Protecting the Heart [and the Brain]
words by eve jacobs / photograph by pete byron
ohn Kostis has “written the book” on preventing heart disease and
stroke and that book is far from finished. A leader in clinical trials that have defined the way medicine is now practiced worldwide, he participated in developing more than 100 pharmacologic agents and devices, some of which decrease heart attack risk, increase the chance of surviving heart attack and make recurrence less likely.
He was the first to construct and use a Doppler ultrasound for diagnosis in cardiology and developed the Myocardial Infarction Data Acquisition System (MIDAS), a compilation of all data related to heart attacks in NJ over the last 20 plus years.
The MIDAS team had their minute of fame on Saturday Night Live more than 15 years ago.
“Happy birthday and good-bye” was the episode’s memorable quip, referring to the group’s finding that having a heart attack on your birthday is about 20 percent more likely than on other days. Recently, the MIDAS team published a lead paper in the New England Journal of Medicine indicating that persons admitted to hospitals with heart attacks on weekends are more likely to die, possibly because they receive different treatment. Some have called it “the never-on-Sunday” paper. These are the more quotable nuggets from Kostis’ studies — although the real essence of his work involves reams of data, tongue-twisting drug names and trials titled with acronyms that defy remembering.
One such massive undertaking called MIDAS — launched and directed by Kostis—has monitored the occurrence, characteristics, diagnostic and therapeutic invasive procedures, and outcomes of all heart attacks occurring in the state since 1986. “Just think about this,” says the cardiologist excitedly, “we’ve determined and published data on what type of patient gets a second heart attack, a pacemaker, a balloon angioplasty, a stent. We’ve reported on disparities in incidence, management, and outcomes in men and women, different ethnic groups and different ages, and on what percentage has diabetes, lung disease and other co-morbidities.”
The 2,500 Google hits on Kostis will take you to other major clinical trials such as ALLHAT— the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; SHEP — the Systolic Hypertension in the Elderly Program; TONE — the Trial of Nonpharmacologic Interventions in the Elderly; SOLVD — the Studies of Left Ventricular Dysfunction; HF-ACTION — a Congestive Heart Failure Trial Investigating Outcomes of Exercise Training; HAT — the Home Automatic External Defibrillator Trial; and TNT— Treating to New Targets. (A paper authored by Kostis and his team, analyzing the TNT trial, was awarded a “best paper” prize at the 2008 meeting of the International Society of Hypertension.)
So, with this alphabet soup of drug and lifestyle studies of cardiovascular disease therapies, where do we begin?
“Let’s start with the cholesterol story,” he says. “Then we’ll go on to the blood pressure story.” Closely intertwined when it comes to the health of the heart, each has its own tale to tell.
The Cholesterol Story
It was 30 years ago that the cardiology team at UMDNJ-Robert Wood Johnson Medical School landed its first blow to coronary heart disease. “The story of stopping heart disease with cholesterol-lowering starts right here — in New Jersey,” Kostis says proudly. Working with Abel Moreyra, MD, under the direction of the late Peter T. Kuo, MD, “we were the first to prove that you can stabilize and, in some instances, improve coronary heart disease by lowering cholesterol with diet and medication,” Kostis states. Since many did not believe that this “progressive” disease could be stopped, the team published many of their arteriograms to make their point. But it took close to a decade for physicians, then the public, to fully comprehend a fact we now take for granted—that there is a close connection between the chance of a heart attack and how much you lower the bad (LDL) cholesterol with lifestyle changes and medications.
“Statins came on the scene in the ’80s and changed everything. They made treatment easier,” relates Kostis. The 10,001-patient TNT trial showed that lowering the bad cholesterol to 77 mg/dL (below the target of 100) decreased the rate of major cardiovascular events. In this study, Kostis, along with other investigators nationwide, reported that for LDL, “the lower the better,” since cutting the levels below 77 — even as low as 40 — resulted in better outcomes.
Niacin played a leading role in early coronary disease studies at RWJMS. Now the vitamin and old work-horse in the cholesterol-lowering pharmacopeia is back on the scene. Not only does it decrease bad cholesterol, but increases the “good cholesterol” (HDL), according to Kostis. The “niacin flush”— a side effect of tingling and redness most often on the face and trunk—has been a deal-breaker for many patients. But the cardiologist says that a new formulation of the drug has fewer side effects and is equally potent.
“Niacin can increase good cholesterol by 25 percent,” explains Kostis, “but researchers are always looking for something better.” In a 13,000 patient clinical trial, investigators, including the team at RWJMS, found that another drug shown to increase good cholesterol, torcetrapib, also almost doubled mortality. “This is further evidence of why we need clinical trials,” he says. “What appears logical sometimes proves dangerous.”
Currently Kostis’ team is recruiting patients in another NIH sponsored clinical niacin trial, AIM-HIGH — Atherthrombosis Interventions in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes. In this study, niacin and a statin are used to control the LDL to the same level in all patients and increase the good cholesterol only in half of them in a double blind fashion.
The Blood Pressure Story
Hypertension is another story. It affects one out of three — 72 million — Americans. While most of us are well aware of the physical devastation it can wreak, about 20 million Americans are unaware of their condition.
The malady, referred to colloquially as “pressure,” cuts unevenly over racial lines and is more common and more severe in African Americans, resulting in a seven-times greater likelihood of developing kidney disease. Kidney failure caused by hypertension in black Americans is 10 to 20 times higher in the 25 to 44 age group than in white Americans of the same age.
The bottom line is “hypertension is treatable and should be treated at all ages, even in those over 85, to ward off cardiovascular disease,” says Kostis.
“Clinical trials have clearly documented the benefits of lowering blood pressure,” he says, pointing first to SHEP. Involving 4,500 participants age 60 and older with isolated systolic hypertension, it was the first study focusing on older people with high systolic (the top number), but with normal diastolic (the bottom number), blood pressure. In this study, patients were either given a placebo or a diuretic followed by other drugs as necessary. “We found that this simple treatment reduced the stroke risk by 36 percent, the risk for coronary disease by 25 percent and the risk of heart failure by more than 50 percent. There are few things doctors do that reduce patient-risk of anything by more than 50 percent,” he says.
“A major criticism of clinical trials is that they don’t continue long enough,” states Kostis. Because of this and because treatment of hypertension with diuretics can increase blood sugar and sometimes bring on diabetes, the cardiologist and his team followed SHEP patients for more than 14 years in a trial called SHEP-X (for extension). Their published results show that patients treated with the diuretic chlorthalidone had the best long-term outcomes and that diabetes occurring during treatment was not as big a problem as the diabetes acquired by eating too much and exercising too little.
The same diuretic was used in ALLHAT, which enrolled more than 42,000 volunteers age 55 and older. The diuretic was compared with three newer blood pressure-lowering drugs and was found to have similar or slightly better outcomes; all four drugs studied in ALLHAT were found to be effective in lowering blood pressure. Kostis sums up the published results this way: in more than 10,000 ALLHAT patients with hypertension and diabetes, the diuretic resulted in improved outcomes. “The most important target is to lower blood pressure. In patients without prior heart attack or stroke, again, the lower the better. It doesn’t really matter which drug you use, especially since many patients need two or three drugs, or more in diabetics, to control the blood pressure,”
But controlling blood pressure alone is not enough. “You achieve the best results when both cholesterol and blood pressure are controlled. And if you stop smoking and control the blood pressure, too, you can cut cardiovascular risk to less than half,” he explains. Epidemiologic studies conducted over the last 30 years have proven that risk factors for CVD do not occur in isolation, and most strokes and heart attacks happen in patients who have modest abnormalities in more than one risk factor.
Keeping such statistics in mind, Kostis continues to advocate for a “global approach” to preventing heart disease that focuses on all major risk factors that can be changed, including smoking, high cholesterol, high blood pressure, obesity and diabetes. “Focusing on just one or two of these risk factors is not enough” he says.
Now Comes the Hard Part
Popping a pill is not all that hard. But losing excess weight, pushing yourself off the couch, cutting down on fat, cholesterol and salt in your diet, and tossing out the cigars and cigarettes are everyday challenges. Those come first in the battle against heart disease, heart attack and stroke, and then come the drugs.
While there has been a major decline in the number of deadly heart attacks and strokes in NJ, and the average age when these happen has been postponed about four years, the number of nonfatal heart attacks and strokes suffered by New Jerseyans is actually increasing, states Kostis. Some major questions remain to be answered.
“Exercise,” says Kostis. “Is it good for you? Is it good for everyone? Just a few years ago we didn’t know if exercise places heart failure patients at high risk.”
How do you find out? A clinical trial, of course. In HF-ACTION, “we found that supervised exercise benefits heart failure patients and does them no harm.” More than 2,300 patients from 82 sites in the US, Canada and France, with an average age of 59, were given a strict exercise regimen and followed for an average of 2.5 years. The trial results, released just a few months ago, demonstrate a lower risk of hospitalization and death for heart failure patients who worked out on a stationary bicycle or walked on a treadmill for 25 to 30 minutes a day, three to five sessions a week.
The Rest of the Story
So, what else have we learned about the ticking of the heart from clinical trials?
According to Kostis, new insights and new medications are coming on fast and furiously. The investigators at the Cardiovascular Institute of New Jersey and Division of Cardiology at RWJMS are currently conducting more than 50 clinical research protocols, among them a clinical trial targeting atrial fibrillation, which he calls an “epidemic. You get clots in the heart, which may go to the brain and cause stroke,” he says, explaining that a blood thinner, such as Warfarin, is needed. “But while it decreases the rate of stroke, it increases the rate of bleeding, making the blood too thick or too thin, and necessitating blood tests at least once monthly forever.” The clinical trial called RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy: dabigatran etexilate vs Warfarin for preventing stroke and systemic embolic events in atrial fibrillation) compares the test drug, dabigatran etexilate, which doesn’t require constant monitoring, to Warfarin. Kostis says the results will be presented soon.
Although for most of us the acronyms identifying the many clinical trials in cardiology are just a scramble of letters, Kostis rattles them off without a hitch.
“How do you remember them?” I ask him.
“Because this is my life,” he says. “This is what I do