Many clinicians are concerned about a possible interaction between the proton pump inhibitor omeprazole (Prilosec) and the antiplatelet drug clopidogrel (Plavix), which is often given to patients as part of dual antiplatelet therapy after an acute coronary syndrome or a percutaneous coronary intervention. Indeed, the US Food and Drug Administration (FDA) has warned that omeprazole reduces the antiplatelet effect of clopidogrel.

Although we should not take such warnings lightly, we also should not be alarmed. The data on which the FDA warning was based came mostly from laboratory assays of platelet function. Preliminary results from a randomized, controlled clinical trial with hard end points show that, for the time being, we should not change the way we manage patients.

PROTON PUMP INHIBITORS DECREASE GASTROINTESTINAL BLEEDING

Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after an acute coronary syndrome or a percutaneous coronary intervention compared with aspirin alone.¹ However, it also increases the risk of gastrointestinal bleeding. A recent analysis determined that dual antiplatelet therapy was the most significant risk factor associated with serious or fatal gastrointestinal bleeding in high-risk survivors of myocardial infarction.²

Given the risks of significant morbidity and death in patients on dual antiplatelet therapy who develop gastrointestinal bleeding, an expert consensus panel recommended the use of proton pump inhibitors in patients on dual antiplatelet therapy who have risk factors for gastrointestinal bleeding.³ Accordingly, these drugs are commonly used for gastrointestinal protection in patients requiring dual antiplatelet therapy.

A POSSIBLE CYP450 INTERACTION

Clopidogrel is metabolized from a prodrug to its active metabolite by the cytochrome P450 (CYP450) system. Proton pump inhibitors also are metabolized by the CYP450 system.⁴ Proton pump inhibitors are thought to diminish the activity of clopidogrel via inhibition of the CYP2C19 isoenzyme. However, the clinical significance of this inhibition is not clear. Different drugs of this class inhibit the CYP450 system to varying degrees.

The potential interaction between proton pump inhibitors and clopidogrel is worrisome for many physicians, since adverse cardiovascular outcomes are more common in patients in whom the antiplatelet response to clopidogrel is impaired.¹ This interaction led to the publication of numerous articles, and prompted the FDA to carefully analyze the potential clinical implications.

In several randomized trials, omeprazole diminished the response to clopidogrel (measured via platelet function assays).^5,6 It is unclear if this is a class effect, as proton pump inhibitors other than omeprazole have not consistently been shown to have this effect.^6,7 Observational studies of the effect of co-administration of a proton pump inhibitor and clopidogrel on cardiovascular outcomes following acute coronary syndromes have had conflicting findings.^8–11

THE FDA ISSUES AN ADVISORY

Given the reports of an impaired platelet response to clopidogrel with omeprazole, the FDA asked the manufacturer for data on this potential interaction. The data showed diminished platelet inhibition when clopidogrel was co-administered with omeprazole or when the two were taken 12 hours apart.

On November 17, 2009, the FDA issued a patient advisory and updated the patient safety information on the package insert for clopidogrel about this drug interaction.¹² Specifically, the FDA warns that omeprazole reduces the antiplatelet effect of clopidogrel by about 50%. The FDA warning sparked debate in the medical community, as the decision was based in part on ex vivo data.

POST HOC ANALYSES FROM RANDOMIZED CONTROLLED TRIALS

Several post hoc analyses of large randomized clinical trials have studied the potential interaction between proton pump inhibitors and clopidogrel.

In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, clopidogrel reduced the incidence of death, myocardial infarction, or stroke to a similar extent regardless of baseline use of a proton pump inhibitor.¹³

In patients undergoing percutaneous coronary intervention, the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation—Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial found that those taking a proton pump inhibitor had significantly less platelet inhibition with clopidogrel compared with those not on one.¹⁴ However, patients taking prasugrel (Effient) and a proton pump inhibitor only had a slight trend towards diminished platelet inhibition.¹⁴

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) found that proton pump inhibitors did not influence the long-term outcome of cardiovascular death, myocardial infarction, or stroke for patients on clopidogrel or prasugrel after an acute coronary syndrome.¹⁴ A subanalysis did not reveal any differences between omeprazole or other drugs of this class as to an effect on the primary outcome.

Though informative, the results of these post hoc analyses need to be validated with data from randomized clinical trials.

‘COGENT’ TRIAL HALTED EARLY, BUT PRELIMINARY RESULTS AVAILABLE

The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial was the first randomized clinical study of the effect of the interaction between clopidogrel and omeprazole on cardiovascular and gastrointestinal outcomes.¹⁵ In a double-blind fashion, patients with acute coronary syndromes or undergoing percutaneous coronary interventions were randomized to receive a fixed-dose combination pill containing either clopidogrel and delayed-release omeprazole or clopidogrel alone. All patients also received aspirin.

Unfortunately, the trial was stopped early because the sponsor declared bankruptcy. However, preliminary results revealed no significant difference in cardiovascular outcomes for patients on clopidogrel and omeprazole compared with clopidogrel alone.¹⁵ Furthermore, adverse gastrointestinal events were significantly fewer in patients on clopidogrel and omeprazole.

Thus, omeprazole appears to be safe and may offer gastrointestinal protection to patients on dual antiplatelet therapy, though we need to await publication of the full results.

‘SPICE ’ TRIAL TO EVALUATE POSSIBLE MECHANISMS OF INTERACTION

The Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE) trial is a mechanistic study that will evaluate platelet function and genetic polymorphisms in patients on clopidogrel and aspirin after a percutaneous coronary intervention. They will be randomized to statin therapy plus different proton pump inhibitors.¹⁶ Prior concerns about an ex vivo interaction between clopidogrel and certain statins were not validated by clinical data.¹⁷

OUR RECOMMENDATIONS

Based on the current evidence, patients on aspirin and clopidogrel who have an indication for a proton pump inhibitor or who are at risk of gastrointestinal bleeding can continue or start taking a proton pump inhibitor, including omeprazole.

Switching to another proton pump inhibitor is not currently supported by any randomized clinical trial, nor is changing to a histamine H₂-receptor antagonist. The effect of proton pump inhibitors other than omeprazole on clopidogrel is unclear, and it is not known if the interaction with clopidogrel is a class effect or specific to certain drugs of this class.¹⁸ On the other hand, we still have no compelling evidence of any major clinical interaction between alternative proton pump inhibitors and clopidogrel.¹⁸

Also, separating the dosing times of clopidogrel and omeprazole by 12 hours is not supported by any randomized clinical trial, and runs contrary to at least some ex vivo data.

It is important that all physicians assess the need for a proton pump inhibitor in their patients, as overuse of these drugs has been documented in certain settings.¹⁹

Clopidogrel and omeprazole share a common metabolic link via CYP2C19. Omeprazole, along with some other proton pump inhibitors, interacts with clopidogrel at the level of the CYP450 system. Platelet function studies show that platelet inhibition by clopidogrel is impaired, though the astute clinician should be aware of the wide variability associated with platelet function assays and clopidogrel.^1,20 However, what may appear to be an interaction at the enzymatic level does not necessarily translate into worse clinical outcomes. Additionally, reliance on nonrandomized studies rather than on randomized clinical trials can be misleading.

Many clinicians are concerned about a possible interaction between the proton pump inhibitor omeprazole (Prilosec) and the antiplatelet drug clopidogrel (Plavix), which is often given to patients as part of dual antiplatelet therapy after an acute coronary syndrome or a percutaneous coronary intervention. Indeed, the US Food and Drug Administration (FDA) has warned that omeprazole reduces the antiplatelet effect of clopidogrel.

Although we should not take such warnings lightly, we also should not be alarmed. The data on which the FDA warning was based came mostly from laboratory assays of platelet function. Preliminary results from a randomized, controlled clinical trial with hard end points show that, for the time being, we should not change the way we manage patients.

PROTON PUMP INHIBITORS DECREASE GASTROINTESTINAL BLEEDING

Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after an acute coronary syndrome or a percutaneous coronary intervention compared with aspirin alone.¹ However, it also increases the risk of gastrointestinal bleeding. A recent analysis determined that dual antiplatelet therapy was the most significant risk factor associated with serious or fatal gastrointestinal bleeding in high-risk survivors of myocardial infarction.²

Given the risks of significant morbidity and death in patients on dual antiplatelet therapy who develop gastrointestinal bleeding, an expert consensus panel recommended the use of proton pump inhibitors in patients on dual antiplatelet therapy who have risk factors for gastrointestinal bleeding.³ Accordingly, these drugs are commonly used for gastrointestinal protection in patients requiring dual antiplatelet therapy.

A POSSIBLE CYP450 INTERACTION

Clopidogrel is metabolized from a prodrug to its active metabolite by the cytochrome P450 (CYP450) system. Proton pump inhibitors also are metabolized by the CYP450 system.⁴ Proton pump inhibitors are thought to diminish the activity of clopidogrel via inhibition of the CYP2C19 isoenzyme. However, the clinical significance of this inhibition is not clear. Different drugs of this class inhibit the CYP450 system to varying degrees.

The potential interaction between proton pump inhibitors and clopidogrel is worrisome for many physicians, since adverse cardiovascular outcomes are more common in patients in whom the antiplatelet response to clopidogrel is impaired.¹ This interaction led to the publication of numerous articles, and prompted the FDA to carefully analyze the potential clinical implications.

In several randomized trials, omeprazole diminished the response to clopidogrel (measured via platelet function assays).^5,6 It is unclear if this is a class effect, as proton pump inhibitors other than omeprazole have not consistently been shown to have this effect.^6,7 Observational studies of the effect of co-administration of a proton pump inhibitor and clopidogrel on cardiovascular outcomes following acute coronary syndromes have had conflicting findings.^8–11

THE FDA ISSUES AN ADVISORY

Given the reports of an impaired platelet response to clopidogrel with omeprazole, the FDA asked the manufacturer for data on this potential interaction. The data showed diminished platelet inhibition when clopidogrel was co-administered with omeprazole or when the two were taken 12 hours apart.

On November 17, 2009, the FDA issued a patient advisory and updated the patient safety information on the package insert for clopidogrel about this drug interaction.¹² Specifically, the FDA warns that omeprazole reduces the antiplatelet effect of clopidogrel by about 50%. The FDA warning sparked debate in the medical community, as the decision was based in part on ex vivo data.

POST HOC ANALYSES FROM RANDOMIZED CONTROLLED TRIALS

Several post hoc analyses of large randomized clinical trials have studied the potential interaction between proton pump inhibitors and clopidogrel.

In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, clopidogrel reduced the incidence of death, myocardial infarction, or stroke to a similar extent regardless of baseline use of a proton pump inhibitor.¹³

In patients undergoing percutaneous coronary intervention, the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation—Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial found that those taking a proton pump inhibitor had significantly less platelet inhibition with clopidogrel compared with those not on one.¹⁴ However, patients taking prasugrel (Effient) and a proton pump inhibitor only had a slight trend towards diminished platelet inhibition.¹⁴

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) found that proton pump inhibitors did not influence the long-term outcome of cardiovascular death, myocardial infarction, or stroke for patients on clopidogrel or prasugrel after an acute coronary syndrome.¹⁴ A subanalysis did not reveal any differences between omeprazole or other drugs of this class as to an effect on the primary outcome.

Though informative, the results of these post hoc analyses need to be validated with data from randomized clinical trials.

‘COGENT’ TRIAL HALTED EARLY, BUT PRELIMINARY RESULTS AVAILABLE

The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial was the first randomized clinical study of the effect of the interaction between clopidogrel and omeprazole on cardiovascular and gastrointestinal outcomes.¹⁵ In a double-blind fashion, patients with acute coronary syndromes or undergoing percutaneous coronary interventions were randomized to receive a fixed-dose combination pill containing either clopidogrel and delayed-release omeprazole or clopidogrel alone. All patients also received aspirin.

Unfortunately, the trial was stopped early because the sponsor declared bankruptcy. However, preliminary results revealed no significant difference in cardiovascular outcomes for patients on clopidogrel and omeprazole compared with clopidogrel alone.¹⁵ Furthermore, adverse gastrointestinal events were significantly fewer in patients on clopidogrel and omeprazole.

Thus, omeprazole appears to be safe and may offer gastrointestinal protection to patients on dual antiplatelet therapy, though we need to await publication of the full results.

‘SPICE ’ TRIAL TO EVALUATE POSSIBLE MECHANISMS OF INTERACTION

The Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE) trial is a mechanistic study that will evaluate platelet function and genetic polymorphisms in patients on clopidogrel and aspirin after a percutaneous coronary intervention. They will be randomized to statin therapy plus different proton pump inhibitors.¹⁶ Prior concerns about an ex vivo interaction between clopidogrel and certain statins were not validated by clinical data.¹⁷

OUR RECOMMENDATIONS

Based on the current evidence, patients on aspirin and clopidogrel who have an indication for a proton pump inhibitor or who are at risk of gastrointestinal bleeding can continue or start taking a proton pump inhibitor, including omeprazole.

Switching to another proton pump inhibitor is not currently supported by any randomized clinical trial, nor is changing to a histamine H₂-receptor antagonist. The effect of proton pump inhibitors other than omeprazole on clopidogrel is unclear, and it is not known if the interaction with clopidogrel is a class effect or specific to certain drugs of this class.¹⁸ On the other hand, we still have no compelling evidence of any major clinical interaction between alternative proton pump inhibitors and clopidogrel.¹⁸

Also, separating the dosing times of clopidogrel and omeprazole by 12 hours is not supported by any randomized clinical trial, and runs contrary to at least some ex vivo data.

It is important that all physicians assess the need for a proton pump inhibitor in their patients, as overuse of these drugs has been documented in certain settings.¹⁹

Clopidogrel and omeprazole share a common metabolic link via CYP2C19. Omeprazole, along with some other proton pump inhibitors, interacts with clopidogrel at the level of the CYP450 system. Platelet function studies show that platelet inhibition by clopidogrel is impaired, though the astute clinician should be aware of the wide variability associated with platelet function assays and clopidogrel.^1,20 However, what may appear to be an interaction at the enzymatic level does not necessarily translate into worse clinical outcomes. Additionally, reliance on nonrandomized studies rather than on randomized clinical trials can be misleading.

Many clinicians are concerned about a possible interaction between the proton pump inhibitor omeprazole (Prilosec) and the antiplatelet drug clopidogrel (Plavix), which is often given to patients as part of dual antiplatelet therapy after an acute coronary syndrome or a percutaneous coronary intervention. Indeed, the US Food and Drug Administration (FDA) has warned that omeprazole reduces the antiplatelet effect of clopidogrel.

Although we should not take such warnings lightly, we also should not be alarmed. The data on which the FDA warning was based came mostly from laboratory assays of platelet function. Preliminary results from a randomized, controlled clinical trial with hard end points show that, for the time being, we should not change the way we manage patients.

PROTON PUMP INHIBITORS DECREASE GASTROINTESTINAL BLEEDING

Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after an acute coronary syndrome or a percutaneous coronary intervention compared with aspirin alone.¹ However, it also increases the risk of gastrointestinal bleeding. A recent analysis determined that dual antiplatelet therapy was the most significant risk factor associated with serious or fatal gastrointestinal bleeding in high-risk survivors of myocardial infarction.²

Given the risks of significant morbidity and death in patients on dual antiplatelet therapy who develop gastrointestinal bleeding, an expert consensus panel recommended the use of proton pump inhibitors in patients on dual antiplatelet therapy who have risk factors for gastrointestinal bleeding.³ Accordingly, these drugs are commonly used for gastrointestinal protection in patients requiring dual antiplatelet therapy.

A POSSIBLE CYP450 INTERACTION

Clopidogrel is metabolized from a prodrug to its active metabolite by the cytochrome P450 (CYP450) system. Proton pump inhibitors also are metabolized by the CYP450 system.⁴ Proton pump inhibitors are thought to diminish the activity of clopidogrel via inhibition of the CYP2C19 isoenzyme. However, the clinical significance of this inhibition is not clear. Different drugs of this class inhibit the CYP450 system to varying degrees.

The potential interaction between proton pump inhibitors and clopidogrel is worrisome for many physicians, since adverse cardiovascular outcomes are more common in patients in whom the antiplatelet response to clopidogrel is impaired.¹ This interaction led to the publication of numerous articles, and prompted the FDA to carefully analyze the potential clinical implications.

In several randomized trials, omeprazole diminished the response to clopidogrel (measured via platelet function assays).^5,6 It is unclear if this is a class effect, as proton pump inhibitors other than omeprazole have not consistently been shown to have this effect.^6,7 Observational studies of the effect of co-administration of a proton pump inhibitor and clopidogrel on cardiovascular outcomes following acute coronary syndromes have had conflicting findings.^8–11

THE FDA ISSUES AN ADVISORY

Given the reports of an impaired platelet response to clopidogrel with omeprazole, the FDA asked the manufacturer for data on this potential interaction. The data showed diminished platelet inhibition when clopidogrel was co-administered with omeprazole or when the two were taken 12 hours apart.

On November 17, 2009, the FDA issued a patient advisory and updated the patient safety information on the package insert for clopidogrel about this drug interaction.¹² Specifically, the FDA warns that omeprazole reduces the antiplatelet effect of clopidogrel by about 50%. The FDA warning sparked debate in the medical community, as the decision was based in part on ex vivo data.

POST HOC ANALYSES FROM RANDOMIZED CONTROLLED TRIALS

Several post hoc analyses of large randomized clinical trials have studied the potential interaction between proton pump inhibitors and clopidogrel.

In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, clopidogrel reduced the incidence of death, myocardial infarction, or stroke to a similar extent regardless of baseline use of a proton pump inhibitor.¹³

In patients undergoing percutaneous coronary intervention, the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation—Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial found that those taking a proton pump inhibitor had significantly less platelet inhibition with clopidogrel compared with those not on one.¹⁴ However, patients taking prasugrel (Effient) and a proton pump inhibitor only had a slight trend towards diminished platelet inhibition.¹⁴

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) found that proton pump inhibitors did not influence the long-term outcome of cardiovascular death, myocardial infarction, or stroke for patients on clopidogrel or prasugrel after an acute coronary syndrome.¹⁴ A subanalysis did not reveal any differences between omeprazole or other drugs of this class as to an effect on the primary outcome.

Though informative, the results of these post hoc analyses need to be validated with data from randomized clinical trials.

‘COGENT’ TRIAL HALTED EARLY, BUT PRELIMINARY RESULTS AVAILABLE

The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial was the first randomized clinical study of the effect of the interaction between clopidogrel and omeprazole on cardiovascular and gastrointestinal outcomes.¹⁵ In a double-blind fashion, patients with acute coronary syndromes or undergoing percutaneous coronary interventions were randomized to receive a fixed-dose combination pill containing either clopidogrel and delayed-release omeprazole or clopidogrel alone. All patients also received aspirin.

Unfortunately, the trial was stopped early because the sponsor declared bankruptcy. However, preliminary results revealed no significant difference in cardiovascular outcomes for patients on clopidogrel and omeprazole compared with clopidogrel alone.¹⁵ Furthermore, adverse gastrointestinal events were significantly fewer in patients on clopidogrel and omeprazole.

Thus, omeprazole appears to be safe and may offer gastrointestinal protection to patients on dual antiplatelet therapy, though we need to await publication of the full results.

‘SPICE ’ TRIAL TO EVALUATE POSSIBLE MECHANISMS OF INTERACTION

The Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE) trial is a mechanistic study that will evaluate platelet function and genetic polymorphisms in patients on clopidogrel and aspirin after a percutaneous coronary intervention. They will be randomized to statin therapy plus different proton pump inhibitors.¹⁶ Prior concerns about an ex vivo interaction between clopidogrel and certain statins were not validated by clinical data.¹⁷

OUR RECOMMENDATIONS

Based on the current evidence, patients on aspirin and clopidogrel who have an indication for a proton pump inhibitor or who are at risk of gastrointestinal bleeding can continue or start taking a proton pump inhibitor, including omeprazole.

Switching to another proton pump inhibitor is not currently supported by any randomized clinical trial, nor is changing to a histamine H₂-receptor antagonist. The effect of proton pump inhibitors other than omeprazole on clopidogrel is unclear, and it is not known if the interaction with clopidogrel is a class effect or specific to certain drugs of this class.¹⁸ On the other hand, we still have no compelling evidence of any major clinical interaction between alternative proton pump inhibitors and clopidogrel.¹⁸

Also, separating the dosing times of clopidogrel and omeprazole by 12 hours is not supported by any randomized clinical trial, and runs contrary to at least some ex vivo data.

It is important that all physicians assess the need for a proton pump inhibitor in their patients, as overuse of these drugs has been documented in certain settings.¹⁹

Clopidogrel and omeprazole share a common metabolic link via CYP2C19. Omeprazole, along with some other proton pump inhibitors, interacts with clopidogrel at the level of the CYP450 system. Platelet function studies show that platelet inhibition by clopidogrel is impaired, though the astute clinician should be aware of the wide variability associated with platelet function assays and clopidogrel.^1,20 However, what may appear to be an interaction at the enzymatic level does not necessarily translate into worse clinical outcomes. Additionally, reliance on nonrandomized studies rather than on randomized clinical trials can be misleading.

Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.^1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.³

Mehta et al⁴ performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative⁵ analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.⁵

Bavry et al⁶ performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al⁷ found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al⁸ conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al⁹ examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al¹⁰ pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).¹⁰

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,¹¹ in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al¹² reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study¹³ corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.¹⁴

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.¹⁵

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I¹⁶ developed an algorithm for deciding on revascularization, posing a series of questions:

• Does the patient need any form of revascularization?
• Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
• Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
• Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.¹⁶

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.¹⁷

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.¹⁸

 

 

Dual therapy for 1 year is the standard of care after acute coronary syndromes

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,¹⁹ published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).²⁰

As a result of these findings, the cardiology society guidelines²¹ recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al²² retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial²³ included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.²⁴ In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.²⁵

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.²⁴ Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document²⁶ in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al²⁷ performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)²⁸ recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.²⁹ In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.²⁹

 

 

Should nonresponders get higher doses of clopidogrel?

In vitro, response to clopidogrel shows a normal bell-shaped distribution.³⁰ In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?³¹

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.³²

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.²⁴

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.^33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.^35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.^1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.³

Mehta et al⁴ performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative⁵ analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.⁵

Bavry et al⁶ performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al⁷ found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al⁸ conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al⁹ examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al¹⁰ pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).¹⁰

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,¹¹ in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al¹² reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study¹³ corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.¹⁴

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.¹⁵

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I¹⁶ developed an algorithm for deciding on revascularization, posing a series of questions:

• Does the patient need any form of revascularization?
• Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
• Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
• Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.¹⁶

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.¹⁷

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.¹⁸

 

 

Dual therapy for 1 year is the standard of care after acute coronary syndromes

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,¹⁹ published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).²⁰

As a result of these findings, the cardiology society guidelines²¹ recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al²² retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial²³ included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.²⁴ In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.²⁵

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.²⁴ Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document²⁶ in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al²⁷ performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)²⁸ recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.²⁹ In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.²⁹

 

 

Should nonresponders get higher doses of clopidogrel?

In vitro, response to clopidogrel shows a normal bell-shaped distribution.³⁰ In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?³¹

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.³²

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.²⁴

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.^33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.^35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.^1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.³

Mehta et al⁴ performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative⁵ analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.⁵

Bavry et al⁶ performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al⁷ found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al⁸ conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al⁹ examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al¹⁰ pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).¹⁰

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,¹¹ in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al¹² reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study¹³ corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.¹⁴

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.¹⁵

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I¹⁶ developed an algorithm for deciding on revascularization, posing a series of questions:

• Does the patient need any form of revascularization?
• Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
• Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
• Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.¹⁶

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.¹⁷

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.¹⁸

 

 

Dual therapy for 1 year is the standard of care after acute coronary syndromes

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,¹⁹ published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).²⁰

As a result of these findings, the cardiology society guidelines²¹ recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al²² retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial²³ included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.²⁴ In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.²⁵

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.²⁴ Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document²⁶ in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al²⁷ performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)²⁸ recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.²⁹ In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.²⁹

 

 

Should nonresponders get higher doses of clopidogrel?

In vitro, response to clopidogrel shows a normal bell-shaped distribution.³⁰ In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?³¹

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.³²

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.²⁴

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.^33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.^35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

Q: Which is the correct diagnosis?

• Scleroderma (systemic sclerosis)
• Scleredema diabeticorum
• Amyloidosis
• Cutaneous sarcoidosis
• Porphyria cutanea tarda

A: The correct answer is scleredema diabeticorum, a common, underdiagnosed skin manifestation of uncontrolled diabetes mellitus seen in 2.5% to 14% of diabetic patients.^1,2 It most often presents with the insidious onset of painless induration and nonpitting thickening of the skin, predominantly on the upper back and neck. Biopsy of the skin usually reveals thickening of the dermis with deposition of collagen and hyaluronic acid without an inflammatory infiltrate.³

Of note, patients may present with similar skin changes acutely in conditions such as postinfectious scleredema (scleredema of Buschke) and paraproteinemias.

Treatment of scleredema is usually difficult, but options include radiotherapy, ultraviolet light therapy, low-dose methotrexate, psoralen, and extracorporeal photopheresis.^4–7

Q: Which is the correct diagnosis?

• Scleroderma (systemic sclerosis)
• Scleredema diabeticorum
• Amyloidosis
• Cutaneous sarcoidosis
• Porphyria cutanea tarda

A: The correct answer is scleredema diabeticorum, a common, underdiagnosed skin manifestation of uncontrolled diabetes mellitus seen in 2.5% to 14% of diabetic patients.^1,2 It most often presents with the insidious onset of painless induration and nonpitting thickening of the skin, predominantly on the upper back and neck. Biopsy of the skin usually reveals thickening of the dermis with deposition of collagen and hyaluronic acid without an inflammatory infiltrate.³

Of note, patients may present with similar skin changes acutely in conditions such as postinfectious scleredema (scleredema of Buschke) and paraproteinemias.

Treatment of scleredema is usually difficult, but options include radiotherapy, ultraviolet light therapy, low-dose methotrexate, psoralen, and extracorporeal photopheresis.^4–7

Q: Which is the correct diagnosis?

• Scleroderma (systemic sclerosis)
• Scleredema diabeticorum
• Amyloidosis
• Cutaneous sarcoidosis
• Porphyria cutanea tarda

A: The correct answer is scleredema diabeticorum, a common, underdiagnosed skin manifestation of uncontrolled diabetes mellitus seen in 2.5% to 14% of diabetic patients.^1,2 It most often presents with the insidious onset of painless induration and nonpitting thickening of the skin, predominantly on the upper back and neck. Biopsy of the skin usually reveals thickening of the dermis with deposition of collagen and hyaluronic acid without an inflammatory infiltrate.³

Of note, patients may present with similar skin changes acutely in conditions such as postinfectious scleredema (scleredema of Buschke) and paraproteinemias.

Treatment of scleredema is usually difficult, but options include radiotherapy, ultraviolet light therapy, low-dose methotrexate, psoralen, and extracorporeal photopheresis.^4–7

For 16 years, we have offered CME based on a collection of articles in each issue (usually four). Many of you have complained that the maximum 1.5 credits for reading the articles and taking the test did not reflect the time you put into the activity.

Starting with this issue, all CME activities are based on individual articles, and you can receive up to 1 credit for each article read and test completed. The change gives you the flexibility to take a CME test for a specific article that interests you. If you want to receive credits for all CME-certified articles in one issue, it will mean extra effort to take separate tests, but you will be able to claim considerably more credit than in the past.

By offering CME for individual articles, we will also be able to offer it to those of you who read CCJM online rather than in print. Because the rules governing CME differ for print activities vs online-only activities, there will be two similar but separate pathways.

Print readers can identify CME-certified articles by the CME logo on the print issue table of contents or on the title page of each article. Those who wish to take the test for a CME-certified article can continue to our home page and click on the CME link. One more click on the appropriate link for print readers will take the reader directly to the test.

Online-only readers will find a link to the CME activity on the online table of contents or in the links next to the full-text version of the online article. They will be required to read the article online before taking the test.

We have tried to make this system as straightforward as possible, while still conforming to all the regulations governing CME.

We are also adding two innovations to our Web site. First, for those into social networking, there is now a social bookmarking feature. You can easily post a link to a CCJM article to a scholarly networking site such as CiteULike, or to a general social networking site such as Facebook, Twitter, or Digg. And second, we will soon add the ability for you to download some of our figures as PowerPoint slides.

Let us know what you think of our latest changes.

For 16 years, we have offered CME based on a collection of articles in each issue (usually four). Many of you have complained that the maximum 1.5 credits for reading the articles and taking the test did not reflect the time you put into the activity.

Starting with this issue, all CME activities are based on individual articles, and you can receive up to 1 credit for each article read and test completed. The change gives you the flexibility to take a CME test for a specific article that interests you. If you want to receive credits for all CME-certified articles in one issue, it will mean extra effort to take separate tests, but you will be able to claim considerably more credit than in the past.

By offering CME for individual articles, we will also be able to offer it to those of you who read CCJM online rather than in print. Because the rules governing CME differ for print activities vs online-only activities, there will be two similar but separate pathways.

Print readers can identify CME-certified articles by the CME logo on the print issue table of contents or on the title page of each article. Those who wish to take the test for a CME-certified article can continue to our home page and click on the CME link. One more click on the appropriate link for print readers will take the reader directly to the test.

Online-only readers will find a link to the CME activity on the online table of contents or in the links next to the full-text version of the online article. They will be required to read the article online before taking the test.

We have tried to make this system as straightforward as possible, while still conforming to all the regulations governing CME.

We are also adding two innovations to our Web site. First, for those into social networking, there is now a social bookmarking feature. You can easily post a link to a CCJM article to a scholarly networking site such as CiteULike, or to a general social networking site such as Facebook, Twitter, or Digg. And second, we will soon add the ability for you to download some of our figures as PowerPoint slides.

Let us know what you think of our latest changes.

For 16 years, we have offered CME based on a collection of articles in each issue (usually four). Many of you have complained that the maximum 1.5 credits for reading the articles and taking the test did not reflect the time you put into the activity.

Starting with this issue, all CME activities are based on individual articles, and you can receive up to 1 credit for each article read and test completed. The change gives you the flexibility to take a CME test for a specific article that interests you. If you want to receive credits for all CME-certified articles in one issue, it will mean extra effort to take separate tests, but you will be able to claim considerably more credit than in the past.

By offering CME for individual articles, we will also be able to offer it to those of you who read CCJM online rather than in print. Because the rules governing CME differ for print activities vs online-only activities, there will be two similar but separate pathways.

Print readers can identify CME-certified articles by the CME logo on the print issue table of contents or on the title page of each article. Those who wish to take the test for a CME-certified article can continue to our home page and click on the CME link. One more click on the appropriate link for print readers will take the reader directly to the test.

Online-only readers will find a link to the CME activity on the online table of contents or in the links next to the full-text version of the online article. They will be required to read the article online before taking the test.

We have tried to make this system as straightforward as possible, while still conforming to all the regulations governing CME.

We are also adding two innovations to our Web site. First, for those into social networking, there is now a social bookmarking feature. You can easily post a link to a CCJM article to a scholarly networking site such as CiteULike, or to a general social networking site such as Facebook, Twitter, or Digg. And second, we will soon add the ability for you to download some of our figures as PowerPoint slides.

Let us know what you think of our latest changes.

Women with Down syndrome who experienced early menopause were almost twice as likely to develop dementia at a younger age than those who entered menopause later, according to research in the January Journal of Alzheimer’s Disease. In a prospective longitudinal cohort study of dementia and mortality in women with Down syndrome, researchers followed 85 postmenopausal subjects for an average of 4.3 years and found a significant correlation between the age at menopause onset and age at diagnosis of dementia. Subjects with an earlier onset of menopause had a 1.8-fold increased risk of dementia. In addition, women who experienced menopause earlier had a twofold increased risk of dying younger.

White, elderly cancer survivors have a reduced risk of developing Alzheimer’s disease, as reported in the January 12 Neurology. Conversely, patients with Alzheimer’s disease have a reduced cancer risk, investigators found. In a prospective cohort study of 3,020 subjects ages 65 and older, the presence of Alzheimer’s disease was associated with a reduced risk of cancer hospitalizations, after adjustments for demographic and other factors. Prevalent cancer was also associated with a reduced risk of Alzheimer’s disease among white subjects after the researchers adjusted for demographics, number of apolipoprotein ε4 alleles, hypertension, diabetes, and coronary heart disease. The opposite was found in minorities, although the sample size was considered too small. No significant association was found between cancer and vascular dementia.

Ginkgo biloba did not preserve cognitive function any better than a placebo, per a study in the December 23, 2009, JAMA. In the randomized, double-blind, placebo-controlled Ginkgo Evaluation of Memory study, researchers at six academic medical centers in the US tracked 3,069 community-dwelling subjects ages 72 to 96 years for an average of 6.1 years. Subjects were given either a twice-daily dose of 120 mg extract of Ginkgo biloba or a placebo. Cognition was measured as rates of change over time in the Modified Mini-Mental State Examination, the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and neuropsychologic domains of memory, attention, visual-spatial construction, language, and executive functions. Investigators found no significant difference in cognitive decline between the herb and placebo.

A decreased ability to smell is common in patients with Alzheimer’s disease and may be a useful early diagnostic tool, researchers reported in the January 13 Journal of Neuroscience. The study linked olfactory dysfunction with an accumulation of amyloid-β protein in Alzheimer’s disease model mice. “The usefulness of olfactory screens to serve as informative indicators of Alzheimer’s is precluded by a lack of knowledge regarding why the disease impacts olfaction,” the study authors stated. The investigators assayed olfactory perception and amyloid-β deposition in the genetically engineered mice and found that amyloid-β pathology first occurred in an area of the brain responsible for smelling. Mice with higher concentrations of amyloid-β also displayed olfactory dysfunction. Researchers noted the “odor cross-habitation test [was] a powerful behavioral assay…[which] may serve to monitor the efficacy of therapies aimed at reducing amyloid-β.”

The Lancet has retracted the 1998 paper by Wakefield et al that suggested a link between autism and the childhood measles, mumps, and rubella (MMR) vaccine. The retraction, published in the February 2 online issue, follows a judgment by the UK General Medical Council’s Fitness to Practice Panel on January 28. “It has become clear that several elements of the 1998 paper by Wakefield et al are incorrect,” the editors wrote. “In particular, the claims in the original paper that children were ‘consecutively referred’ and that investigations were ‘approved’ by the local ethics committee have been proven to be false.” In 2004, 10 of the original authors retracted parts of the study, stating, “in this paper no causal link was established between MMR vaccine and autism as the data were insufficient.”

Advanced maternal age may be linked to an increased risk of autism, researchers reported in the February 8 online Autism Research. In a study of 12,159 cases of autism from a pool of almost 5 million births between 1990 and 1999, the investigators found a monotonic increased risk of autism related to advancing maternal age (40 and older) regardless of paternal age. However, the study authors noted fathers aged 40 and up who mated with women younger than 30 also had an increased risk of autistic offspring, compared with men in their mid- to late-20s. Yet when the mother was older than 30 and the father was 40 or older, the associated autism risk was similar to that of younger men. The investigators also noted that the “recent trend towards delaying childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.”

Depression and migraine headaches appear to share a common genetic factor, a Dutch study of 2,652 people found. As reported in the January 26 Neurology, researchers compared heritability estimates among members of the Erasmus Rucphen family for migraine with and without depression, and depression rates between migraineurs and controls. Of the total study population, 360 had migraines, 151 of whom experienced migraine aura as well. One-quarter of migraineurs also had depression, compared with 13% of the controls. Odds ratios for depression in patients with migraine were 1.29 for those without aura and 1.70 for those with aura. “There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors,” the study authors noted.

The FDA has approved Ampyra (dalfampridine) extended-release tablets to improve walking in patients with multiple sclerosis (MS). In clinical trials, patients treated with dalfampridine had faster walking speeds than those treated with a placebo. It is the first report in which a drug for MS improved function that was lost as a result of the disease. The most common side effects reported were urinary tract infection, insomnia, dizziness, headache, nausea, and others. When taken in doses greater than 10 mg twice a day, seizures may occur. It should not be used in patients with moderate to severe kidney disease. Dalfampridine is distributed by Acorda Therapeutics Inc of Hawthorne, New York.

Black patients with multiple sclerosis showed increased tissue damage and higher lesion volumes compared with white patients, according to research in the February 16 Neurology. In a study of 567 patients, 488 of whom were white and 79 were black, investigators compared quantitative MRI evaluations including T1-, T2-, and gadolinium contrast-enhancing lesion volumes and contrast-enhancing number, global and tissue-specific brain atrophy, and magnetization transfer ratios (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The researchers found that MTR values in lesions and in NAGM and NAWM were significantly lower in black subjects than in whites, and T1- and T2- lesion volumes were greater, both of which indicate a more aggressive clinical disease.

Dopamine agonists can cause or exacerbate compulsive behaviors in patients with Parkinson’s, according to research published in the January 14 Neuron. “A constellation of pathological behaviors, including gambling, shopping, binge eating, and hypersexuality is seen in 17% of patients on dopamine agonists,” the study authors wrote. Because reinforcement learning algorithms allow for computation of prediction error, the researchers used a reinforcement learning model to deconstruct decision-making processes dysregulated by dopamine agonists in patients who are susceptible to compulsive behaviors. The investigators found that the medications increased the rate of learning from gain outcomes and increased striatal prediction error activity, signifying a “better than expected” outcome.

Patients with acute ischemic stroke admitted to the hospital on the weekend are more likely to receive t-PA than those admitted on a weekday, a study in the January Archives of Neurology reported. Researchers analyzed rates of t-PA administration, as well as death rates, among 78,657stroke patients admitted to Virginia hospitals between 1998 and 2006 and found weekend patients (n=20,279) were 20% more likely to receive t-PA than weekday patients (n=58,378). There was no statistically significant difference in patient mortality based on day of admission; however, because a greater percentage of weekend patients received t-PA while death rates remained equal, the study authors noted that those treated with t-PA may be more likely to die in the hospital.

Impaired cognitive function in elderly men may be an independent predictor of subsequent stroke, according to a report in the February 2 Neurology. In a study of 930 elderly men (mean age, 70), Swedish researchers found that taking longer to complete the Trail Making Test B increased stroke risk by as much as 300% for those in the highest quartile, compared with those in the lowest quartile. Each time increase of 1 SD was associated with a 1.48 higher risk of stroke. “Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit,” the study authors wrote.

Women with Down syndrome who experienced early menopause were almost twice as likely to develop dementia at a younger age than those who entered menopause later, according to research in the January Journal of Alzheimer’s Disease. In a prospective longitudinal cohort study of dementia and mortality in women with Down syndrome, researchers followed 85 postmenopausal subjects for an average of 4.3 years and found a significant correlation between the age at menopause onset and age at diagnosis of dementia. Subjects with an earlier onset of menopause had a 1.8-fold increased risk of dementia. In addition, women who experienced menopause earlier had a twofold increased risk of dying younger.

White, elderly cancer survivors have a reduced risk of developing Alzheimer’s disease, as reported in the January 12 Neurology. Conversely, patients with Alzheimer’s disease have a reduced cancer risk, investigators found. In a prospective cohort study of 3,020 subjects ages 65 and older, the presence of Alzheimer’s disease was associated with a reduced risk of cancer hospitalizations, after adjustments for demographic and other factors. Prevalent cancer was also associated with a reduced risk of Alzheimer’s disease among white subjects after the researchers adjusted for demographics, number of apolipoprotein ε4 alleles, hypertension, diabetes, and coronary heart disease. The opposite was found in minorities, although the sample size was considered too small. No significant association was found between cancer and vascular dementia.

Ginkgo biloba did not preserve cognitive function any better than a placebo, per a study in the December 23, 2009, JAMA. In the randomized, double-blind, placebo-controlled Ginkgo Evaluation of Memory study, researchers at six academic medical centers in the US tracked 3,069 community-dwelling subjects ages 72 to 96 years for an average of 6.1 years. Subjects were given either a twice-daily dose of 120 mg extract of Ginkgo biloba or a placebo. Cognition was measured as rates of change over time in the Modified Mini-Mental State Examination, the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and neuropsychologic domains of memory, attention, visual-spatial construction, language, and executive functions. Investigators found no significant difference in cognitive decline between the herb and placebo.

A decreased ability to smell is common in patients with Alzheimer’s disease and may be a useful early diagnostic tool, researchers reported in the January 13 Journal of Neuroscience. The study linked olfactory dysfunction with an accumulation of amyloid-β protein in Alzheimer’s disease model mice. “The usefulness of olfactory screens to serve as informative indicators of Alzheimer’s is precluded by a lack of knowledge regarding why the disease impacts olfaction,” the study authors stated. The investigators assayed olfactory perception and amyloid-β deposition in the genetically engineered mice and found that amyloid-β pathology first occurred in an area of the brain responsible for smelling. Mice with higher concentrations of amyloid-β also displayed olfactory dysfunction. Researchers noted the “odor cross-habitation test [was] a powerful behavioral assay…[which] may serve to monitor the efficacy of therapies aimed at reducing amyloid-β.”

The Lancet has retracted the 1998 paper by Wakefield et al that suggested a link between autism and the childhood measles, mumps, and rubella (MMR) vaccine. The retraction, published in the February 2 online issue, follows a judgment by the UK General Medical Council’s Fitness to Practice Panel on January 28. “It has become clear that several elements of the 1998 paper by Wakefield et al are incorrect,” the editors wrote. “In particular, the claims in the original paper that children were ‘consecutively referred’ and that investigations were ‘approved’ by the local ethics committee have been proven to be false.” In 2004, 10 of the original authors retracted parts of the study, stating, “in this paper no causal link was established between MMR vaccine and autism as the data were insufficient.”

Advanced maternal age may be linked to an increased risk of autism, researchers reported in the February 8 online Autism Research. In a study of 12,159 cases of autism from a pool of almost 5 million births between 1990 and 1999, the investigators found a monotonic increased risk of autism related to advancing maternal age (40 and older) regardless of paternal age. However, the study authors noted fathers aged 40 and up who mated with women younger than 30 also had an increased risk of autistic offspring, compared with men in their mid- to late-20s. Yet when the mother was older than 30 and the father was 40 or older, the associated autism risk was similar to that of younger men. The investigators also noted that the “recent trend towards delaying childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.”

Depression and migraine headaches appear to share a common genetic factor, a Dutch study of 2,652 people found. As reported in the January 26 Neurology, researchers compared heritability estimates among members of the Erasmus Rucphen family for migraine with and without depression, and depression rates between migraineurs and controls. Of the total study population, 360 had migraines, 151 of whom experienced migraine aura as well. One-quarter of migraineurs also had depression, compared with 13% of the controls. Odds ratios for depression in patients with migraine were 1.29 for those without aura and 1.70 for those with aura. “There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors,” the study authors noted.

The FDA has approved Ampyra (dalfampridine) extended-release tablets to improve walking in patients with multiple sclerosis (MS). In clinical trials, patients treated with dalfampridine had faster walking speeds than those treated with a placebo. It is the first report in which a drug for MS improved function that was lost as a result of the disease. The most common side effects reported were urinary tract infection, insomnia, dizziness, headache, nausea, and others. When taken in doses greater than 10 mg twice a day, seizures may occur. It should not be used in patients with moderate to severe kidney disease. Dalfampridine is distributed by Acorda Therapeutics Inc of Hawthorne, New York.

Black patients with multiple sclerosis showed increased tissue damage and higher lesion volumes compared with white patients, according to research in the February 16 Neurology. In a study of 567 patients, 488 of whom were white and 79 were black, investigators compared quantitative MRI evaluations including T1-, T2-, and gadolinium contrast-enhancing lesion volumes and contrast-enhancing number, global and tissue-specific brain atrophy, and magnetization transfer ratios (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The researchers found that MTR values in lesions and in NAGM and NAWM were significantly lower in black subjects than in whites, and T1- and T2- lesion volumes were greater, both of which indicate a more aggressive clinical disease.

Dopamine agonists can cause or exacerbate compulsive behaviors in patients with Parkinson’s, according to research published in the January 14 Neuron. “A constellation of pathological behaviors, including gambling, shopping, binge eating, and hypersexuality is seen in 17% of patients on dopamine agonists,” the study authors wrote. Because reinforcement learning algorithms allow for computation of prediction error, the researchers used a reinforcement learning model to deconstruct decision-making processes dysregulated by dopamine agonists in patients who are susceptible to compulsive behaviors. The investigators found that the medications increased the rate of learning from gain outcomes and increased striatal prediction error activity, signifying a “better than expected” outcome.

Patients with acute ischemic stroke admitted to the hospital on the weekend are more likely to receive t-PA than those admitted on a weekday, a study in the January Archives of Neurology reported. Researchers analyzed rates of t-PA administration, as well as death rates, among 78,657stroke patients admitted to Virginia hospitals between 1998 and 2006 and found weekend patients (n=20,279) were 20% more likely to receive t-PA than weekday patients (n=58,378). There was no statistically significant difference in patient mortality based on day of admission; however, because a greater percentage of weekend patients received t-PA while death rates remained equal, the study authors noted that those treated with t-PA may be more likely to die in the hospital.

Impaired cognitive function in elderly men may be an independent predictor of subsequent stroke, according to a report in the February 2 Neurology. In a study of 930 elderly men (mean age, 70), Swedish researchers found that taking longer to complete the Trail Making Test B increased stroke risk by as much as 300% for those in the highest quartile, compared with those in the lowest quartile. Each time increase of 1 SD was associated with a 1.48 higher risk of stroke. “Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit,” the study authors wrote.

Women with Down syndrome who experienced early menopause were almost twice as likely to develop dementia at a younger age than those who entered menopause later, according to research in the January Journal of Alzheimer’s Disease. In a prospective longitudinal cohort study of dementia and mortality in women with Down syndrome, researchers followed 85 postmenopausal subjects for an average of 4.3 years and found a significant correlation between the age at menopause onset and age at diagnosis of dementia. Subjects with an earlier onset of menopause had a 1.8-fold increased risk of dementia. In addition, women who experienced menopause earlier had a twofold increased risk of dying younger.

White, elderly cancer survivors have a reduced risk of developing Alzheimer’s disease, as reported in the January 12 Neurology. Conversely, patients with Alzheimer’s disease have a reduced cancer risk, investigators found. In a prospective cohort study of 3,020 subjects ages 65 and older, the presence of Alzheimer’s disease was associated with a reduced risk of cancer hospitalizations, after adjustments for demographic and other factors. Prevalent cancer was also associated with a reduced risk of Alzheimer’s disease among white subjects after the researchers adjusted for demographics, number of apolipoprotein ε4 alleles, hypertension, diabetes, and coronary heart disease. The opposite was found in minorities, although the sample size was considered too small. No significant association was found between cancer and vascular dementia.

Ginkgo biloba did not preserve cognitive function any better than a placebo, per a study in the December 23, 2009, JAMA. In the randomized, double-blind, placebo-controlled Ginkgo Evaluation of Memory study, researchers at six academic medical centers in the US tracked 3,069 community-dwelling subjects ages 72 to 96 years for an average of 6.1 years. Subjects were given either a twice-daily dose of 120 mg extract of Ginkgo biloba or a placebo. Cognition was measured as rates of change over time in the Modified Mini-Mental State Examination, the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and neuropsychologic domains of memory, attention, visual-spatial construction, language, and executive functions. Investigators found no significant difference in cognitive decline between the herb and placebo.

A decreased ability to smell is common in patients with Alzheimer’s disease and may be a useful early diagnostic tool, researchers reported in the January 13 Journal of Neuroscience. The study linked olfactory dysfunction with an accumulation of amyloid-β protein in Alzheimer’s disease model mice. “The usefulness of olfactory screens to serve as informative indicators of Alzheimer’s is precluded by a lack of knowledge regarding why the disease impacts olfaction,” the study authors stated. The investigators assayed olfactory perception and amyloid-β deposition in the genetically engineered mice and found that amyloid-β pathology first occurred in an area of the brain responsible for smelling. Mice with higher concentrations of amyloid-β also displayed olfactory dysfunction. Researchers noted the “odor cross-habitation test [was] a powerful behavioral assay…[which] may serve to monitor the efficacy of therapies aimed at reducing amyloid-β.”

The Lancet has retracted the 1998 paper by Wakefield et al that suggested a link between autism and the childhood measles, mumps, and rubella (MMR) vaccine. The retraction, published in the February 2 online issue, follows a judgment by the UK General Medical Council’s Fitness to Practice Panel on January 28. “It has become clear that several elements of the 1998 paper by Wakefield et al are incorrect,” the editors wrote. “In particular, the claims in the original paper that children were ‘consecutively referred’ and that investigations were ‘approved’ by the local ethics committee have been proven to be false.” In 2004, 10 of the original authors retracted parts of the study, stating, “in this paper no causal link was established between MMR vaccine and autism as the data were insufficient.”

Advanced maternal age may be linked to an increased risk of autism, researchers reported in the February 8 online Autism Research. In a study of 12,159 cases of autism from a pool of almost 5 million births between 1990 and 1999, the investigators found a monotonic increased risk of autism related to advancing maternal age (40 and older) regardless of paternal age. However, the study authors noted fathers aged 40 and up who mated with women younger than 30 also had an increased risk of autistic offspring, compared with men in their mid- to late-20s. Yet when the mother was older than 30 and the father was 40 or older, the associated autism risk was similar to that of younger men. The investigators also noted that the “recent trend towards delaying childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.”

Depression and migraine headaches appear to share a common genetic factor, a Dutch study of 2,652 people found. As reported in the January 26 Neurology, researchers compared heritability estimates among members of the Erasmus Rucphen family for migraine with and without depression, and depression rates between migraineurs and controls. Of the total study population, 360 had migraines, 151 of whom experienced migraine aura as well. One-quarter of migraineurs also had depression, compared with 13% of the controls. Odds ratios for depression in patients with migraine were 1.29 for those without aura and 1.70 for those with aura. “There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors,” the study authors noted.

The FDA has approved Ampyra (dalfampridine) extended-release tablets to improve walking in patients with multiple sclerosis (MS). In clinical trials, patients treated with dalfampridine had faster walking speeds than those treated with a placebo. It is the first report in which a drug for MS improved function that was lost as a result of the disease. The most common side effects reported were urinary tract infection, insomnia, dizziness, headache, nausea, and others. When taken in doses greater than 10 mg twice a day, seizures may occur. It should not be used in patients with moderate to severe kidney disease. Dalfampridine is distributed by Acorda Therapeutics Inc of Hawthorne, New York.

Black patients with multiple sclerosis showed increased tissue damage and higher lesion volumes compared with white patients, according to research in the February 16 Neurology. In a study of 567 patients, 488 of whom were white and 79 were black, investigators compared quantitative MRI evaluations including T1-, T2-, and gadolinium contrast-enhancing lesion volumes and contrast-enhancing number, global and tissue-specific brain atrophy, and magnetization transfer ratios (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The researchers found that MTR values in lesions and in NAGM and NAWM were significantly lower in black subjects than in whites, and T1- and T2- lesion volumes were greater, both of which indicate a more aggressive clinical disease.

Dopamine agonists can cause or exacerbate compulsive behaviors in patients with Parkinson’s, according to research published in the January 14 Neuron. “A constellation of pathological behaviors, including gambling, shopping, binge eating, and hypersexuality is seen in 17% of patients on dopamine agonists,” the study authors wrote. Because reinforcement learning algorithms allow for computation of prediction error, the researchers used a reinforcement learning model to deconstruct decision-making processes dysregulated by dopamine agonists in patients who are susceptible to compulsive behaviors. The investigators found that the medications increased the rate of learning from gain outcomes and increased striatal prediction error activity, signifying a “better than expected” outcome.

Patients with acute ischemic stroke admitted to the hospital on the weekend are more likely to receive t-PA than those admitted on a weekday, a study in the January Archives of Neurology reported. Researchers analyzed rates of t-PA administration, as well as death rates, among 78,657stroke patients admitted to Virginia hospitals between 1998 and 2006 and found weekend patients (n=20,279) were 20% more likely to receive t-PA than weekday patients (n=58,378). There was no statistically significant difference in patient mortality based on day of admission; however, because a greater percentage of weekend patients received t-PA while death rates remained equal, the study authors noted that those treated with t-PA may be more likely to die in the hospital.

Impaired cognitive function in elderly men may be an independent predictor of subsequent stroke, according to a report in the February 2 Neurology. In a study of 930 elderly men (mean age, 70), Swedish researchers found that taking longer to complete the Trail Making Test B increased stroke risk by as much as 300% for those in the highest quartile, compared with those in the lowest quartile. Each time increase of 1 SD was associated with a 1.48 higher risk of stroke. “Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit,” the study authors wrote.

A 6-year-old girl was brought by her parents to the emergency department (ED) with an elevated heart rate. According to the parents, the girl was carrying her younger sister when they both fell, landing on their buttocks. The child told them that her heart was beating fast, and the parents said she appeared to be on the verge of fainting.

They stated that their daughter was healthy and active; they denied previous episodes of shortness of breath, headache, weakness, tachycardia, syncope, or fatigue with exercise. Her caffeine intake, they claimed, was limited to one small cup of soda they allowed her each week.

Initial evaluation in the ED revealed an anxious child with tachycardia and shortness of breath. She presented with a temperature of 98.3°F (36.8°C); pulse, 210 beats/min; respirations, 33 breaths/min; blood pressure, 100/72 mm Hg; weight, 78 lb; height, 45 in; and BMI, 27.1. ECG revealed a heart rate exceeding 210 beats/min, and a pediatric cardiologist made a diagnosis of supraventricular tachycardia (SVT).

The pediatric cardiologist prescribed an adenosine IV drip, which successfully stabilized the child’s heart to sinus rhythm. After three hours in the ED, the patient was discharged with a stable heart rate of 100 beats/min. (It is well known that heart rate regulation changes significantly during development; this is most obvious in higher basal rates in infants and children, compared with adults.¹)

The parents were advised to administer atenolol 12.5 mg (one tablet) twice daily and to make a follow-up appointment with a pediatric electrophysiologist. (Although atenolol is not currently FDA approved for this use, a multicenter prospective randomized controlled trial comparing digoxin with beta-blockers for the treatment of SVT in children is presently under way.²)

At that appointment, the pediatric electrophysiologist provided information to the parents regarding the therapeutic options for SVT. The parents continued to administer atenolol to the child, as was deemed necessary until any accessory electrical pathway could be identified and, if so, an ablation procedure could be performed. They were uncertain how to proceed so long as their daughter experienced no recurrent episodes of SVT while receiving pharmacologic therapy.

However, six months after the initial episode, the child (then age 7) presented to the ED once again with recurrent SVT. The pediatric cardiologist ordered an adenosine IV drip, which resulted in successful conversion to sinus rhythm. The parents were instructed to increase the child’s atenolol dosage to 25 mg twice a day.

Six months later, after extensive research and consultation, the parents agreed to an ablation procedure in order to prevent further episodes of SVT. Upon their informed consent, the child was sent to a cardiac catheterization laboratory for an electrophysiology study (EPS), which confirmed the presence of an accessory pathway, as well as the diagnosis of atrioventricular reciprocating tachycardia (AVRT). The procedure was followed by radiofrequency catheter ablation to correct the 7-year-old patient’s accessory pathway–mediated reentry tachycardia.

Discussion
SVT, also known as paroxysmal supraventricular tachycardia (PSVT), is one of the most common symptomatic pediatric arrhythmias, affecting between one in 25,000 and one in 250 children.³ It is defined as rapid heart rhythm (140 to 240 beats/min) that is caused by the presence of additional electrical connections and/or congenital muscle fibers between the atrium and the ventricle or within the atrioventricular (AV) node that did not, for unknown reasons, separate completely during development.⁴ SVT can be triggered by physical or psychological stress automaticity.³

Approximately 50% of children with SVT present with a first episode before age 1. SVT usually occurs in early childhood, between ages 6 and 9.⁴ Almost 90% of pediatric patients with SVT are diagnosed with a reentry mechanism.³ The symptoms experienced may be resolved pharmacologically or by means of an invasive therapy. Serious sequelae associated with SVT include heart failure and cardiac arrest.

For children with rare and mildly symptomatic episodes in whom SVT is easily terminated, the SVT may not warrant treatment. However, it may be advisable to offer medical therapy or transcatheter ablation as therapeutic options for children with episodes that are difficult to terminate, occur frequently, or occur during participation in athletics.⁴

Pathophysiology
SVT generally presents as one of three types: AVRT, which is also known as Wolff-Parkinson-White syndrome; atrioventricular nodal reentry tachycardia (AVNRT); and automatic tachycardia (AT).

AVRT, the most common type of SVT, comprises about 90% of pediatric cases. It is defined by the presence of one or more accessory conduction pathways that are anatomically separated from the normal cardiac conduction system.5 AVRT may be orthodromic (that is, the arrhythmia circuit proceeds down the AV node and retrograde up the accessory conduction pathway) or antedromic (ie, proceeding down the accessory pathway and up the AV node⁵; see figure.^6,7)

AVNRT, considered the second most common type of SVT in children, accounts for about 10% of pediatric cases. AVNRT is caused by an interaction between the two types of pathways within the AV node—one with a fast conduction time and a short refractory period, and the other with a slow conduction time and a long refractory period. AVNRT occurs when the antegrade conduction block in the fast pathway results in conduction over the slow pathway and back up the fast pathway, forming a microreentrant circuit.⁵

AT is the result of rapid depolarization from an automatic focus originating within the atria but outside the sinus node.³

Patient Presentation and History
The typical presentation of AVRT in children of school age includes palpitations, chest pain or tightness, dizziness, anxiety, decrease in exercise tolerance, easy fatigability, and/or shortness of breath.³ Onset is described as abrupt, while termination of SVT is described as slower because the catecholamine levels are typically elevated.⁴

The frequency and duration of SVT can vary greatly, from a few minutes to a few hours; it can occur as regularly as daily or as uncommonly as once or twice per year.⁴ Additionally, SVT symptoms can go unrecognized until a cardiac dysfunction develops. As for the patient in the case study, no apparent factor in her history was identified that may have induced SVT.

The differential diagnosis for SVT is broad, including sinus tachycardia, multifocal atrial tachycardia, and SVT with aberrancy.⁸ Additional considerations include stress, anxiety, hyperthyroidism, electrolyte abnormalities, and dehydration—any of which can present with a tachycardia response.⁴ Furthermore, clinicians are often unlikely to diagnose a child with any cardiac problem because chest pain is more commonly a presenting symptom of a pulmonary or musculoskeletal condition than a cardiac problem.³

Physical Examination
SVT can be diagnosed based on medical history and physical examination. During the physical examination, providers will assess the patient’s blood pressure and pulse, auscultate heart and lung sounds, assess the veins in the patient’s neck for different types of pulsations, and conduct cardiac maneuvers, including the Valsalva maneuver and carotid sinus massage.^9,10

Laboratory Work-up and Diagnosis
Three specific tests help clinicians monitor and evaluate a patient’s conduction system. ECG is important to assess the heart rhythm both at baseline and when symptoms are occurring, if possible.³ Ambulatory ECG (ie, Holter monitoring, event recorders) record the patient’s heart rhythm on a continuous basis.

An EPS, which is performed to classify the mechanism of SVT, is conducted by inserting one or more electrocatheters into the heart by way of the femoral vein or other peripheral vessel.³ Pacing and sensing electrodes at the ends of the catheters record local intracardiac electrical activity and timing information, providing a detailed analysis of the heart’s electrical activity. The EPS is critical to determine the presence of one or more extra electrical pathways within the heart and to localize it by region.^3,11 An ablation procedure may follow.

Management Options
SVT can be treated pharmacologically or nonpharmacologically. First-line pharmacologic options include certain beta-blockers (including atenolol and propranolol), digoxin, and calcium channel blockers. Second-line pharmacologic treatments include amiodarone, flecainide, and sotalol,⁴ all of which are contraindicated in children younger than 1 year because of these patients’ hemodynamic dependency on the heart and inability to generate stroke volume.³ Pharmacologic treatment of SVT is associated with a 68% success rate in children⁴ (see Table 1⁴).

For children in whom pharmacologic treatment is ineffective, an ablation procedure may be performed. Radiofrequency catheter ablation is currently considered first-line therapy for AVRT and AVNRT.¹² In this invasive procedure, intracardiac electrical mapping is performed and the initiating focus of the arrhythmia or the accessory electrical pathway that has been identified within the heart is destroyed by radiofrequency energy, delivered by electrocatheter. Ablations performed during the acute phase of SVT have a 95% success rate.^3,13

Cryoablation is a relatively new treatment in which liquid nitrous oxide is used to cool the catheter to subfreezing temperatures, enabling it to destroy the myocardial tissue by freezing.^3,14 The advantage of cryoablation is the option of reversible cooling, which allows the electrophysiologist to test the area first, confirming the accuracy of the apparent location accessory pathway.¹⁵

Noninvasive, nonpharmacologic interventions that increase the refractoriness of the AV node may be successful in terminating the tachyarrhythmia during episodes of SVT (see Table 2^3,9,13,16). They are used to terminate and diagnose tachydysrhythmias, increase parasympathetic tone, and slow conduction through the AV node.³

Patient Education
It is very important for health care providers to relieve parents’ and caregivers’ stress, anxiety, and uncertainty by educating them about the child’s cardiac condition of SVT. Information to convey include an understanding of what SVT is, what may cause it, what triggers the patient should avoid, what treatments are available and appropriate (including the maneuvers shown in Table 2), and what outcomes may be expected. An excellent patient/family education handout from the Children’s Hospitals and Clinics of Minnesota¹⁷ is available at www.childrensmn.org/Manuals/PFS/Condill/018303.pdf.

Follow-Up
Primary care providers must emphasize the importance of monitoring the patient’s progress, based on the severity of his or her SVT symptoms. The provider may choose to monitor the patient for a few weeks or a few months, assessing the frequency of arrhythmia recurrence and the heart rate, to adjust or substitute medications based on repeat ECG or Holter evaluations, and to plan further therapy, should the condition worsen.⁵

The Case Patient
One month after undergoing radiofrequency catheter ablation, the child presented to the pediatric cardiologist for follow-up. Since the procedure, she had been without any symptoms referable to the cardiovascular system. She denied experiencing any fast heart rate, palpitations, chest pain, shortness of breath, or dizziness. ECG demonstrated normal sinus rhythm.

Two years after undergoing radiofrequency ablation, the child is functioning at a normal activity level with no recurrence of SVT episodes.

Conclusion
The purpose of this case study is to improve primary care providers’ understanding of SVT in children and to convey the importance of identifying the condition in a timely manner and referring patients to a pediatric cardiologist or electrophysiologist. For most children affected by SVT, a regimen of pharmacologic and/or nonpharmacologic treatment—supported by detailed education for their parents and caregivers—can allow them to live a healthy, normal life.

A 6-year-old girl was brought by her parents to the emergency department (ED) with an elevated heart rate. According to the parents, the girl was carrying her younger sister when they both fell, landing on their buttocks. The child told them that her heart was beating fast, and the parents said she appeared to be on the verge of fainting.

They stated that their daughter was healthy and active; they denied previous episodes of shortness of breath, headache, weakness, tachycardia, syncope, or fatigue with exercise. Her caffeine intake, they claimed, was limited to one small cup of soda they allowed her each week.

Initial evaluation in the ED revealed an anxious child with tachycardia and shortness of breath. She presented with a temperature of 98.3°F (36.8°C); pulse, 210 beats/min; respirations, 33 breaths/min; blood pressure, 100/72 mm Hg; weight, 78 lb; height, 45 in; and BMI, 27.1. ECG revealed a heart rate exceeding 210 beats/min, and a pediatric cardiologist made a diagnosis of supraventricular tachycardia (SVT).

The pediatric cardiologist prescribed an adenosine IV drip, which successfully stabilized the child’s heart to sinus rhythm. After three hours in the ED, the patient was discharged with a stable heart rate of 100 beats/min. (It is well known that heart rate regulation changes significantly during development; this is most obvious in higher basal rates in infants and children, compared with adults.¹)

The parents were advised to administer atenolol 12.5 mg (one tablet) twice daily and to make a follow-up appointment with a pediatric electrophysiologist. (Although atenolol is not currently FDA approved for this use, a multicenter prospective randomized controlled trial comparing digoxin with beta-blockers for the treatment of SVT in children is presently under way.²)

At that appointment, the pediatric electrophysiologist provided information to the parents regarding the therapeutic options for SVT. The parents continued to administer atenolol to the child, as was deemed necessary until any accessory electrical pathway could be identified and, if so, an ablation procedure could be performed. They were uncertain how to proceed so long as their daughter experienced no recurrent episodes of SVT while receiving pharmacologic therapy.

However, six months after the initial episode, the child (then age 7) presented to the ED once again with recurrent SVT. The pediatric cardiologist ordered an adenosine IV drip, which resulted in successful conversion to sinus rhythm. The parents were instructed to increase the child’s atenolol dosage to 25 mg twice a day.

Six months later, after extensive research and consultation, the parents agreed to an ablation procedure in order to prevent further episodes of SVT. Upon their informed consent, the child was sent to a cardiac catheterization laboratory for an electrophysiology study (EPS), which confirmed the presence of an accessory pathway, as well as the diagnosis of atrioventricular reciprocating tachycardia (AVRT). The procedure was followed by radiofrequency catheter ablation to correct the 7-year-old patient’s accessory pathway–mediated reentry tachycardia.

Discussion
SVT, also known as paroxysmal supraventricular tachycardia (PSVT), is one of the most common symptomatic pediatric arrhythmias, affecting between one in 25,000 and one in 250 children.³ It is defined as rapid heart rhythm (140 to 240 beats/min) that is caused by the presence of additional electrical connections and/or congenital muscle fibers between the atrium and the ventricle or within the atrioventricular (AV) node that did not, for unknown reasons, separate completely during development.⁴ SVT can be triggered by physical or psychological stress automaticity.³

Approximately 50% of children with SVT present with a first episode before age 1. SVT usually occurs in early childhood, between ages 6 and 9.⁴ Almost 90% of pediatric patients with SVT are diagnosed with a reentry mechanism.³ The symptoms experienced may be resolved pharmacologically or by means of an invasive therapy. Serious sequelae associated with SVT include heart failure and cardiac arrest.

For children with rare and mildly symptomatic episodes in whom SVT is easily terminated, the SVT may not warrant treatment. However, it may be advisable to offer medical therapy or transcatheter ablation as therapeutic options for children with episodes that are difficult to terminate, occur frequently, or occur during participation in athletics.⁴

Pathophysiology
SVT generally presents as one of three types: AVRT, which is also known as Wolff-Parkinson-White syndrome; atrioventricular nodal reentry tachycardia (AVNRT); and automatic tachycardia (AT).

AVRT, the most common type of SVT, comprises about 90% of pediatric cases. It is defined by the presence of one or more accessory conduction pathways that are anatomically separated from the normal cardiac conduction system.5 AVRT may be orthodromic (that is, the arrhythmia circuit proceeds down the AV node and retrograde up the accessory conduction pathway) or antedromic (ie, proceeding down the accessory pathway and up the AV node⁵; see figure.^6,7)

AVNRT, considered the second most common type of SVT in children, accounts for about 10% of pediatric cases. AVNRT is caused by an interaction between the two types of pathways within the AV node—one with a fast conduction time and a short refractory period, and the other with a slow conduction time and a long refractory period. AVNRT occurs when the antegrade conduction block in the fast pathway results in conduction over the slow pathway and back up the fast pathway, forming a microreentrant circuit.⁵

AT is the result of rapid depolarization from an automatic focus originating within the atria but outside the sinus node.³

Patient Presentation and History
The typical presentation of AVRT in children of school age includes palpitations, chest pain or tightness, dizziness, anxiety, decrease in exercise tolerance, easy fatigability, and/or shortness of breath.³ Onset is described as abrupt, while termination of SVT is described as slower because the catecholamine levels are typically elevated.⁴

The frequency and duration of SVT can vary greatly, from a few minutes to a few hours; it can occur as regularly as daily or as uncommonly as once or twice per year.⁴ Additionally, SVT symptoms can go unrecognized until a cardiac dysfunction develops. As for the patient in the case study, no apparent factor in her history was identified that may have induced SVT.

The differential diagnosis for SVT is broad, including sinus tachycardia, multifocal atrial tachycardia, and SVT with aberrancy.⁸ Additional considerations include stress, anxiety, hyperthyroidism, electrolyte abnormalities, and dehydration—any of which can present with a tachycardia response.⁴ Furthermore, clinicians are often unlikely to diagnose a child with any cardiac problem because chest pain is more commonly a presenting symptom of a pulmonary or musculoskeletal condition than a cardiac problem.³

Physical Examination
SVT can be diagnosed based on medical history and physical examination. During the physical examination, providers will assess the patient’s blood pressure and pulse, auscultate heart and lung sounds, assess the veins in the patient’s neck for different types of pulsations, and conduct cardiac maneuvers, including the Valsalva maneuver and carotid sinus massage.^9,10

Laboratory Work-up and Diagnosis
Three specific tests help clinicians monitor and evaluate a patient’s conduction system. ECG is important to assess the heart rhythm both at baseline and when symptoms are occurring, if possible.³ Ambulatory ECG (ie, Holter monitoring, event recorders) record the patient’s heart rhythm on a continuous basis.

An EPS, which is performed to classify the mechanism of SVT, is conducted by inserting one or more electrocatheters into the heart by way of the femoral vein or other peripheral vessel.³ Pacing and sensing electrodes at the ends of the catheters record local intracardiac electrical activity and timing information, providing a detailed analysis of the heart’s electrical activity. The EPS is critical to determine the presence of one or more extra electrical pathways within the heart and to localize it by region.^3,11 An ablation procedure may follow.

Management Options
SVT can be treated pharmacologically or nonpharmacologically. First-line pharmacologic options include certain beta-blockers (including atenolol and propranolol), digoxin, and calcium channel blockers. Second-line pharmacologic treatments include amiodarone, flecainide, and sotalol,⁴ all of which are contraindicated in children younger than 1 year because of these patients’ hemodynamic dependency on the heart and inability to generate stroke volume.³ Pharmacologic treatment of SVT is associated with a 68% success rate in children⁴ (see Table 1⁴).

For children in whom pharmacologic treatment is ineffective, an ablation procedure may be performed. Radiofrequency catheter ablation is currently considered first-line therapy for AVRT and AVNRT.¹² In this invasive procedure, intracardiac electrical mapping is performed and the initiating focus of the arrhythmia or the accessory electrical pathway that has been identified within the heart is destroyed by radiofrequency energy, delivered by electrocatheter. Ablations performed during the acute phase of SVT have a 95% success rate.^3,13

Cryoablation is a relatively new treatment in which liquid nitrous oxide is used to cool the catheter to subfreezing temperatures, enabling it to destroy the myocardial tissue by freezing.^3,14 The advantage of cryoablation is the option of reversible cooling, which allows the electrophysiologist to test the area first, confirming the accuracy of the apparent location accessory pathway.¹⁵

Noninvasive, nonpharmacologic interventions that increase the refractoriness of the AV node may be successful in terminating the tachyarrhythmia during episodes of SVT (see Table 2^3,9,13,16). They are used to terminate and diagnose tachydysrhythmias, increase parasympathetic tone, and slow conduction through the AV node.³

Patient Education
It is very important for health care providers to relieve parents’ and caregivers’ stress, anxiety, and uncertainty by educating them about the child’s cardiac condition of SVT. Information to convey include an understanding of what SVT is, what may cause it, what triggers the patient should avoid, what treatments are available and appropriate (including the maneuvers shown in Table 2), and what outcomes may be expected. An excellent patient/family education handout from the Children’s Hospitals and Clinics of Minnesota¹⁷ is available at www.childrensmn.org/Manuals/PFS/Condill/018303.pdf.

Follow-Up
Primary care providers must emphasize the importance of monitoring the patient’s progress, based on the severity of his or her SVT symptoms. The provider may choose to monitor the patient for a few weeks or a few months, assessing the frequency of arrhythmia recurrence and the heart rate, to adjust or substitute medications based on repeat ECG or Holter evaluations, and to plan further therapy, should the condition worsen.⁵

The Case Patient
One month after undergoing radiofrequency catheter ablation, the child presented to the pediatric cardiologist for follow-up. Since the procedure, she had been without any symptoms referable to the cardiovascular system. She denied experiencing any fast heart rate, palpitations, chest pain, shortness of breath, or dizziness. ECG demonstrated normal sinus rhythm.

Two years after undergoing radiofrequency ablation, the child is functioning at a normal activity level with no recurrence of SVT episodes.

Conclusion
The purpose of this case study is to improve primary care providers’ understanding of SVT in children and to convey the importance of identifying the condition in a timely manner and referring patients to a pediatric cardiologist or electrophysiologist. For most children affected by SVT, a regimen of pharmacologic and/or nonpharmacologic treatment—supported by detailed education for their parents and caregivers—can allow them to live a healthy, normal life.

A 6-year-old girl was brought by her parents to the emergency department (ED) with an elevated heart rate. According to the parents, the girl was carrying her younger sister when they both fell, landing on their buttocks. The child told them that her heart was beating fast, and the parents said she appeared to be on the verge of fainting.

They stated that their daughter was healthy and active; they denied previous episodes of shortness of breath, headache, weakness, tachycardia, syncope, or fatigue with exercise. Her caffeine intake, they claimed, was limited to one small cup of soda they allowed her each week.

Initial evaluation in the ED revealed an anxious child with tachycardia and shortness of breath. She presented with a temperature of 98.3°F (36.8°C); pulse, 210 beats/min; respirations, 33 breaths/min; blood pressure, 100/72 mm Hg; weight, 78 lb; height, 45 in; and BMI, 27.1. ECG revealed a heart rate exceeding 210 beats/min, and a pediatric cardiologist made a diagnosis of supraventricular tachycardia (SVT).

The pediatric cardiologist prescribed an adenosine IV drip, which successfully stabilized the child’s heart to sinus rhythm. After three hours in the ED, the patient was discharged with a stable heart rate of 100 beats/min. (It is well known that heart rate regulation changes significantly during development; this is most obvious in higher basal rates in infants and children, compared with adults.¹)

The parents were advised to administer atenolol 12.5 mg (one tablet) twice daily and to make a follow-up appointment with a pediatric electrophysiologist. (Although atenolol is not currently FDA approved for this use, a multicenter prospective randomized controlled trial comparing digoxin with beta-blockers for the treatment of SVT in children is presently under way.²)

At that appointment, the pediatric electrophysiologist provided information to the parents regarding the therapeutic options for SVT. The parents continued to administer atenolol to the child, as was deemed necessary until any accessory electrical pathway could be identified and, if so, an ablation procedure could be performed. They were uncertain how to proceed so long as their daughter experienced no recurrent episodes of SVT while receiving pharmacologic therapy.

However, six months after the initial episode, the child (then age 7) presented to the ED once again with recurrent SVT. The pediatric cardiologist ordered an adenosine IV drip, which resulted in successful conversion to sinus rhythm. The parents were instructed to increase the child’s atenolol dosage to 25 mg twice a day.

Six months later, after extensive research and consultation, the parents agreed to an ablation procedure in order to prevent further episodes of SVT. Upon their informed consent, the child was sent to a cardiac catheterization laboratory for an electrophysiology study (EPS), which confirmed the presence of an accessory pathway, as well as the diagnosis of atrioventricular reciprocating tachycardia (AVRT). The procedure was followed by radiofrequency catheter ablation to correct the 7-year-old patient’s accessory pathway–mediated reentry tachycardia.

Discussion
SVT, also known as paroxysmal supraventricular tachycardia (PSVT), is one of the most common symptomatic pediatric arrhythmias, affecting between one in 25,000 and one in 250 children.³ It is defined as rapid heart rhythm (140 to 240 beats/min) that is caused by the presence of additional electrical connections and/or congenital muscle fibers between the atrium and the ventricle or within the atrioventricular (AV) node that did not, for unknown reasons, separate completely during development.⁴ SVT can be triggered by physical or psychological stress automaticity.³

Approximately 50% of children with SVT present with a first episode before age 1. SVT usually occurs in early childhood, between ages 6 and 9.⁴ Almost 90% of pediatric patients with SVT are diagnosed with a reentry mechanism.³ The symptoms experienced may be resolved pharmacologically or by means of an invasive therapy. Serious sequelae associated with SVT include heart failure and cardiac arrest.

For children with rare and mildly symptomatic episodes in whom SVT is easily terminated, the SVT may not warrant treatment. However, it may be advisable to offer medical therapy or transcatheter ablation as therapeutic options for children with episodes that are difficult to terminate, occur frequently, or occur during participation in athletics.⁴

Pathophysiology
SVT generally presents as one of three types: AVRT, which is also known as Wolff-Parkinson-White syndrome; atrioventricular nodal reentry tachycardia (AVNRT); and automatic tachycardia (AT).

AVRT, the most common type of SVT, comprises about 90% of pediatric cases. It is defined by the presence of one or more accessory conduction pathways that are anatomically separated from the normal cardiac conduction system.5 AVRT may be orthodromic (that is, the arrhythmia circuit proceeds down the AV node and retrograde up the accessory conduction pathway) or antedromic (ie, proceeding down the accessory pathway and up the AV node⁵; see figure.^6,7)

AVNRT, considered the second most common type of SVT in children, accounts for about 10% of pediatric cases. AVNRT is caused by an interaction between the two types of pathways within the AV node—one with a fast conduction time and a short refractory period, and the other with a slow conduction time and a long refractory period. AVNRT occurs when the antegrade conduction block in the fast pathway results in conduction over the slow pathway and back up the fast pathway, forming a microreentrant circuit.⁵

AT is the result of rapid depolarization from an automatic focus originating within the atria but outside the sinus node.³

Patient Presentation and History
The typical presentation of AVRT in children of school age includes palpitations, chest pain or tightness, dizziness, anxiety, decrease in exercise tolerance, easy fatigability, and/or shortness of breath.³ Onset is described as abrupt, while termination of SVT is described as slower because the catecholamine levels are typically elevated.⁴

The frequency and duration of SVT can vary greatly, from a few minutes to a few hours; it can occur as regularly as daily or as uncommonly as once or twice per year.⁴ Additionally, SVT symptoms can go unrecognized until a cardiac dysfunction develops. As for the patient in the case study, no apparent factor in her history was identified that may have induced SVT.

The differential diagnosis for SVT is broad, including sinus tachycardia, multifocal atrial tachycardia, and SVT with aberrancy.⁸ Additional considerations include stress, anxiety, hyperthyroidism, electrolyte abnormalities, and dehydration—any of which can present with a tachycardia response.⁴ Furthermore, clinicians are often unlikely to diagnose a child with any cardiac problem because chest pain is more commonly a presenting symptom of a pulmonary or musculoskeletal condition than a cardiac problem.³

Physical Examination
SVT can be diagnosed based on medical history and physical examination. During the physical examination, providers will assess the patient’s blood pressure and pulse, auscultate heart and lung sounds, assess the veins in the patient’s neck for different types of pulsations, and conduct cardiac maneuvers, including the Valsalva maneuver and carotid sinus massage.^9,10

Laboratory Work-up and Diagnosis
Three specific tests help clinicians monitor and evaluate a patient’s conduction system. ECG is important to assess the heart rhythm both at baseline and when symptoms are occurring, if possible.³ Ambulatory ECG (ie, Holter monitoring, event recorders) record the patient’s heart rhythm on a continuous basis.

An EPS, which is performed to classify the mechanism of SVT, is conducted by inserting one or more electrocatheters into the heart by way of the femoral vein or other peripheral vessel.³ Pacing and sensing electrodes at the ends of the catheters record local intracardiac electrical activity and timing information, providing a detailed analysis of the heart’s electrical activity. The EPS is critical to determine the presence of one or more extra electrical pathways within the heart and to localize it by region.^3,11 An ablation procedure may follow.

Management Options
SVT can be treated pharmacologically or nonpharmacologically. First-line pharmacologic options include certain beta-blockers (including atenolol and propranolol), digoxin, and calcium channel blockers. Second-line pharmacologic treatments include amiodarone, flecainide, and sotalol,⁴ all of which are contraindicated in children younger than 1 year because of these patients’ hemodynamic dependency on the heart and inability to generate stroke volume.³ Pharmacologic treatment of SVT is associated with a 68% success rate in children⁴ (see Table 1⁴).

For children in whom pharmacologic treatment is ineffective, an ablation procedure may be performed. Radiofrequency catheter ablation is currently considered first-line therapy for AVRT and AVNRT.¹² In this invasive procedure, intracardiac electrical mapping is performed and the initiating focus of the arrhythmia or the accessory electrical pathway that has been identified within the heart is destroyed by radiofrequency energy, delivered by electrocatheter. Ablations performed during the acute phase of SVT have a 95% success rate.^3,13

Cryoablation is a relatively new treatment in which liquid nitrous oxide is used to cool the catheter to subfreezing temperatures, enabling it to destroy the myocardial tissue by freezing.^3,14 The advantage of cryoablation is the option of reversible cooling, which allows the electrophysiologist to test the area first, confirming the accuracy of the apparent location accessory pathway.¹⁵

Noninvasive, nonpharmacologic interventions that increase the refractoriness of the AV node may be successful in terminating the tachyarrhythmia during episodes of SVT (see Table 2^3,9,13,16). They are used to terminate and diagnose tachydysrhythmias, increase parasympathetic tone, and slow conduction through the AV node.³

Patient Education
It is very important for health care providers to relieve parents’ and caregivers’ stress, anxiety, and uncertainty by educating them about the child’s cardiac condition of SVT. Information to convey include an understanding of what SVT is, what may cause it, what triggers the patient should avoid, what treatments are available and appropriate (including the maneuvers shown in Table 2), and what outcomes may be expected. An excellent patient/family education handout from the Children’s Hospitals and Clinics of Minnesota¹⁷ is available at www.childrensmn.org/Manuals/PFS/Condill/018303.pdf.

Follow-Up
Primary care providers must emphasize the importance of monitoring the patient’s progress, based on the severity of his or her SVT symptoms. The provider may choose to monitor the patient for a few weeks or a few months, assessing the frequency of arrhythmia recurrence and the heart rate, to adjust or substitute medications based on repeat ECG or Holter evaluations, and to plan further therapy, should the condition worsen.⁵

The Case Patient
One month after undergoing radiofrequency catheter ablation, the child presented to the pediatric cardiologist for follow-up. Since the procedure, she had been without any symptoms referable to the cardiovascular system. She denied experiencing any fast heart rate, palpitations, chest pain, shortness of breath, or dizziness. ECG demonstrated normal sinus rhythm.

Two years after undergoing radiofrequency ablation, the child is functioning at a normal activity level with no recurrence of SVT episodes.

Conclusion
The purpose of this case study is to improve primary care providers’ understanding of SVT in children and to convey the importance of identifying the condition in a timely manner and referring patients to a pediatric cardiologist or electrophysiologist. For most children affected by SVT, a regimen of pharmacologic and/or nonpharmacologic treatment—supported by detailed education for their parents and caregivers—can allow them to live a healthy, normal life.

When a screening mammogram isn’t enough

A LUMP IN THE BREAST was discovered by a woman in her mid-40s. She underwent a screening (rather than a diagnostic) mammogram; no abnormalities were reported. An ultrasound ordered when the woman returned to her physician the following year noted problems. However, the report that was faxed to the physician never reached him, and no follow-up was done.

A year later, the patient made a follow-up appointment on her own initiative. A diagnostic mammogram and surgical biopsy revealed advanced cancer of the left breast. Vacuum-assisted core biopsy and clip localization performed shortly thereafter identified infiltrating ductal carcinoma.

The patient underwent neoadjuvant chemotherapy, resulting in complications and hospitalization. She subsequently had additional chemotherapy and radiation treatment.

PLAINTIFF’S CLAIM Immediate treatment would have improved the patient’s chances of cure.

THE DEFENSE No information about the defense is available.

VERDICT $575,000 settlement in South Carolina under the Federal Tort Claims Act, plus a $5,000 settlement with a hospital.

COMMENT A couple of lessons from this unfortunate case: Make sure a diagnostic (not screening) mammogram is ordered when evaluating a breast mass, and maintain a tickler file for critical lab and imaging results.

Insurance denied, appeal delayed, treatment of appendicitis deferred

ABDOMINAL PAIN SEVERE ENOUGH TO AWAKEN HER prompted a 48-year-old woman to contact her physician, who saw her 2 days later. The doctor performed an ultrasound examination, which ruled out gallstones, and ordered a computed tomography (CT) scan of the pelvis for the following day.

After the patient was injected with contrast medium for the scan, it was learned that her insurer had refused to approve the test. The patient’s pain persisted, and her doctor prescribed a pain reliever for a presumed pulled muscle. A week later, the doctor appealed the insurer’s denial of the CT scan in writing. The insurer responded that the scan would be approved if a fecal blood test proved negative.

Test results were submitted 4 days later; the CT scan was approved and performed a little more than 3 weeks after the initial order. The patient was diagnosed with appendicitis and underwent emergency surgery, including removal of part of her colon and bowel. Eight days in the hospital and a lengthy recovery followed.

PLAINTIFF’S CLAIM The physician was negligent in failing to follow up promptly on the insurer’s denial of approval for the CT scan.

DOCTOR’S DEFENSE The physician claimed that he had ordered the proper test in a timely manner; denial of approval by the insurer delayed treatment.

VERDICT $1.3 million Kentucky verdict against the physician after the plaintiff settled with the insurer.

COMMENT Ouch! This outcome is one we all fear—the insurer denying approval for a test and the physician bearing the brunt of a malpractice claim. When in doubt, get the test done and sort out the paperwork later.

Undiagnosed heart condition leads to brain injury

A 14-YEAR-OLD BOY collapsed while participating in a rodeo branding event. He was revived and taken to an emergency room (ER), where a physician evaluated him and admitted him to the hospital for overnight monitoring. The heart monitor recorded QT intervals suggesting long QT syndrome, a rare congenital condition that can lead to fainting and, occasionally, death from cardiac arrhythmias. The condition wasn’t diagnosed at the time.

A year and a half later, the patient collapsed again, this time during school wrestling practice. This more severe event resulted in anoxic brain injury, which left the patient disabled and in need of assistance with activities of daily living.

PLAINTIFF’S CLAIM The ER physician failed to diagnose congenital long QT syndrome. Proper diagnosis and treatment after the first incident could have prevented the second incident.

THE DEFENSE No information about the defense is available.

VERDICT Confidential Wyoming settlement, which included a provision that the defendant’s insurer provide inservice training on sudden arrhythmias and long QT syndrome for local doctors and other health care providers.

COMMENT Remember the zebras, as well as the horses, particularly when evaluating a patient for an unusual and potentially life-altering problem. Although syncope may be common in elders, such events in teenagers should prompt a comprehensive and meticulous evaluation.

Suicide follows antidepressant use

A 58-YEAR-OLD MAN with unexplained weight loss, diminished appetite, increased stress, edginess, and decreased libido sought care from his physician. The doctor diagnosed depression and prescribed escitalopram, 10 mg per day. He gave the patient a 5-week supply of sample medication with no warning literature or product information. Twenty days later, the patient hanged himself at home.

PLAINTIFF’S CLAIM The physician wrongly diagnosed depression; he shouldn’t have given the patient escitalopram because the US Food and Drug Administration (FDA) has issued an advisory concerning increased risk of suicide for adults treated with antidepressants. Neither the patient nor his family was informed about the possible side effects of escitalopram.

THE DEFENSE The diagnosis of depression was proper; nothing the defendants did or failed to do contributed to the patient’s death.

VERDICT Ohio defense verdict.

COMMENT Given the FDA’s black-box warning, it is imperative that we counsel and document concerning the risk of suicide when initiating therapy for depression.

When a screening mammogram isn’t enough

A LUMP IN THE BREAST was discovered by a woman in her mid-40s. She underwent a screening (rather than a diagnostic) mammogram; no abnormalities were reported. An ultrasound ordered when the woman returned to her physician the following year noted problems. However, the report that was faxed to the physician never reached him, and no follow-up was done.

A year later, the patient made a follow-up appointment on her own initiative. A diagnostic mammogram and surgical biopsy revealed advanced cancer of the left breast. Vacuum-assisted core biopsy and clip localization performed shortly thereafter identified infiltrating ductal carcinoma.

The patient underwent neoadjuvant chemotherapy, resulting in complications and hospitalization. She subsequently had additional chemotherapy and radiation treatment.

PLAINTIFF’S CLAIM Immediate treatment would have improved the patient’s chances of cure.

THE DEFENSE No information about the defense is available.

VERDICT $575,000 settlement in South Carolina under the Federal Tort Claims Act, plus a $5,000 settlement with a hospital.

COMMENT A couple of lessons from this unfortunate case: Make sure a diagnostic (not screening) mammogram is ordered when evaluating a breast mass, and maintain a tickler file for critical lab and imaging results.

Insurance denied, appeal delayed, treatment of appendicitis deferred

ABDOMINAL PAIN SEVERE ENOUGH TO AWAKEN HER prompted a 48-year-old woman to contact her physician, who saw her 2 days later. The doctor performed an ultrasound examination, which ruled out gallstones, and ordered a computed tomography (CT) scan of the pelvis for the following day.

After the patient was injected with contrast medium for the scan, it was learned that her insurer had refused to approve the test. The patient’s pain persisted, and her doctor prescribed a pain reliever for a presumed pulled muscle. A week later, the doctor appealed the insurer’s denial of the CT scan in writing. The insurer responded that the scan would be approved if a fecal blood test proved negative.

Test results were submitted 4 days later; the CT scan was approved and performed a little more than 3 weeks after the initial order. The patient was diagnosed with appendicitis and underwent emergency surgery, including removal of part of her colon and bowel. Eight days in the hospital and a lengthy recovery followed.

PLAINTIFF’S CLAIM The physician was negligent in failing to follow up promptly on the insurer’s denial of approval for the CT scan.

DOCTOR’S DEFENSE The physician claimed that he had ordered the proper test in a timely manner; denial of approval by the insurer delayed treatment.

VERDICT $1.3 million Kentucky verdict against the physician after the plaintiff settled with the insurer.

COMMENT Ouch! This outcome is one we all fear—the insurer denying approval for a test and the physician bearing the brunt of a malpractice claim. When in doubt, get the test done and sort out the paperwork later.

Undiagnosed heart condition leads to brain injury

A 14-YEAR-OLD BOY collapsed while participating in a rodeo branding event. He was revived and taken to an emergency room (ER), where a physician evaluated him and admitted him to the hospital for overnight monitoring. The heart monitor recorded QT intervals suggesting long QT syndrome, a rare congenital condition that can lead to fainting and, occasionally, death from cardiac arrhythmias. The condition wasn’t diagnosed at the time.

A year and a half later, the patient collapsed again, this time during school wrestling practice. This more severe event resulted in anoxic brain injury, which left the patient disabled and in need of assistance with activities of daily living.

PLAINTIFF’S CLAIM The ER physician failed to diagnose congenital long QT syndrome. Proper diagnosis and treatment after the first incident could have prevented the second incident.

THE DEFENSE No information about the defense is available.

VERDICT Confidential Wyoming settlement, which included a provision that the defendant’s insurer provide inservice training on sudden arrhythmias and long QT syndrome for local doctors and other health care providers.

COMMENT Remember the zebras, as well as the horses, particularly when evaluating a patient for an unusual and potentially life-altering problem. Although syncope may be common in elders, such events in teenagers should prompt a comprehensive and meticulous evaluation.

Suicide follows antidepressant use

A 58-YEAR-OLD MAN with unexplained weight loss, diminished appetite, increased stress, edginess, and decreased libido sought care from his physician. The doctor diagnosed depression and prescribed escitalopram, 10 mg per day. He gave the patient a 5-week supply of sample medication with no warning literature or product information. Twenty days later, the patient hanged himself at home.

PLAINTIFF’S CLAIM The physician wrongly diagnosed depression; he shouldn’t have given the patient escitalopram because the US Food and Drug Administration (FDA) has issued an advisory concerning increased risk of suicide for adults treated with antidepressants. Neither the patient nor his family was informed about the possible side effects of escitalopram.

THE DEFENSE The diagnosis of depression was proper; nothing the defendants did or failed to do contributed to the patient’s death.

VERDICT Ohio defense verdict.

COMMENT Given the FDA’s black-box warning, it is imperative that we counsel and document concerning the risk of suicide when initiating therapy for depression.

When a screening mammogram isn’t enough

A LUMP IN THE BREAST was discovered by a woman in her mid-40s. She underwent a screening (rather than a diagnostic) mammogram; no abnormalities were reported. An ultrasound ordered when the woman returned to her physician the following year noted problems. However, the report that was faxed to the physician never reached him, and no follow-up was done.

A year later, the patient made a follow-up appointment on her own initiative. A diagnostic mammogram and surgical biopsy revealed advanced cancer of the left breast. Vacuum-assisted core biopsy and clip localization performed shortly thereafter identified infiltrating ductal carcinoma.

The patient underwent neoadjuvant chemotherapy, resulting in complications and hospitalization. She subsequently had additional chemotherapy and radiation treatment.

PLAINTIFF’S CLAIM Immediate treatment would have improved the patient’s chances of cure.

THE DEFENSE No information about the defense is available.

VERDICT $575,000 settlement in South Carolina under the Federal Tort Claims Act, plus a $5,000 settlement with a hospital.

COMMENT A couple of lessons from this unfortunate case: Make sure a diagnostic (not screening) mammogram is ordered when evaluating a breast mass, and maintain a tickler file for critical lab and imaging results.

Insurance denied, appeal delayed, treatment of appendicitis deferred

ABDOMINAL PAIN SEVERE ENOUGH TO AWAKEN HER prompted a 48-year-old woman to contact her physician, who saw her 2 days later. The doctor performed an ultrasound examination, which ruled out gallstones, and ordered a computed tomography (CT) scan of the pelvis for the following day.

After the patient was injected with contrast medium for the scan, it was learned that her insurer had refused to approve the test. The patient’s pain persisted, and her doctor prescribed a pain reliever for a presumed pulled muscle. A week later, the doctor appealed the insurer’s denial of the CT scan in writing. The insurer responded that the scan would be approved if a fecal blood test proved negative.

Test results were submitted 4 days later; the CT scan was approved and performed a little more than 3 weeks after the initial order. The patient was diagnosed with appendicitis and underwent emergency surgery, including removal of part of her colon and bowel. Eight days in the hospital and a lengthy recovery followed.

PLAINTIFF’S CLAIM The physician was negligent in failing to follow up promptly on the insurer’s denial of approval for the CT scan.

DOCTOR’S DEFENSE The physician claimed that he had ordered the proper test in a timely manner; denial of approval by the insurer delayed treatment.

VERDICT $1.3 million Kentucky verdict against the physician after the plaintiff settled with the insurer.

COMMENT Ouch! This outcome is one we all fear—the insurer denying approval for a test and the physician bearing the brunt of a malpractice claim. When in doubt, get the test done and sort out the paperwork later.

Undiagnosed heart condition leads to brain injury

A 14-YEAR-OLD BOY collapsed while participating in a rodeo branding event. He was revived and taken to an emergency room (ER), where a physician evaluated him and admitted him to the hospital for overnight monitoring. The heart monitor recorded QT intervals suggesting long QT syndrome, a rare congenital condition that can lead to fainting and, occasionally, death from cardiac arrhythmias. The condition wasn’t diagnosed at the time.

A year and a half later, the patient collapsed again, this time during school wrestling practice. This more severe event resulted in anoxic brain injury, which left the patient disabled and in need of assistance with activities of daily living.

PLAINTIFF’S CLAIM The ER physician failed to diagnose congenital long QT syndrome. Proper diagnosis and treatment after the first incident could have prevented the second incident.

THE DEFENSE No information about the defense is available.

VERDICT Confidential Wyoming settlement, which included a provision that the defendant’s insurer provide inservice training on sudden arrhythmias and long QT syndrome for local doctors and other health care providers.

COMMENT Remember the zebras, as well as the horses, particularly when evaluating a patient for an unusual and potentially life-altering problem. Although syncope may be common in elders, such events in teenagers should prompt a comprehensive and meticulous evaluation.

Suicide follows antidepressant use

A 58-YEAR-OLD MAN with unexplained weight loss, diminished appetite, increased stress, edginess, and decreased libido sought care from his physician. The doctor diagnosed depression and prescribed escitalopram, 10 mg per day. He gave the patient a 5-week supply of sample medication with no warning literature or product information. Twenty days later, the patient hanged himself at home.

PLAINTIFF’S CLAIM The physician wrongly diagnosed depression; he shouldn’t have given the patient escitalopram because the US Food and Drug Administration (FDA) has issued an advisory concerning increased risk of suicide for adults treated with antidepressants. Neither the patient nor his family was informed about the possible side effects of escitalopram.

THE DEFENSE The diagnosis of depression was proper; nothing the defendants did or failed to do contributed to the patient’s death.

VERDICT Ohio defense verdict.

COMMENT Given the FDA’s black-box warning, it is imperative that we counsel and document concerning the risk of suicide when initiating therapy for depression.