Supplement Editor:
Brian F. Mandell, MD, PhD

Contents

Preventing and treating acute gout attacks across the clinical spectrum: A roundtable discussion
Brian F. Mandell, MD, PhD; N. Lawrence Edwards, MD; John S. Sundy, MD, PhD; Peter A. Simkin, MD; and James C. Pile, MD

Supplement Editor:
Brian F. Mandell, MD, PhD

Contents

Preventing and treating acute gout attacks across the clinical spectrum: A roundtable discussion
Brian F. Mandell, MD, PhD; N. Lawrence Edwards, MD; John S. Sundy, MD, PhD; Peter A. Simkin, MD; and James C. Pile, MD

Supplement Editor:
Brian F. Mandell, MD, PhD

Contents

Preventing and treating acute gout attacks across the clinical spectrum: A roundtable discussion
Brian F. Mandell, MD, PhD; N. Lawrence Edwards, MD; John S. Sundy, MD, PhD; Peter A. Simkin, MD; and James C. Pile, MD

Gout is a chronic, often silent disorder in its early stages that is punctuated by acute, extremely painful arthritic flares. Over time, untreated or insufficiently treated gout may progress, with more frequent flares and formation of urate crystal deposits (tophi) and associated chronic, deforming arthritis (gouty arthropathy). One major aim in the management of gout is to treat the pain of acute flares aggressively with anti-inflammatory agents to reduce flare intensity and duration. This CME supplement discusses the risk factors and comorbidities that contribute to and exacerbate acute gout flares, the criteria for establishing a diagnosis of gout and how to establish goals for achieving, sustaining, and monitoring clinically meaningful urate lowering and means for optimizing patient adherence to long-term urate-lowering treatment.

Gout is a chronic, often silent disorder in its early stages that is punctuated by acute, extremely painful arthritic flares. Over time, untreated or insufficiently treated gout may progress, with more frequent flares and formation of urate crystal deposits (tophi) and associated chronic, deforming arthritis (gouty arthropathy). One major aim in the management of gout is to treat the pain of acute flares aggressively with anti-inflammatory agents to reduce flare intensity and duration. This CME supplement discusses the risk factors and comorbidities that contribute to and exacerbate acute gout flares, the criteria for establishing a diagnosis of gout and how to establish goals for achieving, sustaining, and monitoring clinically meaningful urate lowering and means for optimizing patient adherence to long-term urate-lowering treatment.

Gout is a chronic, often silent disorder in its early stages that is punctuated by acute, extremely painful arthritic flares. Over time, untreated or insufficiently treated gout may progress, with more frequent flares and formation of urate crystal deposits (tophi) and associated chronic, deforming arthritis (gouty arthropathy). One major aim in the management of gout is to treat the pain of acute flares aggressively with anti-inflammatory agents to reduce flare intensity and duration. This CME supplement discusses the risk factors and comorbidities that contribute to and exacerbate acute gout flares, the criteria for establishing a diagnosis of gout and how to establish goals for achieving, sustaining, and monitoring clinically meaningful urate lowering and means for optimizing patient adherence to long-term urate-lowering treatment.

The medical management of non-ST-elevation acute coronary syndromes focuses on blocking the coagulation cascade and inhibiting platelets. This—plus diagnostic angiography followed, if needed, by revascularization—has reduced the rates of death and recurrent ischemic events.¹ However, the combination of potent antithrombotic drugs and invasive procedures also increases the risk of bleeding.

This review discusses the incidence and complications associated with bleeding during the treatment of acute coronary syndromes and summarizes recommendations for preventing and managing bleeding in this setting.

THE TRUE INCIDENCE OF BLEEDING IS HARD TO DETERMINE

The optimal way to detect and analyze bleeding events in clinical trials and registries is highly debated. The reported incidences of bleeding during antithrombotic and antiplatelet therapy for non-ST-elevation acute coronary syndromes depend on how bleeding was defined, how the acute coronary syndromes were treated, and on other factors such as how the study was designed.

How was bleeding defined?

Since these classification schemes are based on different types of data, they yield different numbers when applied to the same study population. For instance, Rao et al⁴ pooled the data from the PURSUIT and PARAGON B trials (15,454 patients in all) and found that the incidence of severe bleeding (by the GUSTO criteria) was 1.2%, while the rate of major bleeding (by the TIMI criteria) was 8.2%.

What was the treatment strategy?

Another reason that the true incidence of bleeding is hard to determine is that different studies used treatment strategies that differed in the type, timing, and dose of antithrombotic agents and whether invasive procedures were used early. For example, if unfractionated heparin is used aggressively in regimens that are not adjusted for weight and with a higher target for the activated clotting time, the risk of bleeding is higher than with conservative dosing.^5–7

Subherwal et al⁸ evaluated the effect of treatment strategy on the incidence of bleeding in patients with non-ST-elevation acute coronary syndromes who received two or more antithrombotic drugs in the CRUSADE Quality Improvement Initiative. The risk of bleeding was higher with an invasive approach (catheterization) than with a conservative approach (no catheterization), regardless of baseline bleeding risk.

What type of study was it?

Another source of variation is the design of the study. Registries differ from clinical trials in patient characteristics and in the way data are gathered (prospectively vs retrospectively).

In registries, data are often collected retrospectively, whereas in clinical trials the data are prospectively collected. For this reason, the definition of bleeding in registries is often based on events that are easily identified through chart review, such as transfusion. This may lead to a lower reported rate of bleeding, since other, less serious bleeding events such as access-site hematomas and epistaxis may not be documented in the medical record.

On the other hand, registries often include older and sicker patients, who may be more prone to bleeding and who are often excluded from clinical trials. This may lead to a higher rate of reported bleeding.⁹

Where the study was conducted makes a difference as well, owing to regional practice differences. For example, Moscucci et al¹⁰ reported that the incidence of major bleeding in 24,045 patients with non-ST-elevation acute coronary syndromes in the GRACE registry (in 14 countries worldwide) was 3.9%. In contrast, Yang et al¹¹ reported that the rate of bleeding in the CRUSADE registry (in the United States) was 10.3%.

This difference was partly influenced by different definitions of bleeding. The GRACE registry defined major bleeding as life-threatening events requiring transfusion of two or more units of packed red blood cells, or resulting in an absolute decrease in the hematocrit of 10% or more or death, or hemorrhagic subdural hematoma. In contrast, the CRUSADE data reflect bleeding requiring transfusion. However, practice patterns such as greater use of invasive procedures in the United States may also be responsible.

Rao and colleagues¹² examined international variation in blood transfusion rates among patients with acute coronary syndromes. Patients outside the United States were significantly less likely to receive transfusions, even after adjusting for patient and practice differences.

Taking these confounders into account, it is reasonable to estimate that the frequency of bleeding in patients with non-ST-elevation acute coronary syndromes ranges from less than 1% to 10%.¹³

BLEEDING IS ASSOCIATED WITH POOR OUTCOMES

Regardless of the definition or the data source, hemorrhagic complications are associated with a higher risk of death and nonfatal adverse events, both in the short term and in the long term.

Short-term outcomes

A higher risk of death. In the GRACE registry study by Moscucci et al¹⁰ discussed above, patients who had major bleeding were significantly more likely to die during their hospitalization than those who did not (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.18–2.28).

Rao et al¹⁴ evaluated pooled data from the multicenter international GUSTO IIb, PURSUIT, and PARAGON A and B trials and found that the effects of bleeding in non-ST-elevation acute coronary syndromes extended beyond the hospital stay. The more severe the bleeding (by the GUSTO criteria), the greater the adjusted hazard ratio (HR) for death within 30 days:

• With mild bleeding—HR 1.6, 95% CI 1.3–1.9
• With moderate bleeding—HR 2.7, 95% CI 2.3–3.4
• With severe bleeding—HR 10.6, 95% CI 8.3–13.6.

The pattern was the same for death within 6 months:

• With mild bleeding—HR 1.4, 95% CI 1.2–1.6
• With moderate bleeding—HR 2.1, 95% CI 1.8–2.4
• With severe bleeding, HR 7.5, 95% CI 6.1–9.3.

These findings were confirmed by Eikelboom et al¹⁵ in 34,146 patients with acute coronary syndromes in the OASIS registry, the OASIS-2 trial, and the CURE randomized trial. In the first 30 days, five times as many patients died (12.8% vs 2.5%; P < .0009) among those who developed major bleeding compared with those who did not. These investigators defined major bleeding as bleeding that was life-threatening or significantly disabling or that required transfusion of two or more units of packed red blood cells.

A higher risk of nonfatal adverse events. Bleeding after antithrombotic therapy for non-ST-elevation acute coronary syndromes has also been associated with nonfatal adverse events such as stroke and stent thrombosis.

For example, in the study by Eikelboom et al,¹⁵ major bleeding was associated with a higher risk of recurrent ischemic events. Approximately 1 in 5 patients in the OASIS trials who developed major bleeding during the first 30 days died or had a myocardial infarction or stroke by 30 days, compared with 1 in 20 of those who did not develop major bleeding during the first 30 days. However, after events that occurred during the first 30 days were excluded, the association between major bleeding and both myocardial infarction and stroke was no longer evident between 30 days and 6 months.

Manoukian et al¹⁶ evaluated the impact of major bleeding in 13,819 patients with highrisk acute coronary syndromes undergoing treatment with an early invasive strategy in the ACUITY trial. At 30 days, patients with major bleeding had higher rates of the composite end point of death, myocardial infarction, or unplanned revascularization for ischemia (23.1% vs 6.8%, P < .0001) and of stent thrombosis (3.4% vs 0.6%, P < .0001).

Long-term outcomes

The association between bleeding and adverse outcomes persists in the long term as well, although the mechanisms underlying this association are not well studied.

Kinnaird et al¹⁷ examined the data from 10,974 unselected patients who underwent percutaneous coronary intervention. At 1 year, the following percentages of patients had died:

• After TIMI major bleeding—17.2%
• After TIMI minor bleeding—9.1%
• After no bleeding—5.5%.

However, after adjustment for potential confounders, only transfusion remained a significant predictor of 1-year mortality.

Mehran et al¹⁸ evaluated 1-year mortality data from the ACUITY trial. Compared with the rate in patients who had no major bleeding and no myocardial infarction, the hazard ratios for death were:

• After major bleeding—HR 3.5, 95% CI 2.7–4.4
• After myocardial infarction—HR 3.1, 95% CI 2.4–3.9.

Interestingly, the risk of death associated with myocardial infarction abated after 7 days, while the risk associated with bleeding persisted beyond 30 days and remained constant throughout the first year following the bleeding event.

Similarly, Ndrepepa and colleagues¹⁹ examined pooled data from four ISAR trials using the TIMI bleeding scale and found that myocardial infarction, target vessel revascularization, and major bleeding all had similar discriminatory ability at predicting 1-year mortality.

In patients undergoing elective or urgent percutaneous coronary intervention in the REPLACE-2 trial,²⁰ independent predictors of death by 1 year were²¹:

• Major hemorrhage (OR 2.66, 95% CI 1.44–4.92)
• Periprocedural myocardial infarction (OR 2.46, 95% CI 1.44–4.20).

THEORIES OF HOW BLEEDING MAY CAUSE ADVERSE OUTCOMES

Several mechanisms have been proposed to explain the association between bleeding during treatment for acute coronary syndromes and adverse clinical outcomes.^13,22

The immediate effects of bleeding are thought to be hypotension and a reflex hyperadrenergic state to compensate for the loss of intravascular volume.²³ This physiologic response is believed to contribute to myocardial ischemia by further decreasing myocardial oxygen supply in obstructive coronary disease.

Trying to minimize blood loss, physicians may withhold anticoagulation and antiplatelet therapy, which in turn may lead to further ischemia.²⁴ To compensate for blood loss, physicians may also resort to blood transfusion. However, depletion of 2,3-diphosphoglycerate and nitric oxide in stored donor red blood cells is postulated to reduce oxygen delivery by increasing hemoglobin’s affinity for oxygen, leading to induced microvascular obstruction and adverse inflammatory reactions.^15,25

Recent data have also begun to elucidate the long-term effects of bleeding during acute coronary syndrome management. Patients with anemia during the acute phase of infarction have greater neurohormonal activation.²⁶ These adaptive responses to anemia may lead to eccentric left ventricular remodeling that may lead to higher oxygen consumption, increased diastolic wall stress, interstitial fibrosis, and accelerated myocyte loss.^27–30

Nevertheless, we must point out that although strong associations between bleeding and adverse outcomes have been established, direct causality has not.

TO PREVENT BLEEDING, START BY ASSESSING RISK

The CRUSADE bleeding risk score

The CRUSADE bleeding score (calculator available at http://www.crusadebleedingscore.org/) was developed and validated in more than 89,000 community-treated patients with non-ST-elevation acute coronary syndromes.⁸ It is based on eight variables:

• Sex (higher risk in women)
• History of diabetes (higher risk)
• Prior vascular disease (higher risk)
• Heart rate (the higher the rate, the higher the risk)
• Systolic blood pressure (higher risk with pressures above or below the 121–180 mm Hg range)
• Signs of congestive heart failure (higher risk)
• Baseline hematocrit (the lower the hematocrit, the higher the risk)
• Creatinine clearance (by the Cockcroft-Gault formula; the lower the creatinine clearance, the higher the risk).

Patients who are found to have bleeding scores suggesting a moderate or higher risk of bleeding should be considered for medications associated with a favorable bleeding profile, and for radial access at the time of coronary angiography. Scores are graded as follows⁸:

• < 21: Very low risk
• 21–30: Low risk
• 31–40: Moderate risk
• 41–50: High risk
• > 50: Very high risk.

The CRUSADE bleeding score is unique in that, unlike earlier risk stratification tools, it was developed in a “real world” population, not in subgroups or in a clinical trial. It can be calculated at baseline to help guide the selection of treatment.⁸

Adjusting the heparin regimen in patients at risk of bleeding

Both the joint American College of Cardiology/American Heart Association¹ and the European Society of Cardiology guidelines³¹ for the treatment of non-ST-elevation acute coronary syndromes recommend taking steps to prevent bleeding, such as adjusting the dosage of unfractionated heparin, using safer drugs, reducing the duration of antithrombotic treatment, and using combinations of antithrombotic and antiplatelet agents according to proven indications.³¹

In the CRUSADE registry, 42% of patients with non-ST-elevation acute coronary syndromes received at least one initial dose of antithrombotic drug outside the recommended range, resulting in an estimated 15% excess of bleeding events.³² Thus, proper dosing is a target for prevention.

Appropriate antithrombotic dosing takes into account the patient’s age, weight, and renal function. However, heparin dosage in the current guidelines¹ is based on weight only: a loading dose of 60 U/kg (maximum 4,000 U) by intravenous bolus, then 12 U/kg/hour (maximum 1,000 U/hour) to maintain an activated partial thromboplastin time of 50 to 70 seconds.¹

Renal dysfunction is particularly worrisome in patients with non-ST-elevation acute coronary syndromes because it is associated with higher rates of major bleeding and death. In the OASIS-5 trial,³³ the overall risk of death was approximately five times higher in patients in the lowest quartile of renal function (glomerular filtration rate < 58 mL/min/1.73 m²) than in the highest quartile (glomerular filtration rate ≥ 86 mL/min/1.73 m²).

Renal function must be evaluated not only on admission but also throughout the hospital stay. Patients presenting with acute coronary syndromes often experience fluctuations in renal function that would call for adjustment of heparin dosing, either increasing the dose to maximize the drug’s efficacy if renal function is recovering or decreasing the dose to prevent bleeding if renal function is deteriorating.

Clopidogrel vs prasugrel

Certain medications should be avoided when the risk of bleeding outweighs any potential benefit in terms of ischemia.

For example, in a randomized trial,³⁴ prasugrel (Effient), a potent thienopyridine, was associated with a significantly lower rate of the composite end point of stroke, myocardial infarction, or death than clopidogrel (Plavix) in patients with acute coronary syndromes undergoing percutaneous coronary interventions. However, it did not seem to offer any advantage in patients 75 years old and older, those with prior stroke or transient ischemic attack, or those weighing less than 60 kg, and it posed a substantially higher risk of bleeding.

With clopidogrel, the risk of acute bleeding is primarily in patients who undergo coronary artery bypass grafting within 5 days of receiving a dose.^35,36 Therefore, clopidogrel should be stopped 5 to 7 days before bypass surgery.¹ Importantly, there is no increased risk of recurrent ischemic events during this 5-day waiting period in patients who receive clopidogrel early. Therefore, the recommendation to stop clopidogrel before surgery does not negate the benefits of early treatment.³⁶

Lower-risk drugs: Fondaparinux and bivalirudin

At this time, only two agents have been studied in clinical trials that have specifically focused on reducing bleeding risk: fondaparinux (Arixtra) and bivalirudin (Angiomax).^20,37–39

Fondaparinux

OASIS-5 was a randomized, double-blind trial that compared fondaparinux and enoxaparin (Lovenox) in patients with acute coronary syndromes.³⁸ Fondaparinux was similar to enoxaparin in terms of the combined end point of death, myocardial infarction, or refractory ischemia at 9 days, and fewer patients on fondaparinux developed bleeding (2.2% vs 4.1%, HR 0.52; 95% CI 0.44–0.61). This difference persisted during long-term follow-up.

Importantly, fewer patients died in the fondaparinux group. At 180 days, 638 (6.5%) of the patients in the enoxaparin group had died, compared with 574 (5.8%) in the fondaparinux group, a difference of 64 deaths (P = .05). The authors found that 41 fewer patients in the fondaparinux group than in the enoxaparin group died after major bleeding, and 20 fewer patients in the fondaparinux group died after minor bleeding.³⁸ Thus, most of the difference in mortality rates between the two groups was attributed to a lower incidence of bleeding with fondaparinux.

Unfortunately, despite its safe bleeding profile, fondaparinux has fallen out of favor for use in acute coronary syndromes, owing to a higher risk of catheter thrombosis in the fondaparinux group (0.9%) than in those undergoing percutaneous coronary interventions with enoxaparin alone (0.4%) in the OASIS-5 trial.⁴⁰

 

 

Bivalirudin

The direct thrombin inhibitor bivalirudin has been studied in three large randomized trials in patients undergoing percutaneous coronary interventions.^20,37,41

The ACUITY trial³⁷ was a prospective, open-label, randomized, multicenter trial that compared three regimens in patients with moderate or high-risk non-ST-elevation acute coronary syndromes:

• Heparin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

Bivalirudin alone was as effective as heparin plus a glycoprotein IIb/IIIa inhibitor with respect to the composite ischemia end point, which at 30 days had occurred in 7.8% vs 7.3% of the patients in these treatment groups (P = .32, RR 1.08; 95% CI 0.93–1.24), and it was superior with respect to major bleeding (3.0% vs 5.7%, P < .001, RR 0.53; 95% CI 0.43–0.65).

The HORIZONS-AMI study⁴¹ was a prospective, open-label, randomized, multicenter trial that compared bivalirudin alone vs heparin plus a glycoprotein IIb/IIIa inhibitor in patients with ST-elevation acute coronary syndromes who were undergoing primary percutaneous coronary interventions. The two primary end points were major bleeding and net adverse events.

At 1 year, patients assigned to bivalirudin had a lower rate of major bleeding than did controls (5.8% vs 9.2%, HR 0.61, 95% CI 0.48–0.78, P < .0001), with similar rates of major adverse cardiac events in both groups (11.9% vs 11.9%, HR 1.00, 95% CI 0.82– 1.21, P = .98).⁴¹

Both OASIS 5 and HORIZONS-AMI are examples of clinical trials in which strategies that reduced bleeding risk were also associated with improved survival.

For cardiac catheterization, inserting the catheter in the wrist poses less risk

Bleeding is currently the most common noncardiac complication in patients undergoing percutaneous coronary interventions, and it most often occurs at the vascular access site.¹⁷

Rao et al¹² evaluated data from 593,094 procedures in the National Cardiovascular Data Registry and found that, compared with the femoral approach, the use of transradial percutaneous coronary intervention was associated with a similar rate of procedural success (OR 1.02, 95% CI 0.93–1.12) but a significantly lower risk of bleeding complications (OR 0.42, 95% CI 0.31–0.56) after multivariable adjustment.

The use of smaller sheath sizes (4F–6F) and preferential use of bivalirudin over unfractionated heparin and glycoprotein IIb/IIIa inhibitor therapy are other methods described to decrease the risk of bleeding after percutaneous coronary interventions.^20,41–49

IF BLEEDING OCCURS

Once a bleeding complication occurs, cessation of therapy is a potential option. Stopping or reversing antithrombotic and antiplatelet therapy is warranted in the event of major bleeding (eg, gastrointestinal, retroperitoneal, intracranial).³¹

Stopping antithrombotic and antiplatelet therapy

Whether bleeding is minor or major, the risk of a recurrent thrombotic event must be considered, especially in patients who have undergone revascularization, stent implantation, or both. The risk of acute thrombotic events after interrupting antithrombotic or antiplatelet agents is considered greatest 4 to 5 days following revascularization or percutaneous coronary intervention.¹⁵ If bleeding can be controlled with local treatment such as pressure, packing, or dressing, antithrombotic and antiplatelet therapy need not be interrupted.⁵⁰

Current guidelines recommend strict control of hemorrhage for at least 24 hours before reintroducing antiplatelet or antithrombotic agents.

It is also important to remember that in the setting of gastrointestinal bleeding due to peptic ulcer disease, adjunctive proton pump inhibitors are recommended after restarting antiplatelet or antithrombotic therapy or both.

Importantly, evidence-based antithrombotic medications (especially dual antiplatelet therapy) should be restarted once the acute bleeding event has resolved.³¹

Reversal of anticoagulant and antiplatelet therapies

Unfractionated heparin is reversed with infusion of protamine sulfate at a dose of 1 mg per 100 U of unfractionated heparin given over the previous 4 hours.^51,52 The rate of protamine sulfate infusion should be less than 100 mg over 2 hours, with 50% of the dose given initially and subsequent doses titrated according to bleeding response.^52,53 Protamine sulfate is associated with a risk of hypotension and bradycardia, and for this reason it should be given no faster than 5 mg/min.

Low-molecular-weight heparin (LMWH) can be inhibited by 1 mg of protamine sulfate for each 1 mg of LMWH given over the previous 4 hours.^51,52

However, protamine sulfate only partially neutralizes the anticoagulant effect of LMWH. In cases in which protamine sulfate is unsuccessful in abating bleeding associated with LMWH use, guidelines allow for the use of recombinant factor VIIa (NovoSeven).³¹ In healthy volunteers given fondaparinux, recombinant factor VIIa normalized coagulation times and thrombin generation within 1.5 hours, with a sustained effect for 6 hours.⁵²

It is important to note that the use of this agent has not been fully studied, it is very costly (a single dose of 40 μg/kg costs from $3,000 to $4,000), and it is linked to reports of increased risk of thrombotic complications.^54,55

Antiplatelet agents are more complex to reverse. The antiplatelet actions of aspirin and clopidogrel wear off as new platelets are produced. Approximately 10% of a patient’s platelet count is produced daily; thus, the antiplatelet effects of aspirin and clopidogrel can persist for 5 to 10 days.^31,56

If these agents need to be reversed quickly to stop bleeding, according to expert consensus the aspirin effect can be reversed by transfusion of one unit of platelets. The antiplatelet effect of clopidogrel is more significant than that of aspirin; thus, two units of platelets are recommended.⁵⁶

Glycoprotein IIb/IIIa inhibitors. If a major bleeding event requires the reversal of glycoprotein IIb/IIIa inhibitor therapy, the treatment must take into consideration the pharmacodynamics of the target drug. Both eptifibatide (Integrilin) and tirofiban (Aggrastat) competitively inhibit glycoprotein IIb/IIIa receptors; thus, their effects depend on dosing, elimination, and time. Due to the stoichiometry of both drugs, transfusion of platelets is ineffective. Both eptifibatide and tirofiban are eliminated by the kidney; thus, normal renal function is key to the amount of time it takes for platelet function to return to baseline.⁵⁷ Evidence suggests that fibrinogen-rich plasma can be administered to restore platelet function.^31,58,59

Abciximab (ReoPro). Whereas reversal of eptifibatide and tirofiban focuses on overcoming competitive inhibition, neutralization of abciximab involves overcoming its high receptor affinity. At 24 hours after abciximab infusion is stopped, platelet aggregation may still be inhibited by up to 50%. Fortunately, owing to abciximab’s short plasma half-life and its dilution in serum, platelet transfusion is effective in reversing its antiplatelet effects.^31,57

 

 

Blood transfusion

Long considered beneficial to critically ill patients, blood transfusion to maintain hematocrit levels during acute coronary syndromes has come under intense scrutiny. Randomized trials have shown that transfusion should not be given aggressively to critically ill patients.⁶⁰ In acute coronary syndromes, there are only observational data.

Rao et al⁶¹ used detailed clinical data from 24,112 patients with acute coronary syndromes in the GUSTO IIb, PURSUIT, and PARAGON B trials to determine the association between blood transfusion and outcomes in patients who developed moderate to severe bleeding, anemia, or both during their hospitalization. The rates of death in the hospital and at 30 days were significantly higher in patients who received a transfusion (30-day mortality HR 3.94; 95% CI 3.36–4.75). However, there was no significant association between transfusion and the 30-day mortality rate if the nadir hematocrit was 25% or less.

Of note: no randomized clinical trial has evaluated transfusion strategies in acute coronary syndromes at this time. Until such data are available, it is reasonable to follow published guidelines and to avoid transfusion in stable patients with ischemic heart disease unless the hematocrit is 25% or less.³¹ The risks and benefits of blood transfusion should be carefully weighed. Routine use of transfusion to maintain predefined hemoglobin levels is not recommended in stable patients.

The medical management of non-ST-elevation acute coronary syndromes focuses on blocking the coagulation cascade and inhibiting platelets. This—plus diagnostic angiography followed, if needed, by revascularization—has reduced the rates of death and recurrent ischemic events.¹ However, the combination of potent antithrombotic drugs and invasive procedures also increases the risk of bleeding.

This review discusses the incidence and complications associated with bleeding during the treatment of acute coronary syndromes and summarizes recommendations for preventing and managing bleeding in this setting.

THE TRUE INCIDENCE OF BLEEDING IS HARD TO DETERMINE

The optimal way to detect and analyze bleeding events in clinical trials and registries is highly debated. The reported incidences of bleeding during antithrombotic and antiplatelet therapy for non-ST-elevation acute coronary syndromes depend on how bleeding was defined, how the acute coronary syndromes were treated, and on other factors such as how the study was designed.

How was bleeding defined?

Since these classification schemes are based on different types of data, they yield different numbers when applied to the same study population. For instance, Rao et al⁴ pooled the data from the PURSUIT and PARAGON B trials (15,454 patients in all) and found that the incidence of severe bleeding (by the GUSTO criteria) was 1.2%, while the rate of major bleeding (by the TIMI criteria) was 8.2%.

What was the treatment strategy?

Another reason that the true incidence of bleeding is hard to determine is that different studies used treatment strategies that differed in the type, timing, and dose of antithrombotic agents and whether invasive procedures were used early. For example, if unfractionated heparin is used aggressively in regimens that are not adjusted for weight and with a higher target for the activated clotting time, the risk of bleeding is higher than with conservative dosing.^5–7

Subherwal et al⁸ evaluated the effect of treatment strategy on the incidence of bleeding in patients with non-ST-elevation acute coronary syndromes who received two or more antithrombotic drugs in the CRUSADE Quality Improvement Initiative. The risk of bleeding was higher with an invasive approach (catheterization) than with a conservative approach (no catheterization), regardless of baseline bleeding risk.

What type of study was it?

Another source of variation is the design of the study. Registries differ from clinical trials in patient characteristics and in the way data are gathered (prospectively vs retrospectively).

In registries, data are often collected retrospectively, whereas in clinical trials the data are prospectively collected. For this reason, the definition of bleeding in registries is often based on events that are easily identified through chart review, such as transfusion. This may lead to a lower reported rate of bleeding, since other, less serious bleeding events such as access-site hematomas and epistaxis may not be documented in the medical record.

On the other hand, registries often include older and sicker patients, who may be more prone to bleeding and who are often excluded from clinical trials. This may lead to a higher rate of reported bleeding.⁹

Where the study was conducted makes a difference as well, owing to regional practice differences. For example, Moscucci et al¹⁰ reported that the incidence of major bleeding in 24,045 patients with non-ST-elevation acute coronary syndromes in the GRACE registry (in 14 countries worldwide) was 3.9%. In contrast, Yang et al¹¹ reported that the rate of bleeding in the CRUSADE registry (in the United States) was 10.3%.

This difference was partly influenced by different definitions of bleeding. The GRACE registry defined major bleeding as life-threatening events requiring transfusion of two or more units of packed red blood cells, or resulting in an absolute decrease in the hematocrit of 10% or more or death, or hemorrhagic subdural hematoma. In contrast, the CRUSADE data reflect bleeding requiring transfusion. However, practice patterns such as greater use of invasive procedures in the United States may also be responsible.

Rao and colleagues¹² examined international variation in blood transfusion rates among patients with acute coronary syndromes. Patients outside the United States were significantly less likely to receive transfusions, even after adjusting for patient and practice differences.

Taking these confounders into account, it is reasonable to estimate that the frequency of bleeding in patients with non-ST-elevation acute coronary syndromes ranges from less than 1% to 10%.¹³

BLEEDING IS ASSOCIATED WITH POOR OUTCOMES

Regardless of the definition or the data source, hemorrhagic complications are associated with a higher risk of death and nonfatal adverse events, both in the short term and in the long term.

Short-term outcomes

A higher risk of death. In the GRACE registry study by Moscucci et al¹⁰ discussed above, patients who had major bleeding were significantly more likely to die during their hospitalization than those who did not (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.18–2.28).

Rao et al¹⁴ evaluated pooled data from the multicenter international GUSTO IIb, PURSUIT, and PARAGON A and B trials and found that the effects of bleeding in non-ST-elevation acute coronary syndromes extended beyond the hospital stay. The more severe the bleeding (by the GUSTO criteria), the greater the adjusted hazard ratio (HR) for death within 30 days:

• With mild bleeding—HR 1.6, 95% CI 1.3–1.9
• With moderate bleeding—HR 2.7, 95% CI 2.3–3.4
• With severe bleeding—HR 10.6, 95% CI 8.3–13.6.

The pattern was the same for death within 6 months:

• With mild bleeding—HR 1.4, 95% CI 1.2–1.6
• With moderate bleeding—HR 2.1, 95% CI 1.8–2.4
• With severe bleeding, HR 7.5, 95% CI 6.1–9.3.

These findings were confirmed by Eikelboom et al¹⁵ in 34,146 patients with acute coronary syndromes in the OASIS registry, the OASIS-2 trial, and the CURE randomized trial. In the first 30 days, five times as many patients died (12.8% vs 2.5%; P < .0009) among those who developed major bleeding compared with those who did not. These investigators defined major bleeding as bleeding that was life-threatening or significantly disabling or that required transfusion of two or more units of packed red blood cells.

A higher risk of nonfatal adverse events. Bleeding after antithrombotic therapy for non-ST-elevation acute coronary syndromes has also been associated with nonfatal adverse events such as stroke and stent thrombosis.

For example, in the study by Eikelboom et al,¹⁵ major bleeding was associated with a higher risk of recurrent ischemic events. Approximately 1 in 5 patients in the OASIS trials who developed major bleeding during the first 30 days died or had a myocardial infarction or stroke by 30 days, compared with 1 in 20 of those who did not develop major bleeding during the first 30 days. However, after events that occurred during the first 30 days were excluded, the association between major bleeding and both myocardial infarction and stroke was no longer evident between 30 days and 6 months.

Manoukian et al¹⁶ evaluated the impact of major bleeding in 13,819 patients with highrisk acute coronary syndromes undergoing treatment with an early invasive strategy in the ACUITY trial. At 30 days, patients with major bleeding had higher rates of the composite end point of death, myocardial infarction, or unplanned revascularization for ischemia (23.1% vs 6.8%, P < .0001) and of stent thrombosis (3.4% vs 0.6%, P < .0001).

Long-term outcomes

The association between bleeding and adverse outcomes persists in the long term as well, although the mechanisms underlying this association are not well studied.

Kinnaird et al¹⁷ examined the data from 10,974 unselected patients who underwent percutaneous coronary intervention. At 1 year, the following percentages of patients had died:

• After TIMI major bleeding—17.2%
• After TIMI minor bleeding—9.1%
• After no bleeding—5.5%.

However, after adjustment for potential confounders, only transfusion remained a significant predictor of 1-year mortality.

Mehran et al¹⁸ evaluated 1-year mortality data from the ACUITY trial. Compared with the rate in patients who had no major bleeding and no myocardial infarction, the hazard ratios for death were:

• After major bleeding—HR 3.5, 95% CI 2.7–4.4
• After myocardial infarction—HR 3.1, 95% CI 2.4–3.9.

Interestingly, the risk of death associated with myocardial infarction abated after 7 days, while the risk associated with bleeding persisted beyond 30 days and remained constant throughout the first year following the bleeding event.

Similarly, Ndrepepa and colleagues¹⁹ examined pooled data from four ISAR trials using the TIMI bleeding scale and found that myocardial infarction, target vessel revascularization, and major bleeding all had similar discriminatory ability at predicting 1-year mortality.

In patients undergoing elective or urgent percutaneous coronary intervention in the REPLACE-2 trial,²⁰ independent predictors of death by 1 year were²¹:

• Major hemorrhage (OR 2.66, 95% CI 1.44–4.92)
• Periprocedural myocardial infarction (OR 2.46, 95% CI 1.44–4.20).

THEORIES OF HOW BLEEDING MAY CAUSE ADVERSE OUTCOMES

Several mechanisms have been proposed to explain the association between bleeding during treatment for acute coronary syndromes and adverse clinical outcomes.^13,22

The immediate effects of bleeding are thought to be hypotension and a reflex hyperadrenergic state to compensate for the loss of intravascular volume.²³ This physiologic response is believed to contribute to myocardial ischemia by further decreasing myocardial oxygen supply in obstructive coronary disease.

Trying to minimize blood loss, physicians may withhold anticoagulation and antiplatelet therapy, which in turn may lead to further ischemia.²⁴ To compensate for blood loss, physicians may also resort to blood transfusion. However, depletion of 2,3-diphosphoglycerate and nitric oxide in stored donor red blood cells is postulated to reduce oxygen delivery by increasing hemoglobin’s affinity for oxygen, leading to induced microvascular obstruction and adverse inflammatory reactions.^15,25

Recent data have also begun to elucidate the long-term effects of bleeding during acute coronary syndrome management. Patients with anemia during the acute phase of infarction have greater neurohormonal activation.²⁶ These adaptive responses to anemia may lead to eccentric left ventricular remodeling that may lead to higher oxygen consumption, increased diastolic wall stress, interstitial fibrosis, and accelerated myocyte loss.^27–30

Nevertheless, we must point out that although strong associations between bleeding and adverse outcomes have been established, direct causality has not.

TO PREVENT BLEEDING, START BY ASSESSING RISK

The CRUSADE bleeding risk score

The CRUSADE bleeding score (calculator available at http://www.crusadebleedingscore.org/) was developed and validated in more than 89,000 community-treated patients with non-ST-elevation acute coronary syndromes.⁸ It is based on eight variables:

• Sex (higher risk in women)
• History of diabetes (higher risk)
• Prior vascular disease (higher risk)
• Heart rate (the higher the rate, the higher the risk)
• Systolic blood pressure (higher risk with pressures above or below the 121–180 mm Hg range)
• Signs of congestive heart failure (higher risk)
• Baseline hematocrit (the lower the hematocrit, the higher the risk)
• Creatinine clearance (by the Cockcroft-Gault formula; the lower the creatinine clearance, the higher the risk).

Patients who are found to have bleeding scores suggesting a moderate or higher risk of bleeding should be considered for medications associated with a favorable bleeding profile, and for radial access at the time of coronary angiography. Scores are graded as follows⁸:

• < 21: Very low risk
• 21–30: Low risk
• 31–40: Moderate risk
• 41–50: High risk
• > 50: Very high risk.

The CRUSADE bleeding score is unique in that, unlike earlier risk stratification tools, it was developed in a “real world” population, not in subgroups or in a clinical trial. It can be calculated at baseline to help guide the selection of treatment.⁸

Adjusting the heparin regimen in patients at risk of bleeding

Both the joint American College of Cardiology/American Heart Association¹ and the European Society of Cardiology guidelines³¹ for the treatment of non-ST-elevation acute coronary syndromes recommend taking steps to prevent bleeding, such as adjusting the dosage of unfractionated heparin, using safer drugs, reducing the duration of antithrombotic treatment, and using combinations of antithrombotic and antiplatelet agents according to proven indications.³¹

In the CRUSADE registry, 42% of patients with non-ST-elevation acute coronary syndromes received at least one initial dose of antithrombotic drug outside the recommended range, resulting in an estimated 15% excess of bleeding events.³² Thus, proper dosing is a target for prevention.

Appropriate antithrombotic dosing takes into account the patient’s age, weight, and renal function. However, heparin dosage in the current guidelines¹ is based on weight only: a loading dose of 60 U/kg (maximum 4,000 U) by intravenous bolus, then 12 U/kg/hour (maximum 1,000 U/hour) to maintain an activated partial thromboplastin time of 50 to 70 seconds.¹

Renal dysfunction is particularly worrisome in patients with non-ST-elevation acute coronary syndromes because it is associated with higher rates of major bleeding and death. In the OASIS-5 trial,³³ the overall risk of death was approximately five times higher in patients in the lowest quartile of renal function (glomerular filtration rate < 58 mL/min/1.73 m²) than in the highest quartile (glomerular filtration rate ≥ 86 mL/min/1.73 m²).

Renal function must be evaluated not only on admission but also throughout the hospital stay. Patients presenting with acute coronary syndromes often experience fluctuations in renal function that would call for adjustment of heparin dosing, either increasing the dose to maximize the drug’s efficacy if renal function is recovering or decreasing the dose to prevent bleeding if renal function is deteriorating.

Clopidogrel vs prasugrel

Certain medications should be avoided when the risk of bleeding outweighs any potential benefit in terms of ischemia.

For example, in a randomized trial,³⁴ prasugrel (Effient), a potent thienopyridine, was associated with a significantly lower rate of the composite end point of stroke, myocardial infarction, or death than clopidogrel (Plavix) in patients with acute coronary syndromes undergoing percutaneous coronary interventions. However, it did not seem to offer any advantage in patients 75 years old and older, those with prior stroke or transient ischemic attack, or those weighing less than 60 kg, and it posed a substantially higher risk of bleeding.

With clopidogrel, the risk of acute bleeding is primarily in patients who undergo coronary artery bypass grafting within 5 days of receiving a dose.^35,36 Therefore, clopidogrel should be stopped 5 to 7 days before bypass surgery.¹ Importantly, there is no increased risk of recurrent ischemic events during this 5-day waiting period in patients who receive clopidogrel early. Therefore, the recommendation to stop clopidogrel before surgery does not negate the benefits of early treatment.³⁶

Lower-risk drugs: Fondaparinux and bivalirudin

At this time, only two agents have been studied in clinical trials that have specifically focused on reducing bleeding risk: fondaparinux (Arixtra) and bivalirudin (Angiomax).^20,37–39

Fondaparinux

OASIS-5 was a randomized, double-blind trial that compared fondaparinux and enoxaparin (Lovenox) in patients with acute coronary syndromes.³⁸ Fondaparinux was similar to enoxaparin in terms of the combined end point of death, myocardial infarction, or refractory ischemia at 9 days, and fewer patients on fondaparinux developed bleeding (2.2% vs 4.1%, HR 0.52; 95% CI 0.44–0.61). This difference persisted during long-term follow-up.

Importantly, fewer patients died in the fondaparinux group. At 180 days, 638 (6.5%) of the patients in the enoxaparin group had died, compared with 574 (5.8%) in the fondaparinux group, a difference of 64 deaths (P = .05). The authors found that 41 fewer patients in the fondaparinux group than in the enoxaparin group died after major bleeding, and 20 fewer patients in the fondaparinux group died after minor bleeding.³⁸ Thus, most of the difference in mortality rates between the two groups was attributed to a lower incidence of bleeding with fondaparinux.

Unfortunately, despite its safe bleeding profile, fondaparinux has fallen out of favor for use in acute coronary syndromes, owing to a higher risk of catheter thrombosis in the fondaparinux group (0.9%) than in those undergoing percutaneous coronary interventions with enoxaparin alone (0.4%) in the OASIS-5 trial.⁴⁰

 

 

Bivalirudin

The direct thrombin inhibitor bivalirudin has been studied in three large randomized trials in patients undergoing percutaneous coronary interventions.^20,37,41

The ACUITY trial³⁷ was a prospective, open-label, randomized, multicenter trial that compared three regimens in patients with moderate or high-risk non-ST-elevation acute coronary syndromes:

• Heparin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

Bivalirudin alone was as effective as heparin plus a glycoprotein IIb/IIIa inhibitor with respect to the composite ischemia end point, which at 30 days had occurred in 7.8% vs 7.3% of the patients in these treatment groups (P = .32, RR 1.08; 95% CI 0.93–1.24), and it was superior with respect to major bleeding (3.0% vs 5.7%, P < .001, RR 0.53; 95% CI 0.43–0.65).

The HORIZONS-AMI study⁴¹ was a prospective, open-label, randomized, multicenter trial that compared bivalirudin alone vs heparin plus a glycoprotein IIb/IIIa inhibitor in patients with ST-elevation acute coronary syndromes who were undergoing primary percutaneous coronary interventions. The two primary end points were major bleeding and net adverse events.

At 1 year, patients assigned to bivalirudin had a lower rate of major bleeding than did controls (5.8% vs 9.2%, HR 0.61, 95% CI 0.48–0.78, P < .0001), with similar rates of major adverse cardiac events in both groups (11.9% vs 11.9%, HR 1.00, 95% CI 0.82– 1.21, P = .98).⁴¹

Both OASIS 5 and HORIZONS-AMI are examples of clinical trials in which strategies that reduced bleeding risk were also associated with improved survival.

For cardiac catheterization, inserting the catheter in the wrist poses less risk

Bleeding is currently the most common noncardiac complication in patients undergoing percutaneous coronary interventions, and it most often occurs at the vascular access site.¹⁷

Rao et al¹² evaluated data from 593,094 procedures in the National Cardiovascular Data Registry and found that, compared with the femoral approach, the use of transradial percutaneous coronary intervention was associated with a similar rate of procedural success (OR 1.02, 95% CI 0.93–1.12) but a significantly lower risk of bleeding complications (OR 0.42, 95% CI 0.31–0.56) after multivariable adjustment.

The use of smaller sheath sizes (4F–6F) and preferential use of bivalirudin over unfractionated heparin and glycoprotein IIb/IIIa inhibitor therapy are other methods described to decrease the risk of bleeding after percutaneous coronary interventions.^20,41–49

IF BLEEDING OCCURS

Once a bleeding complication occurs, cessation of therapy is a potential option. Stopping or reversing antithrombotic and antiplatelet therapy is warranted in the event of major bleeding (eg, gastrointestinal, retroperitoneal, intracranial).³¹

Stopping antithrombotic and antiplatelet therapy

Whether bleeding is minor or major, the risk of a recurrent thrombotic event must be considered, especially in patients who have undergone revascularization, stent implantation, or both. The risk of acute thrombotic events after interrupting antithrombotic or antiplatelet agents is considered greatest 4 to 5 days following revascularization or percutaneous coronary intervention.¹⁵ If bleeding can be controlled with local treatment such as pressure, packing, or dressing, antithrombotic and antiplatelet therapy need not be interrupted.⁵⁰

Current guidelines recommend strict control of hemorrhage for at least 24 hours before reintroducing antiplatelet or antithrombotic agents.

It is also important to remember that in the setting of gastrointestinal bleeding due to peptic ulcer disease, adjunctive proton pump inhibitors are recommended after restarting antiplatelet or antithrombotic therapy or both.

Importantly, evidence-based antithrombotic medications (especially dual antiplatelet therapy) should be restarted once the acute bleeding event has resolved.³¹

Reversal of anticoagulant and antiplatelet therapies

Unfractionated heparin is reversed with infusion of protamine sulfate at a dose of 1 mg per 100 U of unfractionated heparin given over the previous 4 hours.^51,52 The rate of protamine sulfate infusion should be less than 100 mg over 2 hours, with 50% of the dose given initially and subsequent doses titrated according to bleeding response.^52,53 Protamine sulfate is associated with a risk of hypotension and bradycardia, and for this reason it should be given no faster than 5 mg/min.

Low-molecular-weight heparin (LMWH) can be inhibited by 1 mg of protamine sulfate for each 1 mg of LMWH given over the previous 4 hours.^51,52

However, protamine sulfate only partially neutralizes the anticoagulant effect of LMWH. In cases in which protamine sulfate is unsuccessful in abating bleeding associated with LMWH use, guidelines allow for the use of recombinant factor VIIa (NovoSeven).³¹ In healthy volunteers given fondaparinux, recombinant factor VIIa normalized coagulation times and thrombin generation within 1.5 hours, with a sustained effect for 6 hours.⁵²

It is important to note that the use of this agent has not been fully studied, it is very costly (a single dose of 40 μg/kg costs from $3,000 to $4,000), and it is linked to reports of increased risk of thrombotic complications.^54,55

Antiplatelet agents are more complex to reverse. The antiplatelet actions of aspirin and clopidogrel wear off as new platelets are produced. Approximately 10% of a patient’s platelet count is produced daily; thus, the antiplatelet effects of aspirin and clopidogrel can persist for 5 to 10 days.^31,56

If these agents need to be reversed quickly to stop bleeding, according to expert consensus the aspirin effect can be reversed by transfusion of one unit of platelets. The antiplatelet effect of clopidogrel is more significant than that of aspirin; thus, two units of platelets are recommended.⁵⁶

Glycoprotein IIb/IIIa inhibitors. If a major bleeding event requires the reversal of glycoprotein IIb/IIIa inhibitor therapy, the treatment must take into consideration the pharmacodynamics of the target drug. Both eptifibatide (Integrilin) and tirofiban (Aggrastat) competitively inhibit glycoprotein IIb/IIIa receptors; thus, their effects depend on dosing, elimination, and time. Due to the stoichiometry of both drugs, transfusion of platelets is ineffective. Both eptifibatide and tirofiban are eliminated by the kidney; thus, normal renal function is key to the amount of time it takes for platelet function to return to baseline.⁵⁷ Evidence suggests that fibrinogen-rich plasma can be administered to restore platelet function.^31,58,59

Abciximab (ReoPro). Whereas reversal of eptifibatide and tirofiban focuses on overcoming competitive inhibition, neutralization of abciximab involves overcoming its high receptor affinity. At 24 hours after abciximab infusion is stopped, platelet aggregation may still be inhibited by up to 50%. Fortunately, owing to abciximab’s short plasma half-life and its dilution in serum, platelet transfusion is effective in reversing its antiplatelet effects.^31,57

 

 

Blood transfusion

Long considered beneficial to critically ill patients, blood transfusion to maintain hematocrit levels during acute coronary syndromes has come under intense scrutiny. Randomized trials have shown that transfusion should not be given aggressively to critically ill patients.⁶⁰ In acute coronary syndromes, there are only observational data.

Rao et al⁶¹ used detailed clinical data from 24,112 patients with acute coronary syndromes in the GUSTO IIb, PURSUIT, and PARAGON B trials to determine the association between blood transfusion and outcomes in patients who developed moderate to severe bleeding, anemia, or both during their hospitalization. The rates of death in the hospital and at 30 days were significantly higher in patients who received a transfusion (30-day mortality HR 3.94; 95% CI 3.36–4.75). However, there was no significant association between transfusion and the 30-day mortality rate if the nadir hematocrit was 25% or less.

Of note: no randomized clinical trial has evaluated transfusion strategies in acute coronary syndromes at this time. Until such data are available, it is reasonable to follow published guidelines and to avoid transfusion in stable patients with ischemic heart disease unless the hematocrit is 25% or less.³¹ The risks and benefits of blood transfusion should be carefully weighed. Routine use of transfusion to maintain predefined hemoglobin levels is not recommended in stable patients.

The medical management of non-ST-elevation acute coronary syndromes focuses on blocking the coagulation cascade and inhibiting platelets. This—plus diagnostic angiography followed, if needed, by revascularization—has reduced the rates of death and recurrent ischemic events.¹ However, the combination of potent antithrombotic drugs and invasive procedures also increases the risk of bleeding.

This review discusses the incidence and complications associated with bleeding during the treatment of acute coronary syndromes and summarizes recommendations for preventing and managing bleeding in this setting.

THE TRUE INCIDENCE OF BLEEDING IS HARD TO DETERMINE

The optimal way to detect and analyze bleeding events in clinical trials and registries is highly debated. The reported incidences of bleeding during antithrombotic and antiplatelet therapy for non-ST-elevation acute coronary syndromes depend on how bleeding was defined, how the acute coronary syndromes were treated, and on other factors such as how the study was designed.

How was bleeding defined?

Since these classification schemes are based on different types of data, they yield different numbers when applied to the same study population. For instance, Rao et al⁴ pooled the data from the PURSUIT and PARAGON B trials (15,454 patients in all) and found that the incidence of severe bleeding (by the GUSTO criteria) was 1.2%, while the rate of major bleeding (by the TIMI criteria) was 8.2%.

What was the treatment strategy?

Another reason that the true incidence of bleeding is hard to determine is that different studies used treatment strategies that differed in the type, timing, and dose of antithrombotic agents and whether invasive procedures were used early. For example, if unfractionated heparin is used aggressively in regimens that are not adjusted for weight and with a higher target for the activated clotting time, the risk of bleeding is higher than with conservative dosing.^5–7

Subherwal et al⁸ evaluated the effect of treatment strategy on the incidence of bleeding in patients with non-ST-elevation acute coronary syndromes who received two or more antithrombotic drugs in the CRUSADE Quality Improvement Initiative. The risk of bleeding was higher with an invasive approach (catheterization) than with a conservative approach (no catheterization), regardless of baseline bleeding risk.

What type of study was it?

Another source of variation is the design of the study. Registries differ from clinical trials in patient characteristics and in the way data are gathered (prospectively vs retrospectively).

In registries, data are often collected retrospectively, whereas in clinical trials the data are prospectively collected. For this reason, the definition of bleeding in registries is often based on events that are easily identified through chart review, such as transfusion. This may lead to a lower reported rate of bleeding, since other, less serious bleeding events such as access-site hematomas and epistaxis may not be documented in the medical record.

On the other hand, registries often include older and sicker patients, who may be more prone to bleeding and who are often excluded from clinical trials. This may lead to a higher rate of reported bleeding.⁹

Where the study was conducted makes a difference as well, owing to regional practice differences. For example, Moscucci et al¹⁰ reported that the incidence of major bleeding in 24,045 patients with non-ST-elevation acute coronary syndromes in the GRACE registry (in 14 countries worldwide) was 3.9%. In contrast, Yang et al¹¹ reported that the rate of bleeding in the CRUSADE registry (in the United States) was 10.3%.

This difference was partly influenced by different definitions of bleeding. The GRACE registry defined major bleeding as life-threatening events requiring transfusion of two or more units of packed red blood cells, or resulting in an absolute decrease in the hematocrit of 10% or more or death, or hemorrhagic subdural hematoma. In contrast, the CRUSADE data reflect bleeding requiring transfusion. However, practice patterns such as greater use of invasive procedures in the United States may also be responsible.

Rao and colleagues¹² examined international variation in blood transfusion rates among patients with acute coronary syndromes. Patients outside the United States were significantly less likely to receive transfusions, even after adjusting for patient and practice differences.

Taking these confounders into account, it is reasonable to estimate that the frequency of bleeding in patients with non-ST-elevation acute coronary syndromes ranges from less than 1% to 10%.¹³

BLEEDING IS ASSOCIATED WITH POOR OUTCOMES

Regardless of the definition or the data source, hemorrhagic complications are associated with a higher risk of death and nonfatal adverse events, both in the short term and in the long term.

Short-term outcomes

A higher risk of death. In the GRACE registry study by Moscucci et al¹⁰ discussed above, patients who had major bleeding were significantly more likely to die during their hospitalization than those who did not (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.18–2.28).

Rao et al¹⁴ evaluated pooled data from the multicenter international GUSTO IIb, PURSUIT, and PARAGON A and B trials and found that the effects of bleeding in non-ST-elevation acute coronary syndromes extended beyond the hospital stay. The more severe the bleeding (by the GUSTO criteria), the greater the adjusted hazard ratio (HR) for death within 30 days:

• With mild bleeding—HR 1.6, 95% CI 1.3–1.9
• With moderate bleeding—HR 2.7, 95% CI 2.3–3.4
• With severe bleeding—HR 10.6, 95% CI 8.3–13.6.

The pattern was the same for death within 6 months:

• With mild bleeding—HR 1.4, 95% CI 1.2–1.6
• With moderate bleeding—HR 2.1, 95% CI 1.8–2.4
• With severe bleeding, HR 7.5, 95% CI 6.1–9.3.

These findings were confirmed by Eikelboom et al¹⁵ in 34,146 patients with acute coronary syndromes in the OASIS registry, the OASIS-2 trial, and the CURE randomized trial. In the first 30 days, five times as many patients died (12.8% vs 2.5%; P < .0009) among those who developed major bleeding compared with those who did not. These investigators defined major bleeding as bleeding that was life-threatening or significantly disabling or that required transfusion of two or more units of packed red blood cells.

A higher risk of nonfatal adverse events. Bleeding after antithrombotic therapy for non-ST-elevation acute coronary syndromes has also been associated with nonfatal adverse events such as stroke and stent thrombosis.

For example, in the study by Eikelboom et al,¹⁵ major bleeding was associated with a higher risk of recurrent ischemic events. Approximately 1 in 5 patients in the OASIS trials who developed major bleeding during the first 30 days died or had a myocardial infarction or stroke by 30 days, compared with 1 in 20 of those who did not develop major bleeding during the first 30 days. However, after events that occurred during the first 30 days were excluded, the association between major bleeding and both myocardial infarction and stroke was no longer evident between 30 days and 6 months.

Manoukian et al¹⁶ evaluated the impact of major bleeding in 13,819 patients with highrisk acute coronary syndromes undergoing treatment with an early invasive strategy in the ACUITY trial. At 30 days, patients with major bleeding had higher rates of the composite end point of death, myocardial infarction, or unplanned revascularization for ischemia (23.1% vs 6.8%, P < .0001) and of stent thrombosis (3.4% vs 0.6%, P < .0001).

Long-term outcomes

The association between bleeding and adverse outcomes persists in the long term as well, although the mechanisms underlying this association are not well studied.

Kinnaird et al¹⁷ examined the data from 10,974 unselected patients who underwent percutaneous coronary intervention. At 1 year, the following percentages of patients had died:

• After TIMI major bleeding—17.2%
• After TIMI minor bleeding—9.1%
• After no bleeding—5.5%.

However, after adjustment for potential confounders, only transfusion remained a significant predictor of 1-year mortality.

Mehran et al¹⁸ evaluated 1-year mortality data from the ACUITY trial. Compared with the rate in patients who had no major bleeding and no myocardial infarction, the hazard ratios for death were:

• After major bleeding—HR 3.5, 95% CI 2.7–4.4
• After myocardial infarction—HR 3.1, 95% CI 2.4–3.9.

Interestingly, the risk of death associated with myocardial infarction abated after 7 days, while the risk associated with bleeding persisted beyond 30 days and remained constant throughout the first year following the bleeding event.

Similarly, Ndrepepa and colleagues¹⁹ examined pooled data from four ISAR trials using the TIMI bleeding scale and found that myocardial infarction, target vessel revascularization, and major bleeding all had similar discriminatory ability at predicting 1-year mortality.

In patients undergoing elective or urgent percutaneous coronary intervention in the REPLACE-2 trial,²⁰ independent predictors of death by 1 year were²¹:

• Major hemorrhage (OR 2.66, 95% CI 1.44–4.92)
• Periprocedural myocardial infarction (OR 2.46, 95% CI 1.44–4.20).

THEORIES OF HOW BLEEDING MAY CAUSE ADVERSE OUTCOMES

Several mechanisms have been proposed to explain the association between bleeding during treatment for acute coronary syndromes and adverse clinical outcomes.^13,22

The immediate effects of bleeding are thought to be hypotension and a reflex hyperadrenergic state to compensate for the loss of intravascular volume.²³ This physiologic response is believed to contribute to myocardial ischemia by further decreasing myocardial oxygen supply in obstructive coronary disease.

Trying to minimize blood loss, physicians may withhold anticoagulation and antiplatelet therapy, which in turn may lead to further ischemia.²⁴ To compensate for blood loss, physicians may also resort to blood transfusion. However, depletion of 2,3-diphosphoglycerate and nitric oxide in stored donor red blood cells is postulated to reduce oxygen delivery by increasing hemoglobin’s affinity for oxygen, leading to induced microvascular obstruction and adverse inflammatory reactions.^15,25

Recent data have also begun to elucidate the long-term effects of bleeding during acute coronary syndrome management. Patients with anemia during the acute phase of infarction have greater neurohormonal activation.²⁶ These adaptive responses to anemia may lead to eccentric left ventricular remodeling that may lead to higher oxygen consumption, increased diastolic wall stress, interstitial fibrosis, and accelerated myocyte loss.^27–30

Nevertheless, we must point out that although strong associations between bleeding and adverse outcomes have been established, direct causality has not.

TO PREVENT BLEEDING, START BY ASSESSING RISK

The CRUSADE bleeding risk score

The CRUSADE bleeding score (calculator available at http://www.crusadebleedingscore.org/) was developed and validated in more than 89,000 community-treated patients with non-ST-elevation acute coronary syndromes.⁸ It is based on eight variables:

• Sex (higher risk in women)
• History of diabetes (higher risk)
• Prior vascular disease (higher risk)
• Heart rate (the higher the rate, the higher the risk)
• Systolic blood pressure (higher risk with pressures above or below the 121–180 mm Hg range)
• Signs of congestive heart failure (higher risk)
• Baseline hematocrit (the lower the hematocrit, the higher the risk)
• Creatinine clearance (by the Cockcroft-Gault formula; the lower the creatinine clearance, the higher the risk).

Patients who are found to have bleeding scores suggesting a moderate or higher risk of bleeding should be considered for medications associated with a favorable bleeding profile, and for radial access at the time of coronary angiography. Scores are graded as follows⁸:

• < 21: Very low risk
• 21–30: Low risk
• 31–40: Moderate risk
• 41–50: High risk
• > 50: Very high risk.

The CRUSADE bleeding score is unique in that, unlike earlier risk stratification tools, it was developed in a “real world” population, not in subgroups or in a clinical trial. It can be calculated at baseline to help guide the selection of treatment.⁸

Adjusting the heparin regimen in patients at risk of bleeding

Both the joint American College of Cardiology/American Heart Association¹ and the European Society of Cardiology guidelines³¹ for the treatment of non-ST-elevation acute coronary syndromes recommend taking steps to prevent bleeding, such as adjusting the dosage of unfractionated heparin, using safer drugs, reducing the duration of antithrombotic treatment, and using combinations of antithrombotic and antiplatelet agents according to proven indications.³¹

In the CRUSADE registry, 42% of patients with non-ST-elevation acute coronary syndromes received at least one initial dose of antithrombotic drug outside the recommended range, resulting in an estimated 15% excess of bleeding events.³² Thus, proper dosing is a target for prevention.

Appropriate antithrombotic dosing takes into account the patient’s age, weight, and renal function. However, heparin dosage in the current guidelines¹ is based on weight only: a loading dose of 60 U/kg (maximum 4,000 U) by intravenous bolus, then 12 U/kg/hour (maximum 1,000 U/hour) to maintain an activated partial thromboplastin time of 50 to 70 seconds.¹

Renal dysfunction is particularly worrisome in patients with non-ST-elevation acute coronary syndromes because it is associated with higher rates of major bleeding and death. In the OASIS-5 trial,³³ the overall risk of death was approximately five times higher in patients in the lowest quartile of renal function (glomerular filtration rate < 58 mL/min/1.73 m²) than in the highest quartile (glomerular filtration rate ≥ 86 mL/min/1.73 m²).

Renal function must be evaluated not only on admission but also throughout the hospital stay. Patients presenting with acute coronary syndromes often experience fluctuations in renal function that would call for adjustment of heparin dosing, either increasing the dose to maximize the drug’s efficacy if renal function is recovering or decreasing the dose to prevent bleeding if renal function is deteriorating.

Clopidogrel vs prasugrel

Certain medications should be avoided when the risk of bleeding outweighs any potential benefit in terms of ischemia.

For example, in a randomized trial,³⁴ prasugrel (Effient), a potent thienopyridine, was associated with a significantly lower rate of the composite end point of stroke, myocardial infarction, or death than clopidogrel (Plavix) in patients with acute coronary syndromes undergoing percutaneous coronary interventions. However, it did not seem to offer any advantage in patients 75 years old and older, those with prior stroke or transient ischemic attack, or those weighing less than 60 kg, and it posed a substantially higher risk of bleeding.

With clopidogrel, the risk of acute bleeding is primarily in patients who undergo coronary artery bypass grafting within 5 days of receiving a dose.^35,36 Therefore, clopidogrel should be stopped 5 to 7 days before bypass surgery.¹ Importantly, there is no increased risk of recurrent ischemic events during this 5-day waiting period in patients who receive clopidogrel early. Therefore, the recommendation to stop clopidogrel before surgery does not negate the benefits of early treatment.³⁶

Lower-risk drugs: Fondaparinux and bivalirudin

At this time, only two agents have been studied in clinical trials that have specifically focused on reducing bleeding risk: fondaparinux (Arixtra) and bivalirudin (Angiomax).^20,37–39

Fondaparinux

OASIS-5 was a randomized, double-blind trial that compared fondaparinux and enoxaparin (Lovenox) in patients with acute coronary syndromes.³⁸ Fondaparinux was similar to enoxaparin in terms of the combined end point of death, myocardial infarction, or refractory ischemia at 9 days, and fewer patients on fondaparinux developed bleeding (2.2% vs 4.1%, HR 0.52; 95% CI 0.44–0.61). This difference persisted during long-term follow-up.

Importantly, fewer patients died in the fondaparinux group. At 180 days, 638 (6.5%) of the patients in the enoxaparin group had died, compared with 574 (5.8%) in the fondaparinux group, a difference of 64 deaths (P = .05). The authors found that 41 fewer patients in the fondaparinux group than in the enoxaparin group died after major bleeding, and 20 fewer patients in the fondaparinux group died after minor bleeding.³⁸ Thus, most of the difference in mortality rates between the two groups was attributed to a lower incidence of bleeding with fondaparinux.

Unfortunately, despite its safe bleeding profile, fondaparinux has fallen out of favor for use in acute coronary syndromes, owing to a higher risk of catheter thrombosis in the fondaparinux group (0.9%) than in those undergoing percutaneous coronary interventions with enoxaparin alone (0.4%) in the OASIS-5 trial.⁴⁰

 

 

Bivalirudin

The direct thrombin inhibitor bivalirudin has been studied in three large randomized trials in patients undergoing percutaneous coronary interventions.^20,37,41

The ACUITY trial³⁷ was a prospective, open-label, randomized, multicenter trial that compared three regimens in patients with moderate or high-risk non-ST-elevation acute coronary syndromes:

• Heparin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

Bivalirudin alone was as effective as heparin plus a glycoprotein IIb/IIIa inhibitor with respect to the composite ischemia end point, which at 30 days had occurred in 7.8% vs 7.3% of the patients in these treatment groups (P = .32, RR 1.08; 95% CI 0.93–1.24), and it was superior with respect to major bleeding (3.0% vs 5.7%, P < .001, RR 0.53; 95% CI 0.43–0.65).

The HORIZONS-AMI study⁴¹ was a prospective, open-label, randomized, multicenter trial that compared bivalirudin alone vs heparin plus a glycoprotein IIb/IIIa inhibitor in patients with ST-elevation acute coronary syndromes who were undergoing primary percutaneous coronary interventions. The two primary end points were major bleeding and net adverse events.

At 1 year, patients assigned to bivalirudin had a lower rate of major bleeding than did controls (5.8% vs 9.2%, HR 0.61, 95% CI 0.48–0.78, P < .0001), with similar rates of major adverse cardiac events in both groups (11.9% vs 11.9%, HR 1.00, 95% CI 0.82– 1.21, P = .98).⁴¹

Both OASIS 5 and HORIZONS-AMI are examples of clinical trials in which strategies that reduced bleeding risk were also associated with improved survival.

For cardiac catheterization, inserting the catheter in the wrist poses less risk

Bleeding is currently the most common noncardiac complication in patients undergoing percutaneous coronary interventions, and it most often occurs at the vascular access site.¹⁷

Rao et al¹² evaluated data from 593,094 procedures in the National Cardiovascular Data Registry and found that, compared with the femoral approach, the use of transradial percutaneous coronary intervention was associated with a similar rate of procedural success (OR 1.02, 95% CI 0.93–1.12) but a significantly lower risk of bleeding complications (OR 0.42, 95% CI 0.31–0.56) after multivariable adjustment.

The use of smaller sheath sizes (4F–6F) and preferential use of bivalirudin over unfractionated heparin and glycoprotein IIb/IIIa inhibitor therapy are other methods described to decrease the risk of bleeding after percutaneous coronary interventions.^20,41–49

IF BLEEDING OCCURS

Once a bleeding complication occurs, cessation of therapy is a potential option. Stopping or reversing antithrombotic and antiplatelet therapy is warranted in the event of major bleeding (eg, gastrointestinal, retroperitoneal, intracranial).³¹

Stopping antithrombotic and antiplatelet therapy

Whether bleeding is minor or major, the risk of a recurrent thrombotic event must be considered, especially in patients who have undergone revascularization, stent implantation, or both. The risk of acute thrombotic events after interrupting antithrombotic or antiplatelet agents is considered greatest 4 to 5 days following revascularization or percutaneous coronary intervention.¹⁵ If bleeding can be controlled with local treatment such as pressure, packing, or dressing, antithrombotic and antiplatelet therapy need not be interrupted.⁵⁰

Current guidelines recommend strict control of hemorrhage for at least 24 hours before reintroducing antiplatelet or antithrombotic agents.

It is also important to remember that in the setting of gastrointestinal bleeding due to peptic ulcer disease, adjunctive proton pump inhibitors are recommended after restarting antiplatelet or antithrombotic therapy or both.

Importantly, evidence-based antithrombotic medications (especially dual antiplatelet therapy) should be restarted once the acute bleeding event has resolved.³¹

Reversal of anticoagulant and antiplatelet therapies

Unfractionated heparin is reversed with infusion of protamine sulfate at a dose of 1 mg per 100 U of unfractionated heparin given over the previous 4 hours.^51,52 The rate of protamine sulfate infusion should be less than 100 mg over 2 hours, with 50% of the dose given initially and subsequent doses titrated according to bleeding response.^52,53 Protamine sulfate is associated with a risk of hypotension and bradycardia, and for this reason it should be given no faster than 5 mg/min.

Low-molecular-weight heparin (LMWH) can be inhibited by 1 mg of protamine sulfate for each 1 mg of LMWH given over the previous 4 hours.^51,52

However, protamine sulfate only partially neutralizes the anticoagulant effect of LMWH. In cases in which protamine sulfate is unsuccessful in abating bleeding associated with LMWH use, guidelines allow for the use of recombinant factor VIIa (NovoSeven).³¹ In healthy volunteers given fondaparinux, recombinant factor VIIa normalized coagulation times and thrombin generation within 1.5 hours, with a sustained effect for 6 hours.⁵²

It is important to note that the use of this agent has not been fully studied, it is very costly (a single dose of 40 μg/kg costs from $3,000 to $4,000), and it is linked to reports of increased risk of thrombotic complications.^54,55

Antiplatelet agents are more complex to reverse. The antiplatelet actions of aspirin and clopidogrel wear off as new platelets are produced. Approximately 10% of a patient’s platelet count is produced daily; thus, the antiplatelet effects of aspirin and clopidogrel can persist for 5 to 10 days.^31,56

If these agents need to be reversed quickly to stop bleeding, according to expert consensus the aspirin effect can be reversed by transfusion of one unit of platelets. The antiplatelet effect of clopidogrel is more significant than that of aspirin; thus, two units of platelets are recommended.⁵⁶

Glycoprotein IIb/IIIa inhibitors. If a major bleeding event requires the reversal of glycoprotein IIb/IIIa inhibitor therapy, the treatment must take into consideration the pharmacodynamics of the target drug. Both eptifibatide (Integrilin) and tirofiban (Aggrastat) competitively inhibit glycoprotein IIb/IIIa receptors; thus, their effects depend on dosing, elimination, and time. Due to the stoichiometry of both drugs, transfusion of platelets is ineffective. Both eptifibatide and tirofiban are eliminated by the kidney; thus, normal renal function is key to the amount of time it takes for platelet function to return to baseline.⁵⁷ Evidence suggests that fibrinogen-rich plasma can be administered to restore platelet function.^31,58,59

Abciximab (ReoPro). Whereas reversal of eptifibatide and tirofiban focuses on overcoming competitive inhibition, neutralization of abciximab involves overcoming its high receptor affinity. At 24 hours after abciximab infusion is stopped, platelet aggregation may still be inhibited by up to 50%. Fortunately, owing to abciximab’s short plasma half-life and its dilution in serum, platelet transfusion is effective in reversing its antiplatelet effects.^31,57

 

 

Blood transfusion

Long considered beneficial to critically ill patients, blood transfusion to maintain hematocrit levels during acute coronary syndromes has come under intense scrutiny. Randomized trials have shown that transfusion should not be given aggressively to critically ill patients.⁶⁰ In acute coronary syndromes, there are only observational data.

Rao et al⁶¹ used detailed clinical data from 24,112 patients with acute coronary syndromes in the GUSTO IIb, PURSUIT, and PARAGON B trials to determine the association between blood transfusion and outcomes in patients who developed moderate to severe bleeding, anemia, or both during their hospitalization. The rates of death in the hospital and at 30 days were significantly higher in patients who received a transfusion (30-day mortality HR 3.94; 95% CI 3.36–4.75). However, there was no significant association between transfusion and the 30-day mortality rate if the nadir hematocrit was 25% or less.

Of note: no randomized clinical trial has evaluated transfusion strategies in acute coronary syndromes at this time. Until such data are available, it is reasonable to follow published guidelines and to avoid transfusion in stable patients with ischemic heart disease unless the hematocrit is 25% or less.³¹ The risks and benefits of blood transfusion should be carefully weighed. Routine use of transfusion to maintain predefined hemoglobin levels is not recommended in stable patients.

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

A 61-year-old woman presents to her primary care physician because for the last 4 weeks she has had difficulty swallowing solid food and a feeling of food “getting stuck in the chest.” She also reports having nausea, mild epigastric pain, and heartburn. She denies having fevers, chills, night sweats, weight loss, vomiting, diarrhea, hematochezia, or melena.

Medical history

For the past 20 years, she has had gastroesophageal reflux disease (GERD), intermittently treated with a proton pump inhibitor. She also has arthritis, hyperlipidemia, hypertension, and asthma, and she has undergone right hip replacement for a hip fracture. She has no known allergies.

She lives in the Midwest region of the United States and is on disability due to her arthritis. She is divorced and has three children.

She quit smoking 3 years ago after smoking half a pack per day for 30 years. She drinks socially; she has never used recreational drugs.

She recalls that an uncle had cancer, but she does not know the specific type.

Physical examination

The patient’s temperature is 96.7°F (35.9°C), heart rate 86 per minute, blood pressure 150/92 mm Hg, respiratory rate 16 per minute, and oxygen saturation 100% on room air.

Differential diagnosis

Although the differential diagnosis at this stage is broad, a few conditions that commonly present like this are:

• Esophageal cancer
• Esophageal stricture
• Esophageal webs
• Esophagitis (infectious, inflammatory)
• Peptic ulcer disease.

WHICH TEST SHOULD BE ORDERED?

1. Which test will you order now for this patient?

• Endoscopy (esophagogastroduodenoscopy)
• Serum Helicobacter pylori antibody testing
• Wireless pH monitoring
• Barium swallow

Endoscopy would be the best test to order. Esophageal cancer and esophageal stricture must be ruled out, in view of her long history of GERD, gastritis, and smoking and her alarming symptoms of difficulty swallowing and food sticking. In this situation, endoscopy is the first test recommended. In addition to its diagnostic value, it offers an opportunity to obtain tissue samples and to perform a therapeutic intervention, if necessary.^1,2

H pyloriantibody testing is used in the “test-and-treat approach” for H pylori infection, an established management strategy for patients who have uninvestigated dyspepsia and who are younger than 55 years and have no “alarm features,” ie, red flags for cancer. The alarm features commonly described are anemia, early satiety, unexplained weight loss, bleeding, odynophagia, progressive dysphagia, unexplained vomiting, and a family history or prior history of gastrointestinal malignancy.³

Our patient’s symptoms raise the possibility of cancer, so that H pylori testing would not be the best test to order at this point.

Ambulatory wireless pH monitoring with a wireless pH capsule is useful for confirming GERD in those with persistent symptoms (whether typical or atypical) who do not have evidence of mucosal damage on initial endoscopy, particularly if a trial of acid suppression has failed.^4–6

Barium swallow is an x-ray examination of the esophagus with contrast. It can show both the anatomy and the function of the esophagus, and it would be the initial diagnostic procedure of choice for patients with dysphagia who have no alarm symptoms.⁷ However, our patient does have alarm symptoms.

First highlight point

• Endoscopy is the first test in patients with dysphagia with alarm symptoms.

CASE CONTINUES: ENDOSCOPY

Multiple biopsies of the nodules show atypical lymphoid infiltrates with small cleaved lymphocytes that are mostly positive for CD5, CD20, and CD43 and negative for CD10 and CD23 by flow cytometry. In addition, a staining test for H pylori is positive.

Comment. Our patient has had GERD for the past 20 years, intermittently treated with a proton pump inhibitor. Acid suppressive therapy with a proton pump inhibitor is the standard of care of patients with erosive esophagitis. In standard doses, these drugs control symptoms in most cases and heal esophagitis in almost 90% of cases within 4 to 8 weeks.⁹ Proton pump inhibitors are also effective for maintaining healing of esophagitis and controlling symptoms in patients who respond to an acute course of therapy for a period of 6 to 12 months.¹⁰

WHAT IS THE DIAGNOSIS?

2. Which is the most likely diagnosis for our patient?

• Fundic gland polyps
• Gastric hyperplastic polyps
• Gastric adenomas
• Mucosa-associated lymphoid tissue (MALT) lymphoma

Fundic gland polyps are small (0.1–0.8 cm), hyperemic, sessile, flat, nodular lesions that have a smooth surface. They occur exclusively in the gastric corpus and are composed of normal gastric corpus-type epithelium arranged in a disorderly or microcystic configuration. ¹¹ This pattern does not match our patient’s findings.

Gastric hyperplastic polyps are elongated, cystic, and distorted foveolar epithelium with marked regeneration. Other histologic findings are stromal inflammation, edema, and smooth muscle hyperplasia.¹² This does not match our patient’s findings.

Adenomas can be flat or polypoid and range in size from a few millimeters to several centimeters. Endoscopically, adenomatous polyps have a velvety, lobulated appearance. Most are solitary (82% of cases), located in the antrum, and less than 2 cm in diameter.¹³ This does not match our patient’s findings.

MALT lymphoma, the correct answer, is characterized by small cleaved lymphocytes positive for CD4, CD20, and CD43. Although CD5 positivity is not characteristic, rare cases of MALT lymphoma may be CD5-positive and may be more aggressive.¹⁴

Other common features of MALT lymphoma are erosions, small nodules, thickening of gastric folds—generally suggesting a benign condition—or hyperemic or even normal gastric mucosa.¹⁵ Our patient’s complaint of food sticking in her chest and difficulty swallowing was most likely related to the erosive esophagitis found on endoscopy.

A TYPE OF NON-HODGKIN LYMPHOMA

Normal gastric mucosa contains no lymphoid tissue.^16,17 Primary gastric lymphoma, of which MALT lymphoma is a subtype, accounts for around 5% of gastric malignancies, with an annual incidence rate of 0.5 per 100,000 people. ^18–20 Although rare, it accounts for 60% to 70% of cases of non-Hodgkin lymphoma of the gastrointestinal tract and can involve the perigastric or abdominal lymph nodes or both.^21–23 Although earlier studies suggested that its incidence was increasing, recent data indicate the incidence may be decreasing, thanks to active H pylori treatment.^24–26

Two subtypes of primary gastric non-Hodgkin lymphoma commonly described are MALT lymphoma and diffuse large B-cell (DLBC) lymphoma. In the Revised European-American Lymphoma Classification, high-grade MALT lymphoma is comparable to DLBC lymphoma and may have transformed from low-grade MALT lymphoma.^27,28 Another reported subtype, mantle cell lymphoma with MALT lymphoma features, should be considered in the differential diagnosis, although it is rare.²⁹

MALT lymphoma is linked to H pylori

H pylori infection is a factor in the development of MALT lymphoma,³⁰ as multiple lines of evidence show:

• H pylori infection has been reported in more than 90% of patients with MALT lymphoma.^31–35
• H pylori antibodies have been found in stored serum drawn from patients who subsequently developed MALT lymphoma.³⁵
• In response to H pylori antigens, T cells from MALT lymphoma proliferate and cause an increase in tumor immunoglobulin production.³⁶
• In animals experimentally infected with H pylori, around one-third develop lymphoid follicles and lymphoepithelial lesions including B cells, which are similar to human MALT lymphoma.³⁷

However, only a minority of patients with H pylori develop lymphoma, owing to a host immune response that is not well defined.

Second highlight point

• Gastric MALT lymphoma is associated with H pylori.

Associated genetic translocations

Three translocations, t(11;18), t(1;14), and t(14;18), are specifically associated with MALT lymphoma, and the genes involved have been characterized.

The t(11;18) translocation, seen in gastric and nongastric MALT lymphoma, is not seen in H pylori gastritis.³⁸ This translocation is usually associated with extension of the disease outside the stomach (ie, to regional lymph nodes or distal sites).²⁷ Most cases that do not respond to H pylori eradication involve the t(11;18) and t(1;14) translocations.²⁸

Clinical presentation of gastric MALT lymphoma

The average age at presentation with gastric MALT lymphoma is 54 to 58 years.

The most common complaint is nonspecific abdominal pain in the epigastric region, sometimes accompanied by weight loss, nausea, vomiting, and, in a quarter of cases, acute or chronic bleeding.^39–41 Weight loss is common, and its extent is associated with the location and the grade of the disease.

Most cases of MALT lymphoma are found serendipitously during endoscopy, on which the appearance of the lesions ranges from small ulcerations to polypoid masses with infiltrated, thickened folds involving predominantly the antrum or prepyloric region.^15,41

MANAGING MALT LYMPHOMA

Our patient undergoes endoscopic ultrasonography, which reveals she has stage I disease, ie, it is limited to the stomach without involving the lymph nodes (stage II), adjacent organs (stage III), or distant organs (stage IV).

3. How will you treat this patient, given the present information?

• Chemotherapy
• Radiation therapy
• Surgery
• Antibiotics with a proton pump inhibitor

Antibiotics with a proton pump inhibitor would be best. According to the Maastricht III Consensus Report,⁴²H pylori eradication is the treatment of first choice for H pylori infection in patients with stage I low-grade gastric MALT lymphoma. This therapy can induce complete histologic remission in 80% to 100% of patients with MALT lymphoma. ⁴³ Several studies have shown regression⁴⁴ or complete remission of low-grade gastric MALT lymphoma after eradication of H pylori with antibiotics, making it a reasonable initial treatment.^45–49

Several regimens are used. The first choice in populations in which the prevalence of resistance to clarithromycin (Biaxin) is less than 15% to 20% is a proton pump inhibitor, clarithromycin, and either amoxicillin or metronidazole (Flagyl). (Metronidazole is preferable to amoxicillin if the prevalence of resistance to metronidazole is less than 40%.)

Sequential treatment—ie, 5 days of a proton pump inhibitor plus amoxicillin followed by 5 additional days of a proton pump inhibitor plus clarithromycin plus tinidazole (Tindamax)— may be better than a 7-day course of the combination of a proton pump inhibitor, amoxicillin, and clarithromycin.^50,51

Treatment with a proton pump inhibitor, clarithromycin (500 mg twice a day), and either amoxicillin (1,000 mg twice a day) or metronidazole (400 or 500 mg twice a day) for 14 days is more effective than treatment for 7 days.⁵²

H pylori reinfection in the general population is quite rare, with an estimated yearly rate as low as 2%.⁵³ Recurrence of the infection is a risk factor for lymphoma relapse.^17,54

Several predictors of the response of MALT lymphoma to eradication therapy have been recognized: H pylori positivity, stage I, lymphoma confined to the stomach; gastric wall invasion confined to mucosa and submucosa, and the absence of the t(11;18) translocation.

The time between H pylori eradication and complete remission of primary gastric lymphoma varies and can be longer than 12 months.⁵⁵

Chemotherapy. In a single study,⁵⁶ complete remission was achieved with oral cyclophosphamide (Cytoxan) in cases of antibiotic-refractory gastric MALT lymphoma. Comparable results were achieved after radiation therapy (see below); hence, oral monotherapy with cyclophosphamide might also be a suitable second-line therapy.⁵⁷

The regimen of cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP) has been recommended for patients with stage III and IV disease.^41,58

Rituximab (Rituxan) has been proven effective in treating t(11;18)-positive MALT lymphoma.⁵⁹

Radiation therapy. Two studies have shown a 100% complete response rate after radiation therapy with a median dose of 30 Gy.^57,60 Tsang et al⁶¹ reported complete remission in up to 90% of patients receiving radiation therapy alone, with excellent 5-year progression-free and overall survival rates of 98% and 77%, respectively.

Although surgery, radiotherapy, and chemotherapy have been used in cases in which eradication therapy failed and in more advanced stages of MALT lymphoma, there is no consensus about their use, so therapy must be individualized.

Fourth highlight point

• Antibiotic treatment for eradication of H pylori infection is the recommended treatment only for stage I low-grade MALT lymphoma.

FOLOW-UP

4. How should you follow patients with MALT lymphoma?

• Endoscopy
• H pylori testing
• Computed tomography and magnetic resonance imaging
• No surveillance required after treatment

Endoscopy is the correct answer. As initial diagnostic biopsies do not exclude aggressive lymphoma, careful endoscopic follow-up is recommended. A recommended schedule is a breath test for H pylori every 2 months in conjunction with repeat endoscopy with biopsies every 3 to 6 months for the first 2 years, and then annually.⁶²

Although H pylori may be eradicated within 1 month of drug therapy, lymphoma may take several months to disappear histologically. In patients with stage I disease with residual lymphoma after H pylori eradication therapy, a simple wait-and-watch strategy is a suitable alternative to oncologic therapy.^63,64

Local relapse may occur after many years of complete remission; thus, patients should be followed closely long-term with endoscopy and possibly endoscopic ultrasonography. ^47–49,63

Patients who fail to attain a complete remission within 12 months should undergo radiation therapy, with or without chemotherapy. The same therapy should be started as soon as possible in patients with progressive disease after antibiotic therapy. Patients negative for H pylori, patients with stage II disease, and patients with t(11;18) translocation should receive antibiotic treatment with endoscopic surveillance every 3 months.

Fifth highlight point

• Surveillance endoscopy is recommended for follow-up of MALT lymphoma.

CASE CONTINUES: HER CONDITION IMPROVES, THEN WORSENS

Computed tomography of the chest, abdomen, and pelvis reveals no evidence of additional sites of tumor. Positron emission tomography reveals increased uptake in the left tonsillar region, for which she has undergoes an ear, nose, and throat evaluation, and no pathology is found.

Due to recurrence of her marginal zone Bcell lymphoma of MALT type of the stomach, the patient is referred to an oncology service. She is treated with radiation, receiving 15 sessions of 30 Gy localized to the stomach. Three months after radiation therapy, she undergoes endoscopy again, which shows no evidence of the previously described nodules. Repeat biopsies are negative for H pylori and MALT lymphoma.

Annual surveillance endoscopy and computed tomography for the past 3 years have been negative for any tumor recurrence.

A 61-year-old woman presents to her primary care physician because for the last 4 weeks she has had difficulty swallowing solid food and a feeling of food “getting stuck in the chest.” She also reports having nausea, mild epigastric pain, and heartburn. She denies having fevers, chills, night sweats, weight loss, vomiting, diarrhea, hematochezia, or melena.

Medical history

For the past 20 years, she has had gastroesophageal reflux disease (GERD), intermittently treated with a proton pump inhibitor. She also has arthritis, hyperlipidemia, hypertension, and asthma, and she has undergone right hip replacement for a hip fracture. She has no known allergies.

She lives in the Midwest region of the United States and is on disability due to her arthritis. She is divorced and has three children.

She quit smoking 3 years ago after smoking half a pack per day for 30 years. She drinks socially; she has never used recreational drugs.

She recalls that an uncle had cancer, but she does not know the specific type.

Physical examination

The patient’s temperature is 96.7°F (35.9°C), heart rate 86 per minute, blood pressure 150/92 mm Hg, respiratory rate 16 per minute, and oxygen saturation 100% on room air.

Differential diagnosis

Although the differential diagnosis at this stage is broad, a few conditions that commonly present like this are:

• Esophageal cancer
• Esophageal stricture
• Esophageal webs
• Esophagitis (infectious, inflammatory)
• Peptic ulcer disease.

WHICH TEST SHOULD BE ORDERED?

1. Which test will you order now for this patient?

• Endoscopy (esophagogastroduodenoscopy)
• Serum Helicobacter pylori antibody testing
• Wireless pH monitoring
• Barium swallow

Endoscopy would be the best test to order. Esophageal cancer and esophageal stricture must be ruled out, in view of her long history of GERD, gastritis, and smoking and her alarming symptoms of difficulty swallowing and food sticking. In this situation, endoscopy is the first test recommended. In addition to its diagnostic value, it offers an opportunity to obtain tissue samples and to perform a therapeutic intervention, if necessary.^1,2

H pyloriantibody testing is used in the “test-and-treat approach” for H pylori infection, an established management strategy for patients who have uninvestigated dyspepsia and who are younger than 55 years and have no “alarm features,” ie, red flags for cancer. The alarm features commonly described are anemia, early satiety, unexplained weight loss, bleeding, odynophagia, progressive dysphagia, unexplained vomiting, and a family history or prior history of gastrointestinal malignancy.³

Our patient’s symptoms raise the possibility of cancer, so that H pylori testing would not be the best test to order at this point.

Ambulatory wireless pH monitoring with a wireless pH capsule is useful for confirming GERD in those with persistent symptoms (whether typical or atypical) who do not have evidence of mucosal damage on initial endoscopy, particularly if a trial of acid suppression has failed.^4–6

Barium swallow is an x-ray examination of the esophagus with contrast. It can show both the anatomy and the function of the esophagus, and it would be the initial diagnostic procedure of choice for patients with dysphagia who have no alarm symptoms.⁷ However, our patient does have alarm symptoms.

First highlight point

• Endoscopy is the first test in patients with dysphagia with alarm symptoms.

CASE CONTINUES: ENDOSCOPY

Multiple biopsies of the nodules show atypical lymphoid infiltrates with small cleaved lymphocytes that are mostly positive for CD5, CD20, and CD43 and negative for CD10 and CD23 by flow cytometry. In addition, a staining test for H pylori is positive.

Comment. Our patient has had GERD for the past 20 years, intermittently treated with a proton pump inhibitor. Acid suppressive therapy with a proton pump inhibitor is the standard of care of patients with erosive esophagitis. In standard doses, these drugs control symptoms in most cases and heal esophagitis in almost 90% of cases within 4 to 8 weeks.⁹ Proton pump inhibitors are also effective for maintaining healing of esophagitis and controlling symptoms in patients who respond to an acute course of therapy for a period of 6 to 12 months.¹⁰

WHAT IS THE DIAGNOSIS?

2. Which is the most likely diagnosis for our patient?

• Fundic gland polyps
• Gastric hyperplastic polyps
• Gastric adenomas
• Mucosa-associated lymphoid tissue (MALT) lymphoma

Fundic gland polyps are small (0.1–0.8 cm), hyperemic, sessile, flat, nodular lesions that have a smooth surface. They occur exclusively in the gastric corpus and are composed of normal gastric corpus-type epithelium arranged in a disorderly or microcystic configuration. ¹¹ This pattern does not match our patient’s findings.

Gastric hyperplastic polyps are elongated, cystic, and distorted foveolar epithelium with marked regeneration. Other histologic findings are stromal inflammation, edema, and smooth muscle hyperplasia.¹² This does not match our patient’s findings.

Adenomas can be flat or polypoid and range in size from a few millimeters to several centimeters. Endoscopically, adenomatous polyps have a velvety, lobulated appearance. Most are solitary (82% of cases), located in the antrum, and less than 2 cm in diameter.¹³ This does not match our patient’s findings.

MALT lymphoma, the correct answer, is characterized by small cleaved lymphocytes positive for CD4, CD20, and CD43. Although CD5 positivity is not characteristic, rare cases of MALT lymphoma may be CD5-positive and may be more aggressive.¹⁴

Other common features of MALT lymphoma are erosions, small nodules, thickening of gastric folds—generally suggesting a benign condition—or hyperemic or even normal gastric mucosa.¹⁵ Our patient’s complaint of food sticking in her chest and difficulty swallowing was most likely related to the erosive esophagitis found on endoscopy.

A TYPE OF NON-HODGKIN LYMPHOMA

Normal gastric mucosa contains no lymphoid tissue.^16,17 Primary gastric lymphoma, of which MALT lymphoma is a subtype, accounts for around 5% of gastric malignancies, with an annual incidence rate of 0.5 per 100,000 people. ^18–20 Although rare, it accounts for 60% to 70% of cases of non-Hodgkin lymphoma of the gastrointestinal tract and can involve the perigastric or abdominal lymph nodes or both.^21–23 Although earlier studies suggested that its incidence was increasing, recent data indicate the incidence may be decreasing, thanks to active H pylori treatment.^24–26

Two subtypes of primary gastric non-Hodgkin lymphoma commonly described are MALT lymphoma and diffuse large B-cell (DLBC) lymphoma. In the Revised European-American Lymphoma Classification, high-grade MALT lymphoma is comparable to DLBC lymphoma and may have transformed from low-grade MALT lymphoma.^27,28 Another reported subtype, mantle cell lymphoma with MALT lymphoma features, should be considered in the differential diagnosis, although it is rare.²⁹

MALT lymphoma is linked to H pylori

H pylori infection is a factor in the development of MALT lymphoma,³⁰ as multiple lines of evidence show:

• H pylori infection has been reported in more than 90% of patients with MALT lymphoma.^31–35
• H pylori antibodies have been found in stored serum drawn from patients who subsequently developed MALT lymphoma.³⁵
• In response to H pylori antigens, T cells from MALT lymphoma proliferate and cause an increase in tumor immunoglobulin production.³⁶
• In animals experimentally infected with H pylori, around one-third develop lymphoid follicles and lymphoepithelial lesions including B cells, which are similar to human MALT lymphoma.³⁷

However, only a minority of patients with H pylori develop lymphoma, owing to a host immune response that is not well defined.

Second highlight point

• Gastric MALT lymphoma is associated with H pylori.

Associated genetic translocations

Three translocations, t(11;18), t(1;14), and t(14;18), are specifically associated with MALT lymphoma, and the genes involved have been characterized.

The t(11;18) translocation, seen in gastric and nongastric MALT lymphoma, is not seen in H pylori gastritis.³⁸ This translocation is usually associated with extension of the disease outside the stomach (ie, to regional lymph nodes or distal sites).²⁷ Most cases that do not respond to H pylori eradication involve the t(11;18) and t(1;14) translocations.²⁸

Clinical presentation of gastric MALT lymphoma

The average age at presentation with gastric MALT lymphoma is 54 to 58 years.

The most common complaint is nonspecific abdominal pain in the epigastric region, sometimes accompanied by weight loss, nausea, vomiting, and, in a quarter of cases, acute or chronic bleeding.^39–41 Weight loss is common, and its extent is associated with the location and the grade of the disease.

Most cases of MALT lymphoma are found serendipitously during endoscopy, on which the appearance of the lesions ranges from small ulcerations to polypoid masses with infiltrated, thickened folds involving predominantly the antrum or prepyloric region.^15,41

MANAGING MALT LYMPHOMA

Our patient undergoes endoscopic ultrasonography, which reveals she has stage I disease, ie, it is limited to the stomach without involving the lymph nodes (stage II), adjacent organs (stage III), or distant organs (stage IV).

3. How will you treat this patient, given the present information?

• Chemotherapy
• Radiation therapy
• Surgery
• Antibiotics with a proton pump inhibitor

Antibiotics with a proton pump inhibitor would be best. According to the Maastricht III Consensus Report,⁴²H pylori eradication is the treatment of first choice for H pylori infection in patients with stage I low-grade gastric MALT lymphoma. This therapy can induce complete histologic remission in 80% to 100% of patients with MALT lymphoma. ⁴³ Several studies have shown regression⁴⁴ or complete remission of low-grade gastric MALT lymphoma after eradication of H pylori with antibiotics, making it a reasonable initial treatment.^45–49

Several regimens are used. The first choice in populations in which the prevalence of resistance to clarithromycin (Biaxin) is less than 15% to 20% is a proton pump inhibitor, clarithromycin, and either amoxicillin or metronidazole (Flagyl). (Metronidazole is preferable to amoxicillin if the prevalence of resistance to metronidazole is less than 40%.)

Sequential treatment—ie, 5 days of a proton pump inhibitor plus amoxicillin followed by 5 additional days of a proton pump inhibitor plus clarithromycin plus tinidazole (Tindamax)— may be better than a 7-day course of the combination of a proton pump inhibitor, amoxicillin, and clarithromycin.^50,51

Treatment with a proton pump inhibitor, clarithromycin (500 mg twice a day), and either amoxicillin (1,000 mg twice a day) or metronidazole (400 or 500 mg twice a day) for 14 days is more effective than treatment for 7 days.⁵²

H pylori reinfection in the general population is quite rare, with an estimated yearly rate as low as 2%.⁵³ Recurrence of the infection is a risk factor for lymphoma relapse.^17,54

Several predictors of the response of MALT lymphoma to eradication therapy have been recognized: H pylori positivity, stage I, lymphoma confined to the stomach; gastric wall invasion confined to mucosa and submucosa, and the absence of the t(11;18) translocation.

The time between H pylori eradication and complete remission of primary gastric lymphoma varies and can be longer than 12 months.⁵⁵

Chemotherapy. In a single study,⁵⁶ complete remission was achieved with oral cyclophosphamide (Cytoxan) in cases of antibiotic-refractory gastric MALT lymphoma. Comparable results were achieved after radiation therapy (see below); hence, oral monotherapy with cyclophosphamide might also be a suitable second-line therapy.⁵⁷

The regimen of cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP) has been recommended for patients with stage III and IV disease.^41,58

Rituximab (Rituxan) has been proven effective in treating t(11;18)-positive MALT lymphoma.⁵⁹

Radiation therapy. Two studies have shown a 100% complete response rate after radiation therapy with a median dose of 30 Gy.^57,60 Tsang et al⁶¹ reported complete remission in up to 90% of patients receiving radiation therapy alone, with excellent 5-year progression-free and overall survival rates of 98% and 77%, respectively.

Although surgery, radiotherapy, and chemotherapy have been used in cases in which eradication therapy failed and in more advanced stages of MALT lymphoma, there is no consensus about their use, so therapy must be individualized.

Fourth highlight point

• Antibiotic treatment for eradication of H pylori infection is the recommended treatment only for stage I low-grade MALT lymphoma.

FOLOW-UP

4. How should you follow patients with MALT lymphoma?

• Endoscopy
• H pylori testing
• Computed tomography and magnetic resonance imaging
• No surveillance required after treatment

Endoscopy is the correct answer. As initial diagnostic biopsies do not exclude aggressive lymphoma, careful endoscopic follow-up is recommended. A recommended schedule is a breath test for H pylori every 2 months in conjunction with repeat endoscopy with biopsies every 3 to 6 months for the first 2 years, and then annually.⁶²

Although H pylori may be eradicated within 1 month of drug therapy, lymphoma may take several months to disappear histologically. In patients with stage I disease with residual lymphoma after H pylori eradication therapy, a simple wait-and-watch strategy is a suitable alternative to oncologic therapy.^63,64

Local relapse may occur after many years of complete remission; thus, patients should be followed closely long-term with endoscopy and possibly endoscopic ultrasonography. ^47–49,63

Patients who fail to attain a complete remission within 12 months should undergo radiation therapy, with or without chemotherapy. The same therapy should be started as soon as possible in patients with progressive disease after antibiotic therapy. Patients negative for H pylori, patients with stage II disease, and patients with t(11;18) translocation should receive antibiotic treatment with endoscopic surveillance every 3 months.

Fifth highlight point

• Surveillance endoscopy is recommended for follow-up of MALT lymphoma.

CASE CONTINUES: HER CONDITION IMPROVES, THEN WORSENS

Computed tomography of the chest, abdomen, and pelvis reveals no evidence of additional sites of tumor. Positron emission tomography reveals increased uptake in the left tonsillar region, for which she has undergoes an ear, nose, and throat evaluation, and no pathology is found.

Due to recurrence of her marginal zone Bcell lymphoma of MALT type of the stomach, the patient is referred to an oncology service. She is treated with radiation, receiving 15 sessions of 30 Gy localized to the stomach. Three months after radiation therapy, she undergoes endoscopy again, which shows no evidence of the previously described nodules. Repeat biopsies are negative for H pylori and MALT lymphoma.

Annual surveillance endoscopy and computed tomography for the past 3 years have been negative for any tumor recurrence.

A 61-year-old woman presents to her primary care physician because for the last 4 weeks she has had difficulty swallowing solid food and a feeling of food “getting stuck in the chest.” She also reports having nausea, mild epigastric pain, and heartburn. She denies having fevers, chills, night sweats, weight loss, vomiting, diarrhea, hematochezia, or melena.

Medical history

For the past 20 years, she has had gastroesophageal reflux disease (GERD), intermittently treated with a proton pump inhibitor. She also has arthritis, hyperlipidemia, hypertension, and asthma, and she has undergone right hip replacement for a hip fracture. She has no known allergies.

She lives in the Midwest region of the United States and is on disability due to her arthritis. She is divorced and has three children.

She quit smoking 3 years ago after smoking half a pack per day for 30 years. She drinks socially; she has never used recreational drugs.

She recalls that an uncle had cancer, but she does not know the specific type.

Physical examination

The patient’s temperature is 96.7°F (35.9°C), heart rate 86 per minute, blood pressure 150/92 mm Hg, respiratory rate 16 per minute, and oxygen saturation 100% on room air.

Differential diagnosis

Although the differential diagnosis at this stage is broad, a few conditions that commonly present like this are:

• Esophageal cancer
• Esophageal stricture
• Esophageal webs
• Esophagitis (infectious, inflammatory)
• Peptic ulcer disease.

WHICH TEST SHOULD BE ORDERED?

1. Which test will you order now for this patient?

• Endoscopy (esophagogastroduodenoscopy)
• Serum Helicobacter pylori antibody testing
• Wireless pH monitoring
• Barium swallow

Endoscopy would be the best test to order. Esophageal cancer and esophageal stricture must be ruled out, in view of her long history of GERD, gastritis, and smoking and her alarming symptoms of difficulty swallowing and food sticking. In this situation, endoscopy is the first test recommended. In addition to its diagnostic value, it offers an opportunity to obtain tissue samples and to perform a therapeutic intervention, if necessary.^1,2

H pyloriantibody testing is used in the “test-and-treat approach” for H pylori infection, an established management strategy for patients who have uninvestigated dyspepsia and who are younger than 55 years and have no “alarm features,” ie, red flags for cancer. The alarm features commonly described are anemia, early satiety, unexplained weight loss, bleeding, odynophagia, progressive dysphagia, unexplained vomiting, and a family history or prior history of gastrointestinal malignancy.³

Our patient’s symptoms raise the possibility of cancer, so that H pylori testing would not be the best test to order at this point.

Ambulatory wireless pH monitoring with a wireless pH capsule is useful for confirming GERD in those with persistent symptoms (whether typical or atypical) who do not have evidence of mucosal damage on initial endoscopy, particularly if a trial of acid suppression has failed.^4–6

Barium swallow is an x-ray examination of the esophagus with contrast. It can show both the anatomy and the function of the esophagus, and it would be the initial diagnostic procedure of choice for patients with dysphagia who have no alarm symptoms.⁷ However, our patient does have alarm symptoms.

First highlight point

• Endoscopy is the first test in patients with dysphagia with alarm symptoms.

CASE CONTINUES: ENDOSCOPY

Multiple biopsies of the nodules show atypical lymphoid infiltrates with small cleaved lymphocytes that are mostly positive for CD5, CD20, and CD43 and negative for CD10 and CD23 by flow cytometry. In addition, a staining test for H pylori is positive.

Comment. Our patient has had GERD for the past 20 years, intermittently treated with a proton pump inhibitor. Acid suppressive therapy with a proton pump inhibitor is the standard of care of patients with erosive esophagitis. In standard doses, these drugs control symptoms in most cases and heal esophagitis in almost 90% of cases within 4 to 8 weeks.⁹ Proton pump inhibitors are also effective for maintaining healing of esophagitis and controlling symptoms in patients who respond to an acute course of therapy for a period of 6 to 12 months.¹⁰

WHAT IS THE DIAGNOSIS?

2. Which is the most likely diagnosis for our patient?

• Fundic gland polyps
• Gastric hyperplastic polyps
• Gastric adenomas
• Mucosa-associated lymphoid tissue (MALT) lymphoma

Fundic gland polyps are small (0.1–0.8 cm), hyperemic, sessile, flat, nodular lesions that have a smooth surface. They occur exclusively in the gastric corpus and are composed of normal gastric corpus-type epithelium arranged in a disorderly or microcystic configuration. ¹¹ This pattern does not match our patient’s findings.

Gastric hyperplastic polyps are elongated, cystic, and distorted foveolar epithelium with marked regeneration. Other histologic findings are stromal inflammation, edema, and smooth muscle hyperplasia.¹² This does not match our patient’s findings.

Adenomas can be flat or polypoid and range in size from a few millimeters to several centimeters. Endoscopically, adenomatous polyps have a velvety, lobulated appearance. Most are solitary (82% of cases), located in the antrum, and less than 2 cm in diameter.¹³ This does not match our patient’s findings.

MALT lymphoma, the correct answer, is characterized by small cleaved lymphocytes positive for CD4, CD20, and CD43. Although CD5 positivity is not characteristic, rare cases of MALT lymphoma may be CD5-positive and may be more aggressive.¹⁴

Other common features of MALT lymphoma are erosions, small nodules, thickening of gastric folds—generally suggesting a benign condition—or hyperemic or even normal gastric mucosa.¹⁵ Our patient’s complaint of food sticking in her chest and difficulty swallowing was most likely related to the erosive esophagitis found on endoscopy.

A TYPE OF NON-HODGKIN LYMPHOMA

Normal gastric mucosa contains no lymphoid tissue.^16,17 Primary gastric lymphoma, of which MALT lymphoma is a subtype, accounts for around 5% of gastric malignancies, with an annual incidence rate of 0.5 per 100,000 people. ^18–20 Although rare, it accounts for 60% to 70% of cases of non-Hodgkin lymphoma of the gastrointestinal tract and can involve the perigastric or abdominal lymph nodes or both.^21–23 Although earlier studies suggested that its incidence was increasing, recent data indicate the incidence may be decreasing, thanks to active H pylori treatment.^24–26

Two subtypes of primary gastric non-Hodgkin lymphoma commonly described are MALT lymphoma and diffuse large B-cell (DLBC) lymphoma. In the Revised European-American Lymphoma Classification, high-grade MALT lymphoma is comparable to DLBC lymphoma and may have transformed from low-grade MALT lymphoma.^27,28 Another reported subtype, mantle cell lymphoma with MALT lymphoma features, should be considered in the differential diagnosis, although it is rare.²⁹

MALT lymphoma is linked to H pylori

H pylori infection is a factor in the development of MALT lymphoma,³⁰ as multiple lines of evidence show:

• H pylori infection has been reported in more than 90% of patients with MALT lymphoma.^31–35
• H pylori antibodies have been found in stored serum drawn from patients who subsequently developed MALT lymphoma.³⁵
• In response to H pylori antigens, T cells from MALT lymphoma proliferate and cause an increase in tumor immunoglobulin production.³⁶
• In animals experimentally infected with H pylori, around one-third develop lymphoid follicles and lymphoepithelial lesions including B cells, which are similar to human MALT lymphoma.³⁷

However, only a minority of patients with H pylori develop lymphoma, owing to a host immune response that is not well defined.

Second highlight point

• Gastric MALT lymphoma is associated with H pylori.

Associated genetic translocations

Three translocations, t(11;18), t(1;14), and t(14;18), are specifically associated with MALT lymphoma, and the genes involved have been characterized.

The t(11;18) translocation, seen in gastric and nongastric MALT lymphoma, is not seen in H pylori gastritis.³⁸ This translocation is usually associated with extension of the disease outside the stomach (ie, to regional lymph nodes or distal sites).²⁷ Most cases that do not respond to H pylori eradication involve the t(11;18) and t(1;14) translocations.²⁸

Clinical presentation of gastric MALT lymphoma

The average age at presentation with gastric MALT lymphoma is 54 to 58 years.

The most common complaint is nonspecific abdominal pain in the epigastric region, sometimes accompanied by weight loss, nausea, vomiting, and, in a quarter of cases, acute or chronic bleeding.^39–41 Weight loss is common, and its extent is associated with the location and the grade of the disease.

Most cases of MALT lymphoma are found serendipitously during endoscopy, on which the appearance of the lesions ranges from small ulcerations to polypoid masses with infiltrated, thickened folds involving predominantly the antrum or prepyloric region.^15,41

MANAGING MALT LYMPHOMA

Our patient undergoes endoscopic ultrasonography, which reveals she has stage I disease, ie, it is limited to the stomach without involving the lymph nodes (stage II), adjacent organs (stage III), or distant organs (stage IV).

3. How will you treat this patient, given the present information?

• Chemotherapy
• Radiation therapy
• Surgery
• Antibiotics with a proton pump inhibitor

Antibiotics with a proton pump inhibitor would be best. According to the Maastricht III Consensus Report,⁴²H pylori eradication is the treatment of first choice for H pylori infection in patients with stage I low-grade gastric MALT lymphoma. This therapy can induce complete histologic remission in 80% to 100% of patients with MALT lymphoma. ⁴³ Several studies have shown regression⁴⁴ or complete remission of low-grade gastric MALT lymphoma after eradication of H pylori with antibiotics, making it a reasonable initial treatment.^45–49

Several regimens are used. The first choice in populations in which the prevalence of resistance to clarithromycin (Biaxin) is less than 15% to 20% is a proton pump inhibitor, clarithromycin, and either amoxicillin or metronidazole (Flagyl). (Metronidazole is preferable to amoxicillin if the prevalence of resistance to metronidazole is less than 40%.)

Sequential treatment—ie, 5 days of a proton pump inhibitor plus amoxicillin followed by 5 additional days of a proton pump inhibitor plus clarithromycin plus tinidazole (Tindamax)— may be better than a 7-day course of the combination of a proton pump inhibitor, amoxicillin, and clarithromycin.^50,51

Treatment with a proton pump inhibitor, clarithromycin (500 mg twice a day), and either amoxicillin (1,000 mg twice a day) or metronidazole (400 or 500 mg twice a day) for 14 days is more effective than treatment for 7 days.⁵²

H pylori reinfection in the general population is quite rare, with an estimated yearly rate as low as 2%.⁵³ Recurrence of the infection is a risk factor for lymphoma relapse.^17,54

Several predictors of the response of MALT lymphoma to eradication therapy have been recognized: H pylori positivity, stage I, lymphoma confined to the stomach; gastric wall invasion confined to mucosa and submucosa, and the absence of the t(11;18) translocation.

The time between H pylori eradication and complete remission of primary gastric lymphoma varies and can be longer than 12 months.⁵⁵

Chemotherapy. In a single study,⁵⁶ complete remission was achieved with oral cyclophosphamide (Cytoxan) in cases of antibiotic-refractory gastric MALT lymphoma. Comparable results were achieved after radiation therapy (see below); hence, oral monotherapy with cyclophosphamide might also be a suitable second-line therapy.⁵⁷

The regimen of cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP) has been recommended for patients with stage III and IV disease.^41,58

Rituximab (Rituxan) has been proven effective in treating t(11;18)-positive MALT lymphoma.⁵⁹

Radiation therapy. Two studies have shown a 100% complete response rate after radiation therapy with a median dose of 30 Gy.^57,60 Tsang et al⁶¹ reported complete remission in up to 90% of patients receiving radiation therapy alone, with excellent 5-year progression-free and overall survival rates of 98% and 77%, respectively.

Although surgery, radiotherapy, and chemotherapy have been used in cases in which eradication therapy failed and in more advanced stages of MALT lymphoma, there is no consensus about their use, so therapy must be individualized.

Fourth highlight point

• Antibiotic treatment for eradication of H pylori infection is the recommended treatment only for stage I low-grade MALT lymphoma.

FOLOW-UP

4. How should you follow patients with MALT lymphoma?

• Endoscopy
• H pylori testing
• Computed tomography and magnetic resonance imaging
• No surveillance required after treatment

Endoscopy is the correct answer. As initial diagnostic biopsies do not exclude aggressive lymphoma, careful endoscopic follow-up is recommended. A recommended schedule is a breath test for H pylori every 2 months in conjunction with repeat endoscopy with biopsies every 3 to 6 months for the first 2 years, and then annually.⁶²

Although H pylori may be eradicated within 1 month of drug therapy, lymphoma may take several months to disappear histologically. In patients with stage I disease with residual lymphoma after H pylori eradication therapy, a simple wait-and-watch strategy is a suitable alternative to oncologic therapy.^63,64

Local relapse may occur after many years of complete remission; thus, patients should be followed closely long-term with endoscopy and possibly endoscopic ultrasonography. ^47–49,63

Patients who fail to attain a complete remission within 12 months should undergo radiation therapy, with or without chemotherapy. The same therapy should be started as soon as possible in patients with progressive disease after antibiotic therapy. Patients negative for H pylori, patients with stage II disease, and patients with t(11;18) translocation should receive antibiotic treatment with endoscopic surveillance every 3 months.

Fifth highlight point

• Surveillance endoscopy is recommended for follow-up of MALT lymphoma.

CASE CONTINUES: HER CONDITION IMPROVES, THEN WORSENS

Computed tomography of the chest, abdomen, and pelvis reveals no evidence of additional sites of tumor. Positron emission tomography reveals increased uptake in the left tonsillar region, for which she has undergoes an ear, nose, and throat evaluation, and no pathology is found.

Due to recurrence of her marginal zone Bcell lymphoma of MALT type of the stomach, the patient is referred to an oncology service. She is treated with radiation, receiving 15 sessions of 30 Gy localized to the stomach. Three months after radiation therapy, she undergoes endoscopy again, which shows no evidence of the previously described nodules. Repeat biopsies are negative for H pylori and MALT lymphoma.

Annual surveillance endoscopy and computed tomography for the past 3 years have been negative for any tumor recurrence.

Q: Which is the most likely diagnosis?

• Pulmonary Langerhans cell histiocytosis
• Cystic fibrosis
• Pneumocystis jirovecii pneumonia
• Alpha-1 antitrypsin deficiency
• Tuberous sclerosis complex with lymphangioleiomyomatosis

A: The correct diagnosis is tuberous sclerosis complex with lymphangioleiomyomatosis. The lymphangioleiomyomatosis was suggested by the CT findings, by the recurrence of pneumothorax, and, later, by biopsy results. Lymphangioleiomyomatosis occurs in about 30% of women with the tuberous sclerosis complex.1 However, 10% to 15% of women with lymphangioleiomyomatosis do not have tuberous sclerosis complex, 2 in which case the condition is called sporadic lymphangioleiomyomatosis.

Tuberous sclerosis complex can involve the nerves (seizures, brain tumors), the lungs (lymphangioleiomyomatosis, causing pneumothorax or chylothorax), and the skin; skin lesions include facial angiofibromas (Figure 1), ash-leaf spot (Figure 2), and shagreen patch (Figure 3). It is also associated with abdominal involvement (lymphangiomyomas, renal angiomyolipomas).³

Lymphangioleiomyomatosis usually presents as spontaneous pneumothorax in women of childbearing age. After initial stabilization of pneumothorax with simple aspiration or thoracostomy, the patient should undergo ipsilateral chemical or surgical pleurodesis, as the risk of recurrent pneumothorax is greater than 70%.⁴ Single or bilateral lung transplantation has been accepted as therapy for end-stage pulmonary lymphangioleiomyomatosis, characterized by recurrent pneumothoraces and chylous pleural fluid collections causing respiratory failure (marked dyspnea, hypoxemia, and reductions in forced expiratory volume in the first second of expiration and in diffusing capacity for carbon monoxide. Recurrence of lymphangioleiomyomatosis in the allograft lung is rare.⁵ Hormone therapies such as intramuscular progesterone, oral progestins, or gonadotropin-releasing hormone agonists have been used for lymphangioleiomyomatosis (not pneumothorax), but they are no longer recommended.

Pulmonary Langerhans cell histiocytosis, cystic fibrosis, Pneumocystis jirovecii pneumonia, and alpha-1 antitrypsin deficiency have all been associated with spontaneous pneumothorax.

Pulmonary Langerhans cell histiocytosis can affect multiple systems, including lung, skin, bone, and the pituitary gland. More than 90% of patients have a history of smoking.⁶ Chest radiography reveals a reticulonodular pattern with involvement of the middle and upper lobes. Later, the nodules tend to cavitate and form contiguous cysts that may mimic lymphangioleiomyomatosis on a high-resolution chest CT.

Cystic fibrosis is most often diagnosed before the age of 3.⁷ In adults, it can present as sinus and pulmonary disease (chronic cough with sputum production, chronic sinusitis with nasal polyposis, radiographic evidence of bronchiectasis and, less commonly, pneumothorax); as a gastrointestinal tract and nutritional abnormality (pancreatic insufficiency, distal intestinal obstruction, focal biliary cirrhosis); and as male infertility.

Pneumocystis jiroveciipneumonia occurs mainly in patients on chronic immunosuppressive drugs or with immune deficiency due to HIV infection. Typical radiographic features are bilateral perihilar interstitial infiltrates that become increasingly homogeneous and diffuse as the disease progresses. Less common findings include solitary or multiple nodules, upper-lobe infiltrates in patients receiving aerosolized pentamidine (NebuPent), pneumatoceles, and pneumothorax.⁸

Alpha-1 antitrypsin is an inhibitor of neutrophil elastase. Deficiency is associated with severe, early-onset panacinar emphysema with a basilar predominance, with chronic liver disease including cirrhosis, and less commonly with panniculitis and vasculitis associated with antineutrophil cytoplasmic antibody.⁹ Coalescence of panacinar emphysema leads to the formation of bullae and is important in the development of spontaneous pneumothorax.¹⁰

The patient underwent bilateral talc pleurodesis. Lung biopsy at the same time confirmed lymphangioleiomyomatosis. One month later, the right pneumothorax recurred, and she underwent pleurodesis in the right hemithorax with tetracycline. Six months after the second pleurodesis, she was asymptomatic.