Early statin withdrawal can endanger patients with acute coronary syndrome
Early statin withdrawal can endanger patients with acute coronary syndrome
Pharmacists should be aware of 'rebound' effect
The benefits of statins on acute coronary outcomes are rapidly lost and outcomes worsened if statins are discontinued during a patient's hospitalization for an acute coronary syndrome, report researchers at Nova Southeastern University in Fort Lauderdale-Davie, FL.
"Withdrawal of statin therapy in the first 24 hours of hospitalization for non-ST-elevation myocardial infarction increased the hospital morbidity and mortality rate versus continued therapy," the report in Pharmacotherapy said. 1
Lead researcher Luigi Cubeddu, MD, PhD, of the Nova Southeastern University departments of Pharmaceutical Sciences and Pharmacy Practice, tells Drug Formulary Review his research was in response to the "well-known fact that high levels of LDL cholesterol are associated with increased risk for adverse cardiovascular events, specifically all events related or due to atherosclerotic vascular disease."
Statins are the medications that have shown the greatest efficacy in lowering serum cholesterol, and that they have been seen to decrease adverse cardiovascular events, he adds. They have good safety profiles and are used extensively, he says.
For many drugs, according to Cubeddu, abruptly discontinuing therapy is often associated with rebound symptoms and complications that are often opposite to what the drugs are indicated for. "When we started thinking about this problem and reviewed the literature for information concerning this aspect, we decided that a review article on statin discontinuation was needed and could make practitioners further aware of the problem," he says.
The literature review the researchers performed found that short-term discontinuation of statin therapy in patients with stable cardiac conditions may not substantially increase risk of acute coronary syndromes. But in patients who already have acute coronary syndrome, the rapid increase in risk of an event may result not only from the lost benefits of the therapy, but also from rebound inhibition of vascular protective substances and activation of vascular deleterious substances. Thus, researchers concluded, in the absence of data from randomized controlled trials, current information suggests that statin therapy should be continued and possibly boosted during hospitalization for an acute coronary syndrome. "Because statins are discontinued during the early hospitalization of many patients, practitioners must ensure that statins are not omitted, unless contraindicated, from the treatment of patients with acute coronary syndromes," they said.
Many have high cholesterol
Nearly 105 million American adults have total blood cholesterol levels of 200 mg/dl or higher, and some 42 million of them have levels of 240 mg/dl or higher and are considered to be at high risk. Individuals with preexisting coronary heart disease or risk equivalents are also at high risk and require aggressive lipid lowering. Statins have assumed the central role in treating high cholesterol because of their superior ability to reduce levels of low-density lipoprotein cholesterol (LDL). Statins reduce coronary heart disease frequency by 21% to 43% and are effective in the primary and secondary prevention of coronary heart disease.
Although statins are generally well tolerated, nearly 1.5% of subjects receiving them develops complications and requires either dosage reduction and/or discontinuation of therapy. Drug-induced muscle weakness, myositis, and rhabdomyolysis with or without acute renal failure were observed with statin use. FDA's MedWatch system recorded 3,339 cases of statin-associated rhabdomyolysis reported between January 1, 1990, and March 31, 2002. Withdrawal of Baycol from the U.S. market in August 2001, after it was associated with some 100 rhabdomyolysis-related deaths, underscores the risk, Cubeddu says.
Less serious adverse effects such as muscle pain and weakness affect some 1% to 5% of patients. Liver toxicity is another important cause of statin discontinuation.
The researchers said that in addition to adverse drug reactions, statins' high cost and their long-term use may negatively affect patient compliance. At six to seven months after the drug was initially supplied, discontinuation rates for statins average 30% and were similar for all statins. Researchers said they are not aware of any guidelines for discontinuing statin therapy, and said discontinuation of therapy may not be without risk. Acute statin discontinuation may reduce endothelial dysfunction and increase risk of cardiovascular events.
Discontinuation raises risks
The researchers found that statin therapy should be continued during a patient's hospitalization for acute coronary syndrome unless contraindicated. Discontinuing statins in patients with acute coronary syndrome appeared to increase the risk for cardiovascular events. A similar increase in risk was not seen in patients with stable cardiac conditions, whose low baseline of events might not have provided enough power to observe significant differences between statin withdrawal and statin continuation. A sudden discontinuation of statin therapy appears to lead to a rapid loss of its vascular protective effects and, in some instances, vascular deleterious and prothrombotic activity may increase above baseline levels. Given those findings, the researchers said from their review of literature on statin withdrawal in healthy subjects, baseline active vascular disease seems to be needed for clinically significant vascular adverse events to develop after statin withdrawal.
"In the trials discussed, an alarmingly high number of patients who took statin therapy had their statin discontinued during early hospitalization for an acute coronary event," Cubeddu wrote. "Motives for discontinuation were not documented and could have been associated with other factors leading to poor hospital outcomes. Equally distressing was the finding that many individuals admitted with an acute coronary syndrome were not receiving statins.... Factors and conditions that make a specific patient susceptible to adverse cardiovascular events after the withdrawal of statins are not understood.... A pressing issue then becomes what to use in place of statins in patients with an acute coronary event who require discontinuation. Investigators found that the vasodilatory effect of nitroglycerin was unaffected during statin withdrawal in mice. The administration of drugs that deliver nitric oxide and/or increase its production, such as organic nitrates, L-arginine, and nebivolol, could theoretically be of value in these patients. In addition, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and drugs that reduce the generation of oxygen free radicals and proinflammatory and proatherogenic substances could be used. However, we know of no studies that directly addressed this aspect."
Cubeddu tells Drug Formulary Review his retrospective analyses of databases was for the purpose of determining whether subjects hospitalized for an acute coronary event (sick subjects who should never have stopped statin treatment), abrupt statin discontinuation would worsen the disease course. He says the data were collected at a time at which the role of statins in primary and secondary prevention was just emerging. Consequently, practitioners were less knowledgeable about the need to continue the statins. Currently, he says, unless it happens inadvertently, physicians are not stopping statins in patients with acute coronary events. "We hope that our article has helped to nail in this concept," he says. "There was a suggestion on the data analyses that events may get worse and be more frequent after statin discontinuation [like a rebound worsening]. The other type of data derives from analyses in subjects who had the disease [chronic] and that stopped the statins for some reason. It was found out that these subjects lose the gained benefits of the treatment. Data on otherwise healthy subjects, who take statins because of high lipids, but not because of cardiovascular disease, suggest that stopping statins does not lead to serious cardiovascular events."
Pharmacists' role in promoting awareness
Asked about the role pharmacists can play in bringing about a different approach to statin use in hospitalized patients, Cubeddu says they should develop a surveillance plan to detect and thus prevent statin discontinuation in subjects admitted with an acute coronary syndrome or cardiovascular event such as a stroke. If the statin the hospital formulary uses is different from the one the patient has been taking, he says, the best approach would be to ask the patient and his or her relatives for the same statin. Absent that, he suggests providing at least an equivalent dose of the other statin. He says practitioners could even consider increasing the dose for the first week, until steady state levels of the new statin have been reached.
Physicians, nurses, and pharmacists should be educated on the problem and share responsibility for changing the approach to statin continuation in some hospitalized patients, Cubeddu emphasizes. He acknowledges pinpointing responsibility for change is a difficult issue. "Obviously, the physician should be the one with the greatest responsibility," he says. "But perhaps pharmacists should play the greatest role." In terms of future research that is needed, Cubeddu says determining the therapy to be used with discontinuing a statin is a must in subjects with an acute coronary event. For example, he says, a patient is destroying his muscle mass [rhabdomyolysis] as a consequence of a statin treatment. In that case, the statin must be discontinued. "We need to provide other meds to control his or her cholesterol," he says, "but in addition we need to protect for a possible worsening of the coronary event."
[Editor's note: Contact Dr. Cubeddu at [email protected].]
Reference
- Cubeddu, LX. Statin Withdrawal: Clinical Implications and Molecular Mechanisms. Pharmacotherapy. 2006;26(9):1288-1296.
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