Heart: An American Medical Odyssey (11 page)

You don’t know it yet, but a blood clot, smaller than a pencil’s eraser, is forming inside one of your coronary arteries, and if it is not dealt with quickly, it can kill you.

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That’s what was happening when Dick Cheney awoke with chest pain in the early-morning hours of June 29, 1988, and was brought to George Washington University Hospital, in DC’s Foggy Bottom neighborhood, six blocks from the White House. When he arrived in the emergency room Congressman Cheney’s blood pressure was 115/70, and his pulse was 64, both normal. But his EKG showed signs of a new MI in the same region affected by heart attacks in 1978 and 1984. This was his third. Cardiologists Allan Ross and P. Jacob Varghese evaluated Cheney and
recommended urgent cardiac catheterization to determine the site of the likely coronary occlusion.

Dr. Ross had come to GW from Yale about a decade earlier and was an internationally known expert in the management of acute myocardial infarction, having helped to pioneer some of the revolutionary new drugs. Dr. Varghese, a legendary clinician, had come to GW from Johns Hopkins around the same time and was the director of the cardiac care unit.

After puncturing the femoral artery at the top of Cheney’s right leg, Ross guided a catheter to the heart, maneuvering it into the aorta and the origin of the coronary arteries where an injection of contrast dye revealed an old occlusion of the circumflex branch (unchanged from 1984) and a new clot blocking the right coronary artery. Ross intended to open the artery with a balloon, but a mechanical malfunction in the cath lab forced him to change his plan. Instead Cheney was administered tissue plasminogen activator (tPA), the new intravenous “clot buster” approved by the FDA seven months earlier.

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In the late 1970s, Dr. Marcus DeWood set out to prove once and for all that blood clots caused heart attacks. DeWood and his colleagues at the University of Washington performed coronary angiography in about three hundred heart attack patients admitted to hospitals in Spokane and Seattle. The demonstration that it was both feasible and safe to perform cardiac catheterization during an acute heart attack was itself a groundbreaking achievement. DeWood found that when angiography was performed within a few hours of symptom onset, it showed that almost 90 percent of the patients had a totally blocked coronary artery, and in many of these patients, a culprit blood clot could be extracted from the vessel. Importantly, when other patients in the study were imaged later, up to twenty-four hours after the onset of pain, fewer arteries were closed, suggesting that with time, some clots spontaneously dissolve, raising the possibility that this intrinsic “clot-busting” process might be induced therapeutically.

At about the same time that DeWood’s study was under way, several groups were working to prove that not all of the at-risk heart muscle (the myocardium) died immediately after a coronary artery closed.
Using a laboratory model involving the temporary occlusion of a dog’s coronary, Keith Reimer from Duke University and Robert Jennings from Northwestern demonstrated that myocardium died over hours, limited initially to the innermost layer of the heart (subendocardium) and over time extending through the full thickness of the muscle to the outermost layer (subepicardium). They showed that if blood flow was restored within fifteen minutes, no permanent heart damage occurred.
Progressively longer occlusions resulted in progressively larger amounts of muscle death, and restoration of blood flow after about six hours would not salvage any muscle at all. The implication of this work was profound: a heart attack could be interrupted, but time was of the essence.

With the cardiology community finally convinced that a typical heart attack resulted from a blood clot and with a potential therapeutic window of several hours, the approach to the management of heart attacks changed from the old largely defensive, watch-and-wait strategy, to a new offensive attempt to open the occluded vessel and salvage heart muscle. But how to open the artery?

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Each of us has more than sixty thousand miles of blood vessels, mostly comprising a microscopic maze of billions of capillaries. The five liters of blood coursing through this complex vascular network must be kept in careful biochemical balance, also known as homeostasis. If blood is too “thin,” spontaneous hemorrhage may occur, and if it is too “thick,” clots may develop.

In 1933, William Tillett and R. L. Garner, working at the Johns Hopkins Medical School in Baltimore, discovered the novel ability of cultures of streptococcal bacteria to completely liquefy a previously solid blood clot. This bacterial protein, which was later called streptokinase, was found to exert its “fibrinolytic” effects by activating a naturally
occurring protein in human blood called plasminogen and converting it to the active enzyme plasmin, which dissolves the fibrin meshwork of a thrombus.

Tillett and his colleagues initially used streptokinase to treat patients with pneumonia or tuberculosis who had developed large gelatinous collections in the pleural space that surrounds the lung. A direct injection of streptokinase into the pleural space between the lung and the chest wall dissolved much of the thick material, enabling drainage from the space and reexpansion of the lung. In 1951, Tillett showed that an experimentally induced clot in an ear vein of a rabbit could be opened when streptokinase was administered systemically, and in the late 1950s, intravenous streptokinase was evaluated in patients with acute myocardial infarction. Despite some data suggesting a potential mortality benefit when the drug was administered relatively early, streptokinase was largely abandoned in the United States because we did not yet know enough about the mechanics of a heart attack.

Twenty years later, with the pathophysiology of heart attacks much clearer, interest in clot-busting drugs returned. In the late 1970s,
Evgenii Chazov in the Soviet Union and
Peter Rentrop in West Germany separately demonstrated that a direct injection of streptokinase by catheter into an occluded coronary could restore the flow of blood, and in 1984 the FDA approved streptokinase for intracoronary use during myocardial infarction. The downside of this approach was that it was fairly complex, took a significant amount of time to perform, and required the use of a cardiac cath lab, at the time available in only a limited number of hospitals in the United States.

In the years that followed, several very large international clinical research trials, enrolling tens of thousands of patients, proved that streptokinase and tPA, a new drug at that time, produced using recombinant DNA techniques (a process whereby different strands of DNA are combined to produce a “designer” molecule), could open many of the arteries with a relatively simple intravenous administration, and compared with placebo, both drugs significantly improved a patient’s likelihood of surviving a heart attack. In November 1987, the FDA
granted approval for the intravenous use of streptokinase and tPA in the United States. Manufactured by Genentech (and at $2,200 a dose, ten times the cost of streptokinase), tPA was enthusiastically embraced by the medical community in the United States. Accelerated by a study in the early 1990s that found myocardial infarction death rates lower after treatment with tPA than after treatment with streptokinase, annual tPA sales soared to more than $300 million.

At the same time that tPA and streptokinase were revolutionizing the treatment of heart attacks, intense research was under way to identify drugs that would help to prevent such events. In the 1950s and 1960s, driven by the increasing body of data linking serum cholesterol to heart disease, numerous pharmaceutical companies developed an interest in the complex biology governing how cholesterol is manufactured in the body.
In 1956, researchers at one of these companies, Merck, isolated mevalonic acid, a key precursor of cholesterol, and three years later, scientists at the Max Planck Institute in Heidelberg, Germany, discovered the enzyme HMG-CoA reductase, which regulated the key step in mevalonic acid production. Theoretically, inhibition of this enzyme should inhibit the production of cholesterol, and over the next twenty years, researchers around the world hunted for a drug that would do that.

The first HMG-CoA reductase inhibitor was discovered in 1976 in the fermentation broth of the bacterium
Penicillium citrinum
by Japanese researcher Akira Endo. The drug, called compactin, was soon found to be effective at lowering cholesterol levels in rabbits, monkeys, and dogs. Meanwhile, in fall 1978, Merck scientists isolated a substance produced by the fungus
Aspergillus terreus
. The agent, a pure inhibitor of HMG-CoA reductase, was given the name lovastatin, and a US patent was filed in June 1979. In April 1980, Merck began clinical trials of the drug.

In September 1980, the Japanese pharmaceutical company Sankyo abruptly ended development of compactin amid concerns regarding cancers in dogs. Although there had been no such adverse safety signals with lovastatin, Merck quickly terminated development of lovastatin, citing
the safety issues with the closely related compactin. Almost two years later, several clinicians petitioned Merck and the FDA for access to lovastatin for patients with severely elevated cholesterol that could not be controlled by treatment with any commercially available drug. Patients with superaggressive coronary disease and off-the-chart cholesterol levels saw their cholesterol drop by 30 percent or more after just a few weeks of lovastatin therapy. Merck promptly reinstituted animal testing in the drug, including long-term toxicology studies in dogs. Even after high doses, no tumors were found in the animals. Human clinical trials of lovastatin resumed in 1984. Merck found that lovastatin was well tolerated, and resulted in great reductions in LDL cholesterol levels. In November 1986, Merck filed a new drug application with the FDA comprised of 160 volumes of lab, animal, and human data. On August 31, 1987, only nine months after the application was filed, the FDA approved lovastatin for use in patients with high cholesterol not controllable by diet. Sold under the trade name Mevacor, the drug was an immediate commercial success, with annual sales eventually reaching $1 billion.

Hospital admissions for acute myocardial infarction began to drop sharply in 1987, the same year that lovastatin was introduced in the United States. Four years later, pravastatin (Pravachol), a derivative of compactin, and simvastatin (Zocor), a synthetic derivative of lovastatin, were approved by the FDA, and collectively the “statins” became some of the most widely prescribed medications in the world. Although the drugs unequivocally and profoundly decreased cholesterol levels, there remained uncertainty about whether improved lab results would translate to improved outcomes such as a reduction in myocardial infarction or death.

Questions concerning the clinical impact of these drugs were put to rest in 1994 when the Scandinavian Simvastatin Survival Study was published. The trial had assigned several thousand patients with high cholesterol to treatment with simvastatin or placebo and followed these patients for five years. The group of patients treated with simvastatin demonstrated a 30 percent or greater reduction in mortality, coronary events,
or need for angioplasty or bypass surgery. This study became a landmark, effectively removing any lingering doubt concerning the benefit of cholesterol reduction. The studies that followed, using a variety of statins, including the newer atorvastatin (Lipitor) and rosuvastatin (Crestor), confirmed these results for patients both with and without a prior history of coronary disease, as well as those with a history of diabetes, peripheral vascular disease, and stroke.

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Throughout most of the 1980s, Dick Cheney’s cholesterol proved resistant to a variety of drugs like cholestyramine and gemfibrozil. In late 1987, Allan Ross started him on newly approved Mevacor, carefully increasing the dose over the next several months and ultimately reaching 80 mg, the maximum daily dose. In October 1988, Cheney’s total cholesterol level, which a year earlier was over 300, was down to 133. The low-density lipoprotein (LDL) component (aka “bad cholesterol,” because elevated levels are associated with an increased risk of heart disease) had plunged from 163 to 65, a 60 percent reduction.

The clinical impact of this effect in this patient cannot be overstated. In the ten years prior to beginning statin therapy, Dick Cheney was hospitalized six times and experienced three myocardial infarctions, resulting in a loss of about 30 percent of his heart’s ability to contract. In the twelve years that followed, even during periods of high stress, including time as secretary of defense during the Gulf War and CEO of a large multinational corporation, Cheney had not a single cardiac event.

The year 1988 was shaping up to be an active and important one for the nation and for me personally. Ronald Reagan’s second term as president was coming to an end, and there was a major battle in the Republican Party for the nomination to succeed him. I did not get involved in the presidential contest because I was focused on my own campaign to win the second-ranking leadership post among House Republicans.

The incumbent GOP whip, my good friend Trent Lott of Mississippi, was stepping down to run for the Senate. If I could win the race to replace him by a unanimous vote of the GOP Conference, I would be well positioned to succeed Bob Michel as GOP leader or even become the first GOP Speaker in more than thirty years if we captured the majority. As chairman of the House Republican Conference, I was slated to serve as the chair of the Convention Rules Committee. I wanted to take advantage of that assignment to get a rule adopted that would grant floor access at national conventions to all GOP members of Congress. The existing rule allowed only members who had been elected as convention delegates from their home states to have floor access. In addition, I had to get reelected to Congress by the voters of Wyoming for my sixth term in the House.

On the morning of June 29, 1988, believing that I might be having another heart attack, I checked myself into George Washington University Hospital. As before, I didn’t experience any major chest pain or other significant symptoms that I can remember, just a general sensation
that something was wrong. EKG and enzyme tests confirmed that I was indeed having my third heart attack. Dr. Ross recommended that we try to reopen the offending heart artery by administering a newly approved clot-busting drug designed to clear a blocked artery. It seemed to work initially, but two days later, the pain returned, and I was given a second dose. Of my five heart attacks, this one did the most damage. I have a distinct memory of a crisis, with many hospital personnel hurrying into my room trying to deal with my “crashing blood pressure.” During that period, I also recall lying in bed listening to reports that an American cruiser, the USS
Vincennes,
had accidentally shot down an Iranian airliner, with significant loss of life, in the Persian Gulf.