Drug Eluting Stents and Stent Thrombosis

Blockages in coronary arteries (coronary stenoses) reduce blood flow to the heart and may result in symptoms of anginal chest pain, heart attack (myocardial infarction), heart failure and even sudden death. Many patients with these conditions require treatment to relieve the blockages. Traditionally this has been done by coronary bypass surgery. From 1980's, interventional cardiology techniques like angioplasty and stenting has overtaken bypass surgery as the treatment of choice as they offer good results without the morbidity of major surgery. However, patients treated with these techniques have greater chances of recurrence of blockages. This is due to the development of restenosis at the site of stenting or angioplasty.

The introduction of drug eluting stents (DES) in the late 1990's was a major landmark in coronary interventions. They could reduce restenosis due to the effects of the drug, the Achilles heel of coronary stents, thus reducing the need for repeat intervention. However, a new problem has surfaced with their use - an increased rate of late stent thrombosis. Stent thrombosis refers to the development of clots within the stent blocking blood flow suddenly and this almost invariably results in a heart attack.

All stents are to some degree thrombogenic, ie, they promote clotting. This tendency is overcome by antiplatelet therapy to reduce clotting at least till the stented part heals by endothelialization. Drug eluting stents appear to be more thrombogenic than bare stents. Stent thrombosis is often a catastrophic event leading to acute myocardial infarction or even death. Delayed reendothelialization of the stented segment due to the effects of the drug has been thought as the mechanism for stent thrombosis. Particularly disturbing are the reports of late stent thrombosis more than a year after stent implantation. Such events are generally associated with stoppage of antiplatelet therapy.

A recently reported study by Kuchulakanti et al in Circulation is one of the first to evaluate the correlates of stent thrombosis. They found that stent thrombosis was significantly higher in patients with diabetes, acute postprocedural renal failure, and chronic renal failure. There were more bifurcation lesions, type C lesions, and a trend for smaller-diameter stents. Discontinuation of clopidogrel was higher in these patients (36.8% versus 10.7%). Multivariate analysis detected cessation of clopidogrel therapy, renal failure, bifurcation lesions, and in-stent restenosis as significant correlates of stent thrombosis. The follow up period in this study was 12 months.

The current best practice to reduce the incidence of stent thrombosis in patients treated with DES (sirolimus and paclitaxel) is to give dual antiplatelet therapy with aspirin and clopidogrel for at least 12 months. Thereafter, patient should be on aspirin lifelong. Aspirin should never be stopped even if the patient is undergoing surgery. As one cardiologist put it: "In the current era, there is no surgery which cannot be done without stopping aspirin". One should still recognize that there may still be instances where aspirin need to be withheld as in intracranial surgery or bleeding. In such situations, time off antiplatelets should be minimized.

Newer drug eluting stents which have a biopolymer coating are claimed not to interfere with endothelial healing. One might hope that they will reduce the risks of late stent thrombosis, while still maintaining low restenosis rates.

Drugs for ADHD and heart risk

The cardiac risk of the drugs for ADHD have attracted interest recently following the recommendation by the Drug Safety and Risk Management Advisory Committee of the FDA to include a black-box warning describing the cardiovascular risks of stimulant drugs used to treat this condition. However, this recommendation has subsequently been toned down by the Pediatric Advisory Committee of the FDA.

ADHD (attention deficit hyperactivity disorder) is a disorder mainly diagnosed in school age children. It is characterized by increased activity, an inability to concentrate and poor school performance. Stimulant drugs have been the mainstay of treatment of ADHD. These include amphetamine and related drugs like methamphetamine and methylphenidate (Ritalin). One popular drug is Adderall, a mixture of amphetamine salts.

It is estimated that 2.5 million children now take stimulants for ADHD in the USA. A growing number of adults also take the drug, with a diagnosis of "adult ADHD", which has recently come into vogue. However, the numbers are quite small in Europe and elsewhere.

Now let us come to the crux of the matter. Why are these drugs supposed to cause heart problems?

These stimulant drugs belong to the class of sympathomimetic amines. Cardiovascular
effects of these compounds have been well studied. They act by stimulating the sympathetic nervous system and increase heart rate and blood pressure significantly. One study with a commercially marketed formulation showed an increase in systolic BP by about 5 mm Hg in treated adults. Such a rise of BP, argues the Drug Safety and Risk Management Advisory committee, can cause definite adverse effects on long term therapy.

The induced increase in heart rate also has well-described adverse effects on the heart. Persistent increase in heart rate may induce chronic heart failure as demonstrated in animal models of dilated cardiomyopathy.

The Committee also cites the examples of Ephedra (ma huang), marketed as a dietary supplement and phenylpropanolamine, an over the counter nasal decongestant, which belong to the same class. They have been known to have caused several well publicized adverse effects. Studies have reported that ephedra containing supplements accounted for 64% of the serious adverse reactions to supplements reported to the Centers for Disease Control and Prevention, although their sales represented less than 1% of all dietary-supplement sales. A 16-fold increase in the risk of stroke has been reported among women taking phenylpropanolamine as a weight loss drug.

Drug Safety and Risk Management Advisory committee studied cases of myocardial infarction, stroke and sudden death in children and adults taking ADHD stimulants which have been reported to the FDA's Adverse Event Reporting System (AERS). This could represent only a tip of the iceberg as only 1 to 10 percent of serious adverse events are actually reported. Some had evidence of undiagnosed heart disease on autopsy and the documentation was frequently incomplete.

Despite these difficulties, the advisory committee decided to recommend strong preemptive action. Factors which the committee cited as the reason for the action included the tendency of these drugs to raise blood pressure and heart rate, the history of serious adverse effects associated with two drugs of the class (ephedra and phenylpropanolamine) and the rapid increase in exposure,particularly among adults. Though the committee noted important potential benefits of these drugs for
certain highly affected children, they felt that the administration of these potent sympathomimetic agents to millions of Americans is inappropriate. The recommendations emphasize more selective and restricted use of these drugs while increasing the awareness of potential hazards.

However, FDA's Pediatric Advisory Committee was of the opinion that adding strong black-box warnings could cause more harm than good and may frighten patients. They, on the other hand, called for new information about health risks on the labels of attention deficit drugs. This would benefit doctors, patients and parents. They said that patients and parents should know about the reports even though it is unclear if the drugs contributed to the problems.

Now, the FDA has to decide on the difficult problem of how to communicate the potential risks associated with ADHD drugs. The FDA will consider both panels' recommendations before making a final labeling decision.

Fondaparinux as effective as enoxaparin in acute coronary syndromes

Acute coronary syndromes require treatment with multiple drugs which reduce blood clotting to prevent recurrent ischemia. However, this is attained at a cost of mild increase in bleeding episodes.

Here we report the findings of a new study which assessed whether fondaparinux would preserve the anti-ischemic benefits of the low molecular weight heparin, enoxaparin, while reducing bleeding. Fondaprinux is direct thrombin inhibitor.

Results of the study showed that Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days in patients with acute coronary syndromes, but it substantially reduces major bleeding and improves long term mortality and morbidity.

The full study will be published in NEJM on April 6th.

Abstract link

Enoxaparin better than unfractionated heparin as adjunct therapy for heart attacks

A simple-to-use strategy that prevents blood clots in patients who have suffered a heart attack markedly reduces the risk of repeat heart attack or death when compared to an older, more widely used blood thinning strategy, according to a large international study presented at the American College of Cardiology's 55th Annual Scientific Session and the inaugural Innovation in Intervention: The i2 Summit 2006 in Atlanta.

The ExTRACT-TIMI 25 trial compared a strategy using enoxaparin, a type of low-molecular-weight heparin, to a strategy using unfractionated heparin as adjunctive therapy in patients whose primary treatment for heart attack, or myocardial infarction (MI), was clot-busting medication, known as fibrinolytic drugs. Both unfractionated heparin and enoxaparin inhibit thrombin, a blood protein that plays a key role in the formation of new blood clots. However, unfractionated heparin is delivered by intravenous infusion, while enoxaparin can simply be injected under the skin. Enoxaparin also appears to have more powerful anti-clotting effects by more effectively blocking the clotting mechanism at an earlier stage than unfractionated heparin.

Read the full story here

Aspirin Alone or Clopidogrel and Aspirin for the Prevention of Atherothrombotic Events

Traditionally most patients at high risk of cardiovascular events have been treated with aspirin alone. Recently dual antiplatelet therapy with aspirin and clopidogrel has become more widely prescribed. This study published in NEJm compares both strategies.

15,603 patients with either clinically evident cardiovascular disease or multiple risk factors were randomized to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes.

In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes.

Read the full article here