Special Report: Affairs of the heart


Experts call for a cocktail of drugs, even devices, to treat acute coronary syndrome.




Experts call for the use of a cocktail of drugs to treat acute coronary syndrome

Acute coronary syndrome (ACS) can be thought of in terms of bad oxygen economics of the heart. Essentially, any situation in which oxygen demand exceeds oxygen supply—like angina pectoris or myocardial infarction (MI)—is lumped into the ACS category. Last year, the American College of Cardiology (ACC) and the American Heart Association (AHA) jointly put out new guidelines for managing ACS patients, and the European Society of Cardiology (ESC) revised its own guidelines for this condition. Specifically, the guidelines are intended for managing those with unstable angina and non-ST-segment elevation MI.

According to current guidelines, anti-ischemic therapies and antiplatelet/anticoagulation therapies have a primary role in managing acute situations, but other pharmacotherapies are also recommended for use in stabilized patients. As with any set of guidelines, new drugs, studies, and treatments always challenge existing clinical paradigms. What do pharmacists need to know?

"The most important aspect for pharmacists is prevention," said Cynthia Sanoski, Pharm.D., assistant professor of clinical pharmacy, University of the Sciences, Philadelphia. For example, R.Ph.s are in a key position to monitor blood pressure and conduct cholesterol panels. Whether it be primary prevention or secondary prevention, pharmacists can play a key role in identifying and helping patients modify their risk factors and in monitoring appropriate drug therapy.


Anti-ischemic therapies for managing ACS rely on getting oxygen to the heart, while simultaneously decreasing the heart's demand for oxygen. Nitrates, calcium-channel blockers, ACE inhibitors, and beta-blockers may be appropriate in managing ACS in both acute and long-term situations.

Beta-blockers, especially selective beta-1 receptor antagonists, reduce heart contractility, slow heart rate, and decrease blood pressure. All of these effects translate into reduced myocardial oxygen consumption. Beta-blockers should be considered standard therapy for all ACS patients unless a contraindication such as AV block, asthma, congestive heart failure, or severe left ventricular dysfunction is present.

However, recent findings from a study published in the American Heart Journal indicate that beta-blockers are underprescribed and underdosed in many patients with ACS. Of 14,057 patients admitted to study hospitals with a primary acute MI between 1996 and 1998, only 54% of patients were given prescriptions for beta-blockers at the time of discharge. Furthermore, of those patients prescribed beta-blockers, only 20% were prescribed adequate doses during the entire first year after hospitalization. The vast majority of patients given beta-blockers received doses considered to be subtherapeutic, based upon doses shown to improve survival in clinical trials.

One author of this study, Louise Pilote, M.D., Ph.D., of McGill University, had this to say about her findings: "Physicians must increase their prescription of evidence-based medications post-acute-MI because, once prescribed, patients adhere to the medications. Pharmacists who see post-acute-MI patients should question the physicians if patients aren't prescribed ACE inhibitors, beta-blockers, aspirin, and a lipid-lowering drug. Inappropriate dosages should also be questioned."


Antithrombotic therapy is essential to slow the progression of ACS. The old adage, "An aspirin a day keeps the doctor away," just might hold true for ACS patients. Aspirin irreversibly prevents platelet aggregation promoted by cyclooxygenase actions on the thromboxane A2 pathway. Doses as small as 75 mg prevent platelet aggregation and should be recommended for all ACS patients unless contraindications like active bleeding, untreated hypertension, or allergy are present.

Aspirin should be part of both acute and long-term treatment plans for managing ACS. According to Pilote's study findings, the rates of discharge medications for aspirin were suboptimal in ACS patients (65%). However, when aspirin was prescribed, dosages were almost always in line with those shown to be effective in clinical trials.

Adenosine diphosphate receptor antagonists like ticlopidine (Ticlid, Roche) or clopidogrel (Plavix, Bristol-Myers Squibb) are also useful for antiplatelet effects. Either of these drugs would do the job. But the adverse-effect profile of ticlopidine, especially the risk of life-threatening neutropenia, limits its utility and provides a clear advantage to clopidogrel.

According to the ACC/AHA guidelines, clopidogrel can—and should—be added to aspirin therapy unless patients are scheduled for major surgery or elective coronary artery bypass graft (CABG). Since the mechanisms of clopidogrel and aspirin differ, there is potential for synergistic effects.

In terms of acute care for ACS, anticoagulants can also be useful. Unfractionated heparin or low molecular weight heparins may be added to antiplatelet therapies, and platelet GP IIb/IIIa antagonists like eptifibatide (Integrilin, COR Therapeutics) or tirofiban (Aggrastat, Merck), can also be prescribed for patients in whom catheterization and percutaneous coronary interventions (PCI) are planned. On the other hand, there's no indication long-term anticoagulation with warfarin (Coumadin, DuPont) offers additional advantages for managing ACS.

Other drug management for ACS

Lipid-lowering medications like gemfibrozil, niacin, and the statins are all part of the long-term treatment plan for those with ACS. Unfortunately, according to Pilote's study findings, only 21% of ACS patients are discharged from the hospital with an Rx for lipid-lowering therapy. Perhaps new indications for some of the statins will heighten awareness and improve these poor prescribing patterns. Fluvastatin (Lescol and Lescol XL, Novartis) recently received a new indication—to reduce the risks associated with coronary revascularization procedures in patients with coronary heart disease. When fluvastatin was initiated after PCI in the Lescol Intervention Prevention Study (LIPS), the drug significantly reduced the risk of recurrent adverse cardiac events.


Acute pharmacologic anti-ischemic therapies

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Other statins are also making headlines in the ACS realm. Bristol-Myers Squibb was recently given the go-ahead from the Food & Drug Administration for Pravigard PAC. This new product will be available in six different dosage regimens and will feature pravastatin (Pravachol, BMS) and buffered aspirin packaged together to reduce the risk of heart attack and death in patients with evidence of cardiovascular diseases. Dual packaging may improve compliance for those who can benefit from taking both drugs.

The benefits of statins are probably related to factors other than just lipid lowering. Statins also possess anti-inflammatory properties. Inflammation plays a role in coronary atherosclerosis and acute coronary events. Elevations in high-sensitivity C-reactive protein (hsCRP), a recognized marker of inflammation, have been shown to predict major cardiac events. In a recent study of 1,552 patients undergoing PCI, those receiving statins had lower hsCRP levels and a lower likelihood of an MI. Although preliminary, these results suggest that using statin therapies to optimize hsCRP levels may soon become a common way to prevent cardiac events.

Additionally, it may be somewhat of a surprise to find that antidepressants are just what the doctor ordered for ACS. This is because post-MI patients with major depression have worse outcomes than patients without depression. According to J. Robert Swenson, M.D., associate professor at the University of Ottawa heart institute and department of psychiatry, 15% to 20% of patients with ACS have major depression. Results from recent clinical studies found that in patients with ACS, severity of depression is the biggest predictor of poor quality of life, even more important, he said, than "the traditional parameters like ejection fraction and myocardial ischemia."

Data from a sub-analysis of one trial found that sertraline (Zoloft, Pfizer) improved quality of life and function in ACS patients also diagnosed with major depression. However, said Swenson, we still don't know whether treating depression will reduce cardiovascular mortality. Larger studies will be needed to address this question in the future.

Bottom line for ACS therapy

In the long-term management of ACS there isn't one therapy that fits all needs. Instead, said Sanoski, treatment really involves a cocktail of drugs. At a minimum, aspirin, beta-blockers, cholesterol-lowering therapies, and ACE inhibitors should be onboard, plus or minus other therapies, including clopidogrel or even drug-eluting stents, the first of which was approved in April. At least four other drug-eluting stents are in various stages of development.

Kelly Dowhower Karpa, Ph.D., R.Ph.


Kelly Karpa. Special Report: Affairs of the heart. Drug Topics Oct. 20, 2003;147:HSE11.

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