The Magic Bullet

Dr. Robert Guthrie

The first two articles of our series focused on two of the most important medical problems that we treat to prevent the development of heart disease, or more specifically the development of coronary atherosclerosis, the hardening of the arteries of the heart leading to heart attack. Now, I will build on the previous advice by discussing the treatments to take if you have already experienced a heart attack or stroke.

Mechanism of Heart Attack

While the process that leads up to a heart attack is very complex, the heart attack itself involves a cascade of events that start very subtlety then rapidly proceed to a climax. In general, a heart attack occurs at a partial blockage in one of the arteries that supply blood to the muscles of the heart. These blockages, called plaques, are relatively common developments as we age, and are frequently small, obstructing only about 20% of the artery.

Heart attacks happen when the blockages rupture, spilling their contents into the artery of the heart. The contents from the ruptured plaque set off the clotting mechanisms inside the artery, leading it to clot off completely and almost instantaneously. The actual mechanisms of the clotting are very complex, but it begins with activation of the platelets, which then trigger the clotting process. Efforts to inhibit the activation of the platelets to decrease the likelihood of a plaque rupture setting off the complete clotting process include having the patients take a daily aspirin, which inhibits one of the platelet activation mechanisms. Plavix (®), or clopidogrel, is another potent inhibitor of platelet activation, and is widely used in patients who have already developed a heart attack or a stroke.

Why the plaques tend to rupture remains a point of great medical interest and debate, though certain risk factors such as elevated cholesterol, systemic inflammation, high blood pressure, and high blood sugar are associated with plaque rupture and subsequent heart attack. Treating these, specifically reducing cholesterol and controlling blood pressure, decrease heart attack risk, however, the exact mechanisms at the level of plaque formation and plaque rupture are still under investigation.

Questions that Patients with Heart Disease Would Like to Ask (but usually don't get the chance to):

Why do they want me to take all of these new medications?

In an ideal situation, after the first appearance of significant chest pain a patient will call the emergency squad for transport to a hospital with specialized heart facilities. Once there, a patient with an apparent fresh heart attack will be rushed into the heart catheterization lab, where X-ray dye will be injected into the arteries of the heart. If this test shows a suspect blockage(s), then they will open the blockages up with a balloon angioplasty, by inserting a tiny balloon across the blockage, inflating the balloon to open the artery, and then inserting a circular metal mesh stent that pops open to keep the newly opened artery open.

However, the angioplasty and stent repair only treat some of the plaque areas in the system of arteries that supply the heart muscle, leaving many smaller plaque areas untouched since those early plaques are too small to be causing acute problems. The typical patient who needs an angioplasty and a stent will also have five or six other plaques causing partial blockages already formed in their heart arteries, usually blocking only about 20% of the artery where they are located. Any of these could rupture at any time in the future, leading to another clot and complete blockage of an artery in a location totally different than the one previously fixed with the stent. Therefore, while the angioplasty and stent have opened up the critical blockage(s) causing the heart attack, this patient is at a very high risk of another heart attack in the future.

As we have researched the prevention of heart attacks over the years, several specific groups of medications have been shown clearly to reduce subsequent heart attacks in patients with heart disease. Two agents work by reducing the stickiness of the platelets, the agents in the blood stream that set off the mechanism leading to clotting on top of a ruptured plaque. The first of these is an old friend, aspirin,—the original chemically produced medication, artificially developed by Bayer in Germany in the 1880s. Prior to aspirin’s development, all medications used were direct extracts of plant compounds, such as digitalis leaf which was extracted from the foxglove plant. Over the last several decades, aspirin has been widely used for the reduction of heart attack and stroke in patients at risk of those problems. While there is some debate as to whether patients without previous stroke or heart attack should be taking aspirin strictly as a preventative, there is consensus that all patients with heart disease or stroke will benefit from long term aspirin therapy. Recently, we have come to recognize that aspirin is just as effective when used in the very low daily dose of 81 mg, originally the children’s dose here in the United States. While aspirin is known to cause bleeding of the stomach and intestinal system, using the much lower dose of 81 mg reduces, but does not eliminate, that risk.

Clopidogrel (Plavix®) also reduces the stickiness of platelets, though using a different mechanism than aspirin. It has become standard long term therapy in addition to aspirin, to prevent recurrent heart attacks. Clopidogrel has recently become a low cost generic medication, reducing its cost for long term use considerably. Several other similar agents have been brought to the market, like prasugrel (Efficent®), but their long term use in the market is yet to be determined. Adding clopidogrel to daily aspirin does slightly increase the risk of bleeding problems, but this risk overall is low and acceptable if the aspirin dose is limited to 81 mg.

Statin therapy, as the HMG-CoA reductase inhibitor drugs that are very potent lowers of cholesterol in the blood are called, is also mandatory treatment for any person with a previous heart attack or stroke. These agents, which include simvastatin (Zocor®), atorvastatin (Lipitor®), and rosuvastatin (Crestor®), lower cholesterol significantly, and with that also reduce recurrent heart attack and even death from heart attack. They work so well at reducing heart attack that all heart attack patients, regardless of their cholesterol level, need to be aggressively treated with one of the statin agents. These agents target the LDL cholesterol level, lowering our target for that level to less than 70 mg/dl, which is much lower than our treatment goal just a few years ago. These agents are extremely safe, with only very rare major muscle problems, and the concern about liver issues has been curbed just recently, with the FDA no longer recommending monitoring of liver enzymes.

Interestingly, recent research can offer more specific guidance on how to direct our statin, or cholesterol lowering treatments. First, several studies have shown that, in patients who have already had heart problems or stroke, we need to be very aggressive with our statin therapy, aiming to lower the LDL (or bad cholesterol) to a level of 70 mg/dl or lower. This often means prescribing higher doses of the more potent statins like atorvastatin (Lipitor®) or rosuvastatin (Crestor®). The fact that atorvastatin has recently become a low cost generic medication will make this much easier to implement.

Secondly, recent research has shown that adding a second cholesterol medication of a different type, specifically niacin or a fibric acid medication, to increase the HDL (good cholesterol) and lower the triglycerides did not reduce the heart attack rate when compared to statin therapy by itself. So, even though patients and physicians are tempted to add another cholesterol agent, the more is better philosophy isn't true in this instance.

Beta Blockers are medications with a long history of use in the treatment of a wide variety of heart ailments. For the last several decades, beta blockers have been known to reduce recurrent heart attack in patients with a previous heart attack. Their mechanisms of action that produce this benefit are complex, but basically they block the effects of the adrenergic, or adrenalin, nervous system. This effect lowers the rate of heart beats and reduces the needs for oxygen by the heart muscle. These and other effects lower the strain on the heart muscles, reducing the risk for heart attack, angina pectoris (chest pain from reduced blood supply to the heart muscle), and dangerous abnormal rhythms of the heart beat. A wide variety of beta blockers are on the market, with two of the most popular being metoprolol ER (Toprol XL®) and atenolol (Tenormin®). Several of the beta blockers have been shown to help patients who have developed heart failure, where the heart muscle is so damaged that it struggles to pump the blood throughout the body. Beta blockers are also used to treat other conditions like migraine headaches, tremors, or shaking of the hands. While the beta blockers can have a variety of side effects, including fatigue, lethargy, and sexual dysfunction, these are manageable, especially considering the life saving potential for these agents.

Angiotensin Inhibitors, commonly called ACE inhibitors, are also requisite therapy in patients with known heart disease. These agents were initially developed to treat high blood pressure, which they do very well. Over the years, they have been studied and proven to be useful in a wide variety of conditions, including heart failure, kidney disease, and in the prevention of diabetic kidney disease. Several studies showed that ACE inhibitors were valuable in all patients with known heart disease, regardless of whether the blood pressure is already controlled. The exact mechanism of how these agents reduce heart disease is not clear, but they block a different reflex system in the body called the renin-angiotensin, or RAAS, system, reducing recurrent heart attack and even the development of heart failure. ACE inhibitors are generally well tolerated, and their cost is low since they are all inexpensive generic medications. Their most common side effect is a dry, tickle in the throat cough. Very rarely they can cause a condition called angioedema, with a swelling of the lips, face, and throat.

When patients cannot tolerate an ACE inhibitor, there has been interest in similar agents that also affect the RAAS system, known as Angiotensin Receptor Blockers, or ARBs. The ARBs block the RAAS at a different point than the ACE inhibitors, leading to the assumption that they might be able to reduce recurrent heart attack also. At this point, only one agent in this class, telmisartan (Micardis®), has been studied and found to be as effective as an ACE inhibitor in preventing recurrence of a heart problem. However, in this class of agents, there are considerable differences in potency between the various drugs on the market, so we cannot assume that the other ARBs will have the same benefit. Therefore, if a person with a known heart problem cannot take an ACE, telmisartan is the only ARB that we know can produce the same degree of protection an ACE would. This is not a popular statement, since Micardis® is a more expensive brand medication, while the cheaper generic ARBs, losartan and valsartan, might not be effective in these complicated patients.

When all five of these groups of medications are combined, they are what I call the Post Angioplasty Cocktail. Every newly diagnosed heart attack patient should start taking this panel at the time of their hospital admission. Repeated efforts by hospitals and other groups have been made to establish a pattern of use of all five of these medications in heart attack patients.

What else can I do to reduce my risk of another heart attack besides taking my medications?

There are a number of lifestyle issues that will reduce your risk of a second heart attack. Chief among them is to not smoke or to quit smoking if you do already. Cigarette smoking is one of the greatest risks for the development of initial or repeat heart attacks. While it is not easy and involves many issues in the lives of smokers, quitting cigarette smoking is critical.

For most of our patients who do not smoke, there are other key lifestyle issues. Maintaining an exercise or activity regimen is extremely important after someone has been stricken with heart disease. Almost all communities now have official cardiac rehabilitation programs. These programs are directed by trained physicians and therapists that will develop a conditioning program appropriate for each individual patient. The critical issue for the patient is to continue the activity program after they have been graduated from the official rehabilitation program. It is very tempting for patients to go back to their old unhealthy lifestyle, but do not fall into that trap. Research has shown over and over again that a physically active lifestyle reduces the risk for heart disease, both before and after the first heart problem has developed. Though the exact mechanism that produces this benefit is unclear, the importance of a regular physical activity regimen is very clear. While we certainly cannot control our weight without an exercise program, the exercise program itself is what produces the greatest benefit to the reduction of our heart attack risk.

Other lifestyle issues are less clear. Dietary modification is one of those issues. Proper diet is very important for overall health and comfort, but how much proper dietary changes directly reduce repeat heart attack is not clear. Do not misunderstand me. Proper control of our diets is critical in many ways: 

  • controlling our risk for developing diabetes which is driven significantly by our weight and caloric intake
  • reducing the strain on our joints to reduce our rate of arthritis as we get older
  • improving our self image and exercise capacity.

However, the direct effect of traditional diets on reducing heart attack risk is important but less so than the benefit from the correct use of the medications previously discussed.

While we want there to be some magic food for us to eat, like more fish or nuts, it is probably much more important for heart attack prevention that we avoid what we should not eat, like high fat and high calorie foods like bacon cheeseburgers, rather than to expect magical protective properties from other foods.

Advocates for very severe diets, like a vegan or Pritikin diet, claim significant heart benefits, but those diets are so extreme that very few Americans can adhere to them longer than a few weeks. Surgical interventions, like the gastric bypass operations for weight loss, are also drastic and too complicated to discuss in this paper. In general, traditional diets that reduce and control caloric intake and lower cholesterol intake for the long haul over many years are the best option and are important for us to follow.

I see all these ads for food supplements, do they really help?

The direct and simple answer to this question is "No, not at all!" This statement encompasses all of the vitamins, fiber supplements, anti-oxidants, and fish oil supplements that are heavily advertised in all forms of the media. Remember that the food supplement industry is huge, generating multi-billions of dollars in sales every year. Supplements are essentially unregulated by the FDA and manufacturers are not required to prove the claims that they advertise, in contrast to the companies that market prescriptions medications.

The original support for vitamin therapy to reduce heart disease risk came from population studies which found that groups whose diets were higher in fresh fruits and vegetables had less heart disease. While that is true, it led people to jump to the conclusion that it was what the people ate, like fruits or fish, rather than what they did not eat, like bacon cheeseburgers, providing the benefit. This assumption (actually a guess) led to the widely popular belief (hope, actually) that just popping the vitamin pill could substitute for eating a healthy diet.

Actually, a series of very well designed and conducted research trials did look at the question of whether there is any value to vitamin supplements in preventing heart disease. All of these studies showed that the vitamin supplements had no benefit in reducing heart disease (or cancer). Each study compared the vitamin supplement to a placebo (dummy pill) and went for a number of years. Not only did none of the supplements offer any benefit, there were hints that they may actually be harmful: 

  • increased cancer development with beta-carotene
  • possibly increased heart failure with Vitamin E and other anti-oxidants
  • a slight increase in stroke risk when niacin (a B vitamin) was added to statin therapy

Ominously, there is one study that followed thousands of women in Iowa for many years. These women could choose whether to take vitamins or not. The group of women that chose to take vitamins had a higher death rate than the women who did not take vitamins. Interestingly, the group of women who took vitamins and had a higher death rate also led a healthier lifestyle than those who did not take vitamins. This study was conducted by just observing the women, so it is not proof. However, it raises the question of whether vitamins might tend to enhance the disease development process in some fashion.

One study specifically looked at the Homocysteine question. Patients with an increased risk for heart disease frequently have an elevated level of homocysteine, an amino acid, in the blood. Patients with heart disease and an elevated homocysteine were treated with folic acid, a vitamin that reduces homocysteine, versus a placebo (dummy pill). While the folic acid lowered the homocysteine to normal, it had no effect on the risk of heart attack or other heart problems. This study is an important example of the need to do quality research to answer questions like this. Elevated homocysteine in these patients did not cause the increased heart attack risk; it was only a marker for it, so treating it would not make any difference.

Omega-3 Fish Oil supplements are one of the new fads. Again, the rage for this is based on assumptions and a liberal interpretation of limited research. It has long been known that populations that eat a diet higher in fish, but therefore lower in bacon cheeseburgers, have lower rates of heart disease. Again, this observation does not prove that there is a particular benefit in fish versus the well known problems in bacon cheeseburgers. Several years ago there was a marginal study done in which some fish oil supplements were given to patients who had recently experienced a heart attack. However, the study did not have a group that received placebo in comparison, so the results of the study are questionable. Patients that were given the fish oil tablets had a brief reduction in sudden death from heart issues, but no reduction in heart attack. This benefit lasted only about six months and disappeared at one year. The authors of the study concluded that the short term benefit was an effect on the rhythm of the heart, not on the risk of heart attack, which did not change.

All the enthusiasm is based on this one marginal study, with no clear support from other studies. More interesting still, were a series of studies using Omega-3 supplements in patients with heart disease who have defibrillators implanted in their hearts. Of these three studies, two showed no improvement in the heart rhythms, and one study showed an increase in potentially dangerous rhythms, a pattern seen with other agents that affect heart rhythm. Comprehensive studies examing Omega-3 agents are coming in now, with none of them demonstrating any clear long term benefit on heart problems. Based on the lack of clear evidence of benefit and the clear potential for damage to the heart rhythm, I do not recommend these agents, and I would not take one myself. As good long term studies are in process, we may find the use of these agents to be the latest attempt at trying to prove the benefits of food supplement therapy.

Vitamin D deficiency is the other hot issue currently. A variety of researchers have identified that they tend to find lower Vitamin D levels in patients with early heart disease. This observation does not prove that the lower Vitamin D levels are causing the heart disease, merely that the two observations can be seen together, like the homocysteine issue that we discussed earlier. This has led a number of physicians to start patients on Vitamin D therapy without clear evidence that such treatment might reduce heart attack risk.

However, the early studies using a Vitamin D supplement to treat heart disease risk and other problems have not shown any benefit. Indeed, in one study, it seemed to increase the risk of heart problems in those taking it. Therefore, the Vitamin D issue is unclear at best. I suspect that the interest in Vitamin D to prevent heart problems may go the way of the other supplements and probably be of no value. We shall see.

In summary, once a patient has developed a heart attack or similar problem, comprehensive medical care is critical to preventing a repeat heart attack and the complications of heart disease that can develop. Evidence is very clear that comprehensive management by the combination of medications that have been shown to protect the diseased heart is critical for a long and healthy life after that: 

  • Statins to lower cholesterol,
  • Aspirin at 81 mg, clopidogrel (Plavix®) or a similar agent
  • Beta Blockers, and
  • An ACE Inhibitor (or telmisartan-Micardis®).

This cocktail of medications is the magic bullet that we need. A professionally designed exercise program is extremely important, and a cautious low cholesterol and reduced calorie diet is also very helpful. At this point, there is no evidence that the various food supplements marketed to assist in this area actually are beneficial.
Work with you doctor, take your medication, don’t smoke, watch your diet, and exercise.

Robert Guthrie M.D., is both a family physician and a general internist, and he currently is a professor at The Ohio State University in Columbus, OH. At Ohio State, he conducts research projects to develop new medications for the treatment of common disorders like high blood pressure and diabetes. He has published one book, numerous medical articles, has lectured extensively nationally and internationally, and been a long-term participant on local and national radio broadcasts. This column will discuss a wide variety of health topics of interest to the general public.