Drug therapy options vary for prevention and treatment of MI

During the past 3 decades, major evidence-based advances in the pharmacologic approach to primary and secondary MI prevention have been introduced into clinical practice. This includes the routine use of lipid-lowering drugs, specifically statins; antiplatelet drugs such as aspirin, clopidogrel and prasugrel; and renin-angiotensin-aldosterone system antagonists (including ACE inhibitors, ARBs, aldosterone blockers, and beta-adrenergic blockers).

“We can no longer look at risk factors for MI in silos,” William H. Frishman, MD, co-editor of the textbook Cardiovascular Pharmacotherapeutics – 3rd edition and a member of the Cardiology Today Editorial Board, said in an interview. “We have to look at the whole patient and the global risk in making clinical decisions about treatment, and patients will often be on agents from all the drug classes recommended for MI prevention.”

Statins

Statins reduce LDL in the blood by blocking the production in the liver of 3-hydroxy-3-methylglutaryl coenzyme A reductase, making it a mainstay of cholesterol-lowering therapy for the prevention of MI. According to Frishman, individuals with normal or even low cholesterol levels, especially patients with diabetes mellitus and hypertension, also can benefit from this treatment.

William Frishman, MD

“Recent reports of development of diabetes during long-term statin treatment are of some concern, but the documented beneficial effects of statins in post MI patients, in my opinion, outweigh this concern at present,” Udho Thadani, MD, of the University of Oklahoma and VA Medical Center, told Cardiology Today.

“In fact, it’s a standard recommendation from the American Diabetes Association and it’s also in the American College of Cardiology and American Heart Association guidelines that all patients with diabetes be put on statins because the risk for atherosclerosis is so markedly increased in this patient population,” Joseph S. Alpert, MD, Cardiology Today Editorial Board member and professor of medicine at the University of Arizona Health Science Center, Tucson, said in an interview.

Patients for whom statins are contraindicated may include those with intracerebral hemorrhage, according to a study published earlier this year in the Archives of Neurology. “Statins do prevent strokes, specifically thrombotic strokes,” Frishman said. “However, we still do not understand why there may be a slight increase in the risk of intracerebral hemorrhage with this treatment.”

Joseph Alpert, MD

“Statins are probably the best-tested drug that we have,” Alpert explained. “Their safety record is superb and the risk is extremely low. Most of these patients are taking aspirin, and that increases your risk for intracerebral hemorrhage as well. And then of course, if you’re taking two platelet agents (like patients who have had stents do with clopidogrel and aspirin), that also increases your risk. However, the risk is still very small, particularly if BP is controlled.”

The major adverse effects of statins, according to Frishman, are myalgia and, rarely, rhabdomyolysis. “Myalgia is a nuisance side effect, but it’s real. Most patients can live with the myalgia; however, in some individuals, other cholesterol therapies need to be used, including niacin, fibrates, bile acid resins and the cholesterol absorption inhibitor, ezetimibe (Zetia, Merck/Schering-Plough). The best survival data come from studies with statins, and in some patients, statins are combined with other therapies to maximize cholesterol reduction.”

Antiplatelet therapy

Because of their proven ability to prevent the formation of blood clots, this class of drugs is characteristically indicated in patients with known CVD, including patients who have undergone CABG and stenting. “The data for secondary prevention following an MI is most compelling,” Frishman said. “[Antiplatelet] use in primary prevention should be considered in individuals with risk factors for MI, especially in men over 40 and women over 50 years of age.”

The side effects of aspirin include gastrointestinal distress or bleeding, but at the recommended low doses, most individuals tolerate the treatment. “If you are talking about cost-effectiveness and prevention, then aspirin is best,” Frishman said. “If aspirin is not tolerated, then clopidogrel (Plavix, Sanofi-Aventis) or prasugrel (Effient, Daiichi Sankyo/Eli Lilly) can be used. In some patients, especially in those who survived an MI with a stent combination, antiplatelet therapy is also used.”

“The duration and the intensity of antiplatelet therapy depend on the type of stent they’ve had or whether they’ve had a stent at all,” Nanette K. Wenger, MD, professor of medicine at Emory University School of Medicine in Atlanta and a Cardiology Today Editorial Board member, said in an interview.

ACE inhibitors, ARBs

By blocking the production of angiotensin-converting enzyme in the blood, ACE inhibitors help lower BP, making them useful for treating hypertension and congestive HF. “They have also been shown to prevent MI in patients with known vascular disease, including patients with congestive heart failure,” Frishman said.

Because this class of drugs helps protect the kidneys, patients with diabetes can also benefit from ACE inhibitors. “The presence of diabetes has been shown to confer the same risk as if a patient had a previous MI,” he said.

This class of drugs is contraindicated “if there is evidence of hypotension, severe chronic kidney disease, hyperkalemia or if the patient has a known allergic reaction,” Thadani said. “These contraindications may change over time or following an acute MI.”

“In general, the ACE inhibitors are well tolerated,” Frishman said. “The one nuisance side effect is a dry cough, which may be caused by an increase in bradykinin levels with ACE inhibition.”

Udho Thadani, MD

For patients who do not tolerate ACE inhibitors, angiotensin receptor blockers (ARBs) offer an alternative, according to Frishman. “ARBs have a much lower incidence of cough. There are also favorable survival data for ARBs, but there are more data with ACE inhibitors and more of them are generic, so they are cheaper. There are some, however, who think the two classes are interchangeable.”

In 2009, the FDA approved the use of telmisartan (Micardis, Boehringer-Ingelheim), and ARB, for the prevention of MI in patients 55 years of age and older unable to take ACE inhibitors such as ramipril (Altace, King Pharmaceuticals).

Beta-adrenergic blockers

Beta-adrenergic blockers inhibit the effects of catecholamines on the vascular system and have been shown useful for treating arrhythmias, angina pectoris, hypertension and for prolonging life in survivors of an acute MI; their benefit in primary prevention of MI has not been documented, however.

“Beta-blockers are one of the cornerstones of HF therapy,” Alpert said. “We start MI patients on beta-blockers the moment they get to the hospital, even patients who are headed to the catheterization laboratory to have their arteries opened. All are almost routinely put on beta-blockers, unless the patient has asthma or a history of other serious lung disease with wheezing.”

“Beta-blockers are contraindicated in the presence of sinus bradycardia, high-grade atrioventricular block, asthma, hypotension or a known allergy to the medication,” Thadani said.

“Because beta-blockers can slow the electrical conduction in the heart, another area where there can be a problem is in people who have a lot of conduction system disease or elderly people with sinus node disease who can get marked slowing of the heart rate, and so they can get dizzy or very fatigued,” Alpert said.

“As an MI prevention therapy, these were the first drugs shown to prolong life and to prevent secondary heart attacks,” Frishman said. “But fatigue is definitely a side effect of this drug. There are many people who feel great on these — especially those who are wound up — and this kind of brings them back to baseline. For others, there is a feeling of being washed out.”

For post-MI patients intolerant of beta-blockers, calcium antagonists are useful alternatives, “especially for controlling hypertension and angina,” Wenger said.

“But it’s very important to note that you want to use a heart rate-lowering calcium antagonist such as verapamil or diltiazem,” Frishman said.

New drugs on the horizon

“We are in an exciting era,” said Frishman. “There are new pharmacologic therapies being studied for MI prevention: antiplatelet drugs such as ticagrelor; oral direct thrombin inhibitors; oral factor Xa inhibitors; innovative cholesterol-lowering therapies such as mipomersen; and new treatments for raising HDL levels. Newly designed coronary stents are also being evaluated in clinical trials.”

There is also the possibility of a “poly-pill,” which would combine all four major medications for the prevention and treatment of MI, according to Frishman. “Patient compliance would be better, theoretically, but the dosing would be difficult,” he said.

“Four generic drugs in one pill could be manufactured inexpensively,” Alpert said. “But it would be a fixed dose. So it’s a therapy that is best suited to financially impoverished groups of people. In the US now, it’s not very expensive to be on these medications, particularly if you are using generic aspirin and other generic forms of the other drugs. And if the pills are separate, you can individualize therapy.”

Nanette Wenger, MD

Besides pharmacological advances, however, “lifestyle modifications are always indicated in addition to drug treatments — smoking cessation, healthy diet, weight management and regular exercise,” Wenger added. – by Whitney McKnight

Westover M. Arch Neurol. 2011;doi:10.1001/archneurol.2010.356.

Disclosures: Dr. Alpert reports having received consulting fees/honoraria from Daiichi Pharmaceuticals and Sanofi Aventis. Dr. Frishman reports no relevant financial disclosures. Dr. Thadani reports serving on the speaker’s bureau for Eli Lilly and Daiichi Sankyo. Dr. Wenger reports receiving consulting fees/honoraria from Merck.

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