos, JG Jollis, M Kremers, JC Messinger, JWM Moore, I Moussa, WJ Oetgen, PD Varosy, RN Vincent, J Wei, JP Curtis, MT Roe, JA Spertus. Trends in U.S. cardiovascular Care. 2016 Reports from 4 ACC National Cardiovascular Registries. J Am Col Cardiol 2016; 69:1427–1450.
48. Morbidity and Mortality. 2012 Chartbook on Cardiovascular, Lung and Blood Diseases, NIH-NHLBI. Chart 3–22. https://www.nhlbi.nih.gov/files/docs/research/2012_ChartBook_508.pdf.
JE Dalen, JS Alpert, RJ Goldberg, RS Weinstein. The epidemic of the 20th century: Coronary Heart Disease. The American Journal of Medicine 2014; 127:807–812.
49. PA Kavsak, AR MacRae, V Lustig, R Bhargava, R Vandersluis, GE Polomaki, ML Yerna, AS Jaffe. The impact of the ESC/ACC redefinition of myocardial infarction and new sensitive troponin assays on the frequency of acute myocardial infarction. Am Heart J 2005; 152:118–125.
50. Morbidity and Mortality. 2012 Chartbook on Cardiovascular, Lung and Blood Diseases, NIH-NHLBI. Charts 3–22, 3–23, and 3–24. https://www.nhlbi.nih.gov/files/docs/research/2012_ChartBook_508.pdf.
Health, United States. 2012 Updates. https://www.cdc.gov/nchs/data/hus/2012/001.pdf.
51. RW Yeh, S Sydney, M Chandra, M Sorel, JV Selby, AS Go. Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med 2010; 362:2155–2165.