Drug Therapy

Antiplatelet and anticoagulant drugs are a cornerstone of the medical treatment of acute coronary syndrome (ACS), reducing the rates of both morbidity and death.^1–4 However, reductions in ischemic events with these drugs have uniformly been accompanied by increases in bleeding complications, which reduce the net benefit.⁵ Thus, clinical research has been exploring ways to maximize the benefit while minimizing the risk.

Here, we review the guidelines and evidence supporting the use of antiplatelet and anticoagulant drugs in ACS.

ACUTE CORONARY SYNDROMES WITH OR WITHOUT ST ELEVATION

A key distinction when treating ACS is whether the electrocardiogram shows ST-segment elevation. In cases of non-ST-elevation ACS (ie, unstable angina or non-ST-elevation myocardial infarction), a second key question is whether the initial strategy will be invasive (with angiography performed urgently) or conservative (with angiography performed later). In ST-elevation myocardial infarction, another distinction is how perfusion is to be restored, ie, with primary percutaneous coronary intervention or with thrombolysis. All these questions affect the choice of antiplatelet and anticoagulant therapy.

Figure 1 and Figure 2 summarize the guidelines of the American College of Cardiology Foundation and American Heart Association.^1,2,6,7

ANTIPLATELET THERAPY

Aspirin for all

Aspirin irreversibly acetylates the enzyme cyclooxygenase-1, blocking intraplatelet formation of thromboxane A2 (Figure 3), a potent platelet aggregator and endothelial vasoconstrictor. Large clinical trials have confirmed that aspirin reduces morbidity and mortality rates by as much as 50% in patients with ACS.⁸

The ISIS-2 trial⁹ found that giving aspirin early in the emergency department significantly reduced the mortality rate.

The Antithrombotic Trialists’ Collaboration,¹⁰ in a meta-analysis of randomized controlled trials comparing different doses of aspirin in high-risk ACS patients, found no greater benefit for doses of aspirin higher than 162 mg per day when used long-term.

How to use. During an ACS, the patient should receive one dose of aspirin 325 mg (the standard high-dose pill in the United States). This dose should be chewed, as buccal absorption results in more rapid systemic effects.¹¹

Adapted from Storey RF. New developments in antiplatelet therapy. Eur Heart J Suppl 2008; 10(suppl D):D30-D37.

Thereafter, the patient should take 81 mg per day, continued indefinitely. The 81-mg dose also applies to patients who undergo a percutaneous coronary intervention with a drug-eluting stent.⁷ Previous recommendations called for higher doses, but studies have shown that higher doses pose a higher risk of bleeding without additional clinical benefit. The use of enteric-coated aspirin does not reduce this risk,¹² and its delayed release may in fact cause aspirin “pseudoresistance.”¹³

The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, as NSAIDs reversibly bind to platelets, thus preventing aspirin from binding.¹⁴ As aspirin washes out of the body, NSAIDs may then become unbound from platelets, leaving platelets activated.

P2Y12 receptor inhibitors: Clopidogrel, prasugrel, ticagrelor

These agents bind to P2Y12 receptors on platelets to inhibit adenosine diphosphate-mediated platelet activation (Figure 3). Clopidogrel and prasugrel are irreversible prodrugs, whereas ticagrelor binds reversibly.

Clopidogrel, a prodrug

Clopidogrel has a half-life of 8 hours and a time to peak concentration of 4 hours. Eighty-five percent of a dose is inactivated by gut esterases. The remainder is metabolized primarily by the cytochrome P4502C19 enzyme system into its active metabolite.

How to use. The recommended dosage is a 600-mg bolus early in the course of ACS. This is associated with a lower rate of cardiovascular events than a 300-mg dose,2,15 although no trial has rigorously compared 300-mg vs 600-mg doses using major clinical end points. In patients presenting with ACS who cannot tolerate aspirin because of hypersensitivity or major gastrointestinal contraindication, clopidogrel is an alternative.1

The CURE trial¹⁶ randomized 12,526 patients with non-ST-elevation ACS to receive clopidogrel or placebo in addition to standard therapy. Clopidogrel was associated with a 20% lower rate of cardiovascular death, myocardial infarction, or stroke in both low- and high-risk patients regardless of whether an invasive or conservative strategy was pursued.

However, patients who underwent coronary artery bypass grafting (CABG) had a 53% higher risk of bleeding (an absolute risk of 3.3%) if they received clopidogrel within 5 days of the surgery. This has led to the practice in some centers of delaying giving clopidogrel until after the coronary anatomy has been defined. This deprives the patient of the anti-ischemic benefits conferred by giving clopidogrel early and remains a contentious issue, with most suggesting that the risk-benefit ratio still favors giving clopidogrel early, before angiography, unless there is a high likelihood that surgery will ultimately be required.17 Alternatively, one could consider using a shorter-acting intravenous glycoprotein IIb/IIIa inhibitor such as eptifibatide as a “bridge” until a definitive reperfusion strategy is chosen.

Effect of CYP2C19 variants. The CLOVIS-2 study¹⁸ assessed the effects of genetic variants on the clopidogrel concentration in 106 patients who had had a myocardial infarction. The study confirmed that patients who carry certain variants of the CYP2C19 gene attain lower plasma concentrations of clopidogrel after receiving this drug.¹⁹ This accounts for its delayed onset of action as well as its variability in response in patients who have reduced expression or inhibition of this enzyme system. Doubling the standard dose in patients who carry these variants does not appear to provide clinical benefit.²⁰

Thus, the thought is emerging that one should consider using prasugrel or ticagrelor instead of clopidogrel in patients who have these polymorphisms, though this is yet to be backed by robust clinical evidence.

Possible interaction with proton pump inhibitors. Controversy exists about whether proton pump inhibitors inhibit clopidogrel’s action. Although the US Food and Drug Administration continues to warn against the concurrent use of omeprazole and clopidogrel,²¹ an analysis of the PLATO trial²² concluded that patients with ACS who were taking proton pump inhibitors were at higher risk of ischemic events regardless of whether they had been randomized to clopidogrel or ticagrelor (a drug that acts independently of the cytochrome P450 system). This observation suggests that patients on proton pump inhibitors are generally sicker and at higher risk of ischemic events regardless of the choice of antiplatelet therapy. The use of other gastroprotective agents did not appear to mitigate these risks.

Prasugrel: Faster metabolism to active drug

Prasugrel is an irreversible P2Y12 receptor antagonist (Figure 3) that is metabolized into its active metabolite faster and in a more predictable fashion than clopidogrel.²³

The TRITON-TIMI 38 study²⁴ included 13,608 ACS patients in whom an early invasive strategy was planned and who were pretreated with prasugrel or clopidogrel in addition to standard treatment. The rate of the primary efficacy end point of death, myocardial infarction, or stroke was 19% lower in the prasugrel group. In those who underwent percutaneous coronary intervention, the incidence of in-stent thrombosis was more than 50% lower in the prasugrel group regardless of whether bare metal stents or drug-eluting stents were used.

Greater platelet inhibition came at the price of a higher incidence of serious bleeding, particularly in the subgroups of patients who were over age 75, had a history of stroke or transient ischemic attack, or weighed less than 60 kg. Prasugrel is therefore contraindicated in patients with a history of transient ischemic attack or stroke. Some suggest that a 5-mg dose can be used with caution (rather than the usual 10-mg dose) in patients over age 75 years or those who have low body weight.

The TRILOGY-ACS trial²⁵ compared prasugrel and clopidogrel in medically managed patients with high-risk non-ST-elevation ACS. It found no difference in the rates of the primary end points of cardiovascular death, myocardial infarction, or stroke at 1 year. In the prespecified subset of patients over age 75 years, the rate of bleeding end points was no higher with prasugrel 5 mg once daily than with clopidogrel.

Prasugrel’s half-life is 7 hours, and its peak antiplatelet effect is within 30 minutes after an oral dose, compared with 4 hours with clopidogrel. Therefore, if a patient with non-ST-elevation ACS is going to go to the catheterization laboratory soon, he or she should not receive prasugrel beforehand, and should receive it later only if the results of angiography indicate that CABG will not be needed urgently. This is an important consideration when using prasugrel, as the rate of surgery-related bleeding was four times higher than with clopidogrel. If possible, this drug should be withheld for at least 7 days before CABG.

Ticagrelor, a direct P2Y12 receptor inhibitor

Ticagrelor, a reversible direct inhibitor of the P2Y12 receptor, inhibits adenosine diphosphate-mediated activation and aggregation (Figure 3). It has a median time to peak concentration of 1.3 to 2 hours and a half-life of 9 hours.

The PLATO trial²⁶ enrolled 18,624 patients with ACS who were given either ticagrelor or clopidogrel in addition to standard therapy. At 12 months, the composite primary end point of myocardial infarction, death, or stroke had occurred in 16% fewer patients receiving ticagrelor than in the clopidogrel group. Analyzed separately, there were 16% fewer myocardial infarctions, 21% fewer cardiovascular deaths, and 22% fewer deaths from any cause, regardless of whether an invasive or conservative strategy was used, and with or without prior clopidogrel use. Fewer cases of stent thrombosis occurred in the ticagrelor group, and the rate of major bleeding was the same.

In a prospectively defined subgroup analysis,²⁷ ticagrelor was beneficial only in patients who received lower doses of aspirin (< 100 mg daily): the hazard ratio for the primary end point was 0.79 (95% confidence interval [CI] 0.71–0.88) in ticagrelor recipients who received low-dose aspirin and 1.45 (95% CI 1.01–2.09) in those who received high-dose aspirin.

Although this analysis is underpowered and controversial, the current evidence suggests that when used in combination with ticagrelor, the aspirin dose should be 81 mg.

Ticagrelor was also associated with a 19% higher incidence of non-CABG- or procedure-related major bleeding, more nonfatal and fatal intracranial bleeding, a higher incidence of dyspnea, and significantly more ventricular pauses.

Although ticagrelor carries no black-box warning about its use in patients with prior stroke or transient ischemic attack, the number of such patients in PLATO was small. Thus, caution should still be used in these patients.²⁸

Ticagrelor should preferably be discontinued 5 days before CABG.

Glycoprotein IIb/IIIa inhibitors: Eptifibatide, tirofiban, abciximab

Glycoprotein IIb/IIIa inhibitors are intravenous agents that act by inhibiting fibrinogen-and von Willebrand factor-mediated platelet-to-platelet cross-linkage, the final pathway of platelet aggregation (Figure 3).

Use of these agents in ACS has been decreasing, as evidence supporting their use was largely established before the era of dual antiplatelet therapy.

A meta-analysis29 of 46,374 patients with non-ST-elevation ACS found that routinely adding a glycoprotein IIb/IIIa inhibitor “upstream” as a third agent in patients receiving dual antiplatelet therapy bought only a modest (11%) reduction in death or myocardial infarction at 30 days, at the price of a 23% increase in major bleeding and no decrease in the overall rate of death. Roughly 70% of the patients were receiving dual antiplatelet therapy before cardiac catheterization.

These agents can be considered in high-risk ACS patients, such as those with ST-segment changes or elevated troponin concentrations, and in diabetic patients, on the assumption that these patients likely have a high intracoronary thrombus burden and are at higher risk of microvascular embolization.^6,30 They can also be considered at the time of primary percutaneous coronary intervention in selected patients receiving heparin.⁷

Eptifibatide

Eptifibatide is a small-molecule, short-acting glycoprotein IIb/IIIa inhibitor with a half-life of 2.5 hours. Its inhibition of platelet aggregation is reversible by stopping the drug infusion and is thought to be a result of dissociation of the drug from platelets.

The PURSUIT trial³¹ studied 10,948 patients presenting with non-ST-elevation ACS randomized to placebo, eptifibatide in a 180-μg/kg bolus followed by a 2.0-μg/kg/min infusion, or eptifibatide in a 180-μg/kg bolus followed by a 1.3-μg/kg/min infusion. Both eptifibatide groups had a 1.5% absolute reduction in the incidence of the primary end point of death or myocardial infarction, a benefit that was apparent at 96 hours and that persisted through 30 days. Bleeding was more common in the eptifibatide groups, but there was no increase in the rate of hemorrhagic stroke.

The ACUITY trial³² found that early use of eptifibatide or tirofiban had no effect on the primary outcome. (See the section below on bivalirudin for more information about the ACUITY trial.)

PARENTERAL ANTICOAGULANTS

Unfractionated heparin: A declining role

Heparin binds to antithrombin and induces a conformational change, causing rapid inhibition of factor IIa (thrombin), factor IXa, and factor Xa, thus preventing further thrombus propagation (Figure 4). An intravenous bolus of 60 units/kg produces a time to peak of 5 to 10 minutes and a half-life of 30 to 60 minutes.

Heparin can be reversed by giving protamine sulfate (1 mg per 100 units of heparin). For ACS, it is given in a bolus of 60 units/kg not exceeding 4,000 units, followed by an infusion of 12 units/kg/hour, with monitoring of the activated partial thromboplastin time every 6 hours with a goal value of 50 to 70 seconds or 1.5 to 2.5 times control.

Side effects include thrombocytopenia, heparin-induced thrombocytopenia (a distinct condition), and bleeding.

The use of unfractionated heparin was tested in ACS in the early 1990s. Oler et al³³ performed a meta-analysis of six randomized trials and found a 33% lower rate of death in patients treated with heparin in addition to aspirin in ACS, as well less reported ischemic pain.

Advantages of unfractionated heparin are that it has stood the test of time, is inexpensive, and can be rapidly reversed. The disadvantages are that it can have serious side effects, including heparin-induced thrombocytopenia, and is more likely to cause bleeding than the newer intravenous anticoagulants discussed below. Thus, its position as the main anticoagulant in ACS is being challenged.

Bivalirudin is a synthetic direct thrombin inhibitor of fluid-phase and clot-bound thrombin (Figure 4). It also inhibits platelets directly.

The ACUITY trial³² randomized 13,819 patients with moderate to high-risk ACS scheduled for invasive treatment into three treatment groups:

• Heparin (either unfractionated heparin or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor (either eptifibatide, tirofiban, or abciximab)
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

The bivalirudin-alone treatment was as sociated with noninferior rates of composite ischemia end points and significantly lower rates of major bleeding, adding up to a significant reduction in the net clinical outcome end point. An important caveat is that bivalirudin’s noninferiority was mostly in the group of patients already receiving a thienopyridine before angiography and percutaneous coronary intervention (RR 0.97 vs 1.27, P = .054). There was less major, nonmajor, minor, CABG-related, and non-CABG-related bleeding as well as need for transfusion in the bivalirudin-alone group, making bivalirudin monotherapy an attractive option in ACS patients with or without ST-segment elevation undergoing a percutaneous coronary intervention.^1,31

The ISAR-REACT trial³⁴ later compared bivalirudin alone vs unfractionated heparin and abciximab in patients with non-ST-elevation myocardial infarction undergoing percutaneous coronary intervention pretreated with aspirin and clopidogrel. The composite rate of ischemia was similar in the two treatment groups, with significantly lower rates of bleeding in the bivalirudin group.

HORIZONS-AMI³⁵ randomized 3,602 patients with ST-elevation myocardial infarction receiving aspirin and clopidogrel either to unfractionated heparin and a glycoprotein IIb/IIIa inhibitor or to bivalirudin. As in the ACUITY trial, there was no difference in ischemic end points and a 40% to 45% lower rate of major bleeding end points in the bivalirudin group, translating into an overall lower rate of death.

Enoxaparin, a low-molecular weight heparin

Enoxaparin is a low-molecular-weight heparin that inhibits factor IIa and factor Xa via antithrombin, roughly in a ratio of 1:3 (Figure 4). It has a time to peak effect of 10 minutes when given intravenously³⁶ and 3 to 5 hours when given subcutaneously.³⁷ Its half-life is 4.5 hours, but it is longer in patients with renal dysfunction, requiring dose adjustments in this population.

Its anticoagulant effect is partially reversible. If it is to be reversed between 0 and 8 hours after dosing, the recommended reversal regimen is 1 mg of protamine sulfate for every 1 mg of enoxaparin used. At 8 to 12 hours, it is 0.5 mg of protamine for every 1 mg of enoxaparin. After 12 hours, no protamine is required.

Compared with unfractionated heparin, enoxaparin has less plasma protein binding and a more consistent anticoagulant effect. Its high bioavailability also allows for subcutaneous dosing. Its greater anti-Xa activity inhibits thrombin generation more effectively, and it causes lower rates of thrombocytopenia and heparin-induced thrombocytopenia.

de Lemos et al³⁸ found that, in ACS patients in whom an early conservative approach of medical management was planned, enoxaparin was more efficacious than unfractionated heparin and caused a similar rate of bleeding.

Murphy et al,³⁹ in a meta-analysis of 12 trials in 49,088 ACS patients, also found that enoxaparin had a net clinical benefit compared with unfractionated heparin in reducing rates of myocardial infarction and death despite more bleeding.

The ESSENCE trial⁴⁰ compared enoxaparin vs unfractionated heparin in 3,171 patients with ACS. It found fewer ischemic events with enoxaparin in the early phase, more minor bleeding, but no increase in major bleeding.

The SYNERGY trial,⁴¹ in 10,027 patients with high-risk non-ST-elevation ACS undergoing percutaneous coronary intervention, compared subcutaneous enoxaparin with intravenous heparin. Enoxaparin was found to be noninferior to heparin but caused more bleeding, including major bleeding, drops in hemoglobin, and intracranial hemorrhage.

The EXTRACT-TIMI 25 trial.⁴² In patients with ST-elevation myocardial infarction, enoxaparin has been shown to be beneficial both in patients treated with fibrinolysis and in those who underwent primary percutaneous coronary intervention. The EXTRACT-TIMI 25 trial randomized 20,749 patients to receive either enoxaparin (an intravenous bolus and maintenance subcutaneous dosing based on renal function) or intravenous heparin in addition to thrombolysis within 6 hours of the diagnosis of ST-elevation myocardial infarction. Although the enoxaparin group had more bleeding end points, they had fewer primary and secondary efficacy end points, translating into an overall net clinical benefit in favor of enoxaparin.

The ATOLL trial⁴³ examined the use of enoxaparin (0.5 mg/kg intravenously) or unfractionated heparin in 910 patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (via the radial artery in 66% to 69%). Although there was a trend towards benefit in terms of the primary end point of death, myocardial infarction complications, procedure failure, and major bleeding favoring enoxaparin, it was not statistically significant (95% CI 0.68–1.01, P = .06).

However, there was a 37% to 42% lower rate of the secondary end point of death, recurrent myocardial infarction or ACS, or urgent target-vessel revascularization in the enoxaparin group, with a 40% reduction in death from any cause, death from a cardiac cause, or shock. The safety profiles of the two drugs were similar, and the net clinical benefit significantly favored enoxaparin.

Fondaparinux, a factor Xa inhibitor

Fondaparinux is a synthetic pentasaccharide that indirectly inhibits factor Xa through the action of antithrombin (Figure 4). After a 2.5-mg subcutaneous dose, it has a time to peak concentration of 2 hours and a half-life of 17 to 21 hours.

The OASIS-5 trial⁴⁴ compared fondaparinux and enoxaparin in 20,078 patients treated for non-ST-elevation ACS. Although the rates of death, myocardial infarction, and refractory ischemia at 9 days were similar for both drugs, the fondaparinux group had a significantly (almost 50%) lower rate of bleeding at 30 days, translating into significantly fewer deaths at 30 days. However, patients receiving fondaparinux who underwent percutaneous coronary intervention had a threefold higher rate of catheter-related thrombosis.

The OASIS-6 trial⁴⁵ compared fondaparinux vs usual care (placebo in those in whom unfractionated heparin was not indicated or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days) in 12,092 patients with ST-elevation myocardial infarction. There was a 1.5% absolute risk reduction in death and reinfarction without an increase in bleeding at 30 days, with trends persisting 6 months into the study. However, fondaparinux was not superior to heparin in the 3% of patients who underwent primary percutaneous coronary intervention. As in OASIS-5, there was more catheter-related thrombosis in the fondaparinux group.

Although the use of supplemental unfractionated heparin appears to have mitigated this risk, fondaparinux remains a less-than-ideal option in the era of primary percutaneous coronary intervention for ST-elevation myocardial infarction and has therefore found limited use in this group of patients. It should, however, be considered in patients for whom a conservative strategy is planned, especially if bleeding risk is deemed to be high.

ORAL ANTICOAGULANTS

Oral anticoagulants provide ischemic benefit in selected patients with ACS—at the price of a higher risk of significant bleeding.

Warfarin

Warfarin was investigated after myocardial infarction in the WARIS II,⁴⁶ CARS,⁴⁷ and CHAMP⁴⁸ trials.

WARIS II⁴⁶ looked at the use of aspirin alone, warfarin alone, and aspirin and warfarin in combination. The rates of the primary end points of stroke, nonfatal infarction, and death were lower in the warfarin group.

CARS⁴⁷ found no difference in the rate of the primary end point of fatal infarction, nonfatal ischemic stroke, or cardiovascular death with aspirin vs warfarin plus aspirin.

CHAMP⁴⁸ saw similar trends, ie, no difference in the rate of death, recurrent myocardial infarction, or stroke with warfarin plus aspirin vs aspirin alone.

All three studies showed increases in major bleeding with warfarin use.

Putting these trials into context, the significant net clinical benefit of dual antiplatelet therapy in the current era compared with the significant bleeding and questionable conflicting evidence supporting benefit with warfarin has limited its use in ACS patients.

Rivaroxaban, an oral factor Xa inhibitor

Rivaroxaban is a novel oral direct reversible factor Xa inhibitor.

The ATLAS ACS 2-TIMI 51 trial⁴⁹ found rivaroxaban 2.5 mg or 5 mg to yield a significantly lower rate of the primary outcome of cardiovascular death, myocardial infarction, ischemic stroke, and in-stent thrombosis compared with placebo, but significantly more major non-CABG bleeding and intracranial hemorrhage.

The dose used in this trial was much lower than the dose used in trials investigating the role of this drug in stroke prophylaxis in atrial fibrillation.

Apixaban, an oral factor Xa inhibitor

Apixaban is another direct factor Xa inhibitor.

The APPRAISE-2 trial⁵⁰ compared apixaban 5 mg twice daily vs placebo in ACS. There was no difference in the rate of cardiovascular death, myocardial infarction, or stroke, but there was significantly more bleeding in the apixaban group, prompting early termination of this study.

Dabigatran, an oral thrombin inhibitor

Dabigatran is an oral direct thrombin inhibitor.

The RE-DEEM trial⁵¹ compared four doses of dabigatran (50, 75, 110, and 150 mg twice daily) and placebo in ACS patients. The dabigatran groups had more major and minor bleeding, and the higher the dose, the higher the incidence of bleeding. In addition, the rates of ischemic end points were no lower with dabigatran, although this trial was not powered to show differences in clinical events.

REDUCING THE RISK OF BLEEDING

In the treatment of ACS, the benefits of restoring perfusion by preventing further propagation of thrombus and platelet aggregation come at a significant price of higher bleeding risk. This in turn increases the risk of death through various mechanisms, including shock, worsening ischemia, discontinuation of antiplatelet and anticoagulation therapy causing stent thrombosis, and anemia leading to transfusion, which propagates the underlying inflammatory milieu.⁵²

Giugliano and Braunwald⁵³ provide practical suggestions to reduce this risk, advising physicians to:

• Avoid inappropriately high dosing, particularly in patients with renal insufficiency
• Preferentially use agents that cause less bleeding (eg, bivalirudin, fondaparinux) without compromising anti-ischemic efficacy
• Minimize the concomitant use of other drugs that cause bleeding (eg, NSAIDs)
• Use drugs that protect against bleeding (eg, proton pump inhibitors) in patients at high risk
• Prevent access-site bleeding by using the radial artery, smaller sheaths, and appropriate sheath and closure device management. Indeed, the use of radial interventions in ACS has been shown to reduce access-site-related bleeding, even in patients at high risk.⁵⁴

The reduction in bleeding risk may provide future trials the opportunity to increase antithrombotic efficacy of different agents with goals of reducing ischemic end points.

Antiplatelet and anticoagulant drugs are a cornerstone of the medical treatment of acute coronary syndrome (ACS), reducing the rates of both morbidity and death.^1–4 However, reductions in ischemic events with these drugs have uniformly been accompanied by increases in bleeding complications, which reduce the net benefit.⁵ Thus, clinical research has been exploring ways to maximize the benefit while minimizing the risk.

Here, we review the guidelines and evidence supporting the use of antiplatelet and anticoagulant drugs in ACS.

ACUTE CORONARY SYNDROMES WITH OR WITHOUT ST ELEVATION

A key distinction when treating ACS is whether the electrocardiogram shows ST-segment elevation. In cases of non-ST-elevation ACS (ie, unstable angina or non-ST-elevation myocardial infarction), a second key question is whether the initial strategy will be invasive (with angiography performed urgently) or conservative (with angiography performed later). In ST-elevation myocardial infarction, another distinction is how perfusion is to be restored, ie, with primary percutaneous coronary intervention or with thrombolysis. All these questions affect the choice of antiplatelet and anticoagulant therapy.

Figure 1 and Figure 2 summarize the guidelines of the American College of Cardiology Foundation and American Heart Association.^1,2,6,7

ANTIPLATELET THERAPY

Aspirin for all

Aspirin irreversibly acetylates the enzyme cyclooxygenase-1, blocking intraplatelet formation of thromboxane A2 (Figure 3), a potent platelet aggregator and endothelial vasoconstrictor. Large clinical trials have confirmed that aspirin reduces morbidity and mortality rates by as much as 50% in patients with ACS.⁸

The ISIS-2 trial⁹ found that giving aspirin early in the emergency department significantly reduced the mortality rate.

The Antithrombotic Trialists’ Collaboration,¹⁰ in a meta-analysis of randomized controlled trials comparing different doses of aspirin in high-risk ACS patients, found no greater benefit for doses of aspirin higher than 162 mg per day when used long-term.

How to use. During an ACS, the patient should receive one dose of aspirin 325 mg (the standard high-dose pill in the United States). This dose should be chewed, as buccal absorption results in more rapid systemic effects.¹¹

Adapted from Storey RF. New developments in antiplatelet therapy. Eur Heart J Suppl 2008; 10(suppl D):D30-D37.

Thereafter, the patient should take 81 mg per day, continued indefinitely. The 81-mg dose also applies to patients who undergo a percutaneous coronary intervention with a drug-eluting stent.⁷ Previous recommendations called for higher doses, but studies have shown that higher doses pose a higher risk of bleeding without additional clinical benefit. The use of enteric-coated aspirin does not reduce this risk,¹² and its delayed release may in fact cause aspirin “pseudoresistance.”¹³

The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, as NSAIDs reversibly bind to platelets, thus preventing aspirin from binding.¹⁴ As aspirin washes out of the body, NSAIDs may then become unbound from platelets, leaving platelets activated.

P2Y12 receptor inhibitors: Clopidogrel, prasugrel, ticagrelor

These agents bind to P2Y12 receptors on platelets to inhibit adenosine diphosphate-mediated platelet activation (Figure 3). Clopidogrel and prasugrel are irreversible prodrugs, whereas ticagrelor binds reversibly.

Clopidogrel, a prodrug

Clopidogrel has a half-life of 8 hours and a time to peak concentration of 4 hours. Eighty-five percent of a dose is inactivated by gut esterases. The remainder is metabolized primarily by the cytochrome P4502C19 enzyme system into its active metabolite.

How to use. The recommended dosage is a 600-mg bolus early in the course of ACS. This is associated with a lower rate of cardiovascular events than a 300-mg dose,2,15 although no trial has rigorously compared 300-mg vs 600-mg doses using major clinical end points. In patients presenting with ACS who cannot tolerate aspirin because of hypersensitivity or major gastrointestinal contraindication, clopidogrel is an alternative.1

The CURE trial¹⁶ randomized 12,526 patients with non-ST-elevation ACS to receive clopidogrel or placebo in addition to standard therapy. Clopidogrel was associated with a 20% lower rate of cardiovascular death, myocardial infarction, or stroke in both low- and high-risk patients regardless of whether an invasive or conservative strategy was pursued.

However, patients who underwent coronary artery bypass grafting (CABG) had a 53% higher risk of bleeding (an absolute risk of 3.3%) if they received clopidogrel within 5 days of the surgery. This has led to the practice in some centers of delaying giving clopidogrel until after the coronary anatomy has been defined. This deprives the patient of the anti-ischemic benefits conferred by giving clopidogrel early and remains a contentious issue, with most suggesting that the risk-benefit ratio still favors giving clopidogrel early, before angiography, unless there is a high likelihood that surgery will ultimately be required.17 Alternatively, one could consider using a shorter-acting intravenous glycoprotein IIb/IIIa inhibitor such as eptifibatide as a “bridge” until a definitive reperfusion strategy is chosen.

Effect of CYP2C19 variants. The CLOVIS-2 study¹⁸ assessed the effects of genetic variants on the clopidogrel concentration in 106 patients who had had a myocardial infarction. The study confirmed that patients who carry certain variants of the CYP2C19 gene attain lower plasma concentrations of clopidogrel after receiving this drug.¹⁹ This accounts for its delayed onset of action as well as its variability in response in patients who have reduced expression or inhibition of this enzyme system. Doubling the standard dose in patients who carry these variants does not appear to provide clinical benefit.²⁰

Thus, the thought is emerging that one should consider using prasugrel or ticagrelor instead of clopidogrel in patients who have these polymorphisms, though this is yet to be backed by robust clinical evidence.

Possible interaction with proton pump inhibitors. Controversy exists about whether proton pump inhibitors inhibit clopidogrel’s action. Although the US Food and Drug Administration continues to warn against the concurrent use of omeprazole and clopidogrel,²¹ an analysis of the PLATO trial²² concluded that patients with ACS who were taking proton pump inhibitors were at higher risk of ischemic events regardless of whether they had been randomized to clopidogrel or ticagrelor (a drug that acts independently of the cytochrome P450 system). This observation suggests that patients on proton pump inhibitors are generally sicker and at higher risk of ischemic events regardless of the choice of antiplatelet therapy. The use of other gastroprotective agents did not appear to mitigate these risks.

Prasugrel: Faster metabolism to active drug

Prasugrel is an irreversible P2Y12 receptor antagonist (Figure 3) that is metabolized into its active metabolite faster and in a more predictable fashion than clopidogrel.²³

The TRITON-TIMI 38 study²⁴ included 13,608 ACS patients in whom an early invasive strategy was planned and who were pretreated with prasugrel or clopidogrel in addition to standard treatment. The rate of the primary efficacy end point of death, myocardial infarction, or stroke was 19% lower in the prasugrel group. In those who underwent percutaneous coronary intervention, the incidence of in-stent thrombosis was more than 50% lower in the prasugrel group regardless of whether bare metal stents or drug-eluting stents were used.

Greater platelet inhibition came at the price of a higher incidence of serious bleeding, particularly in the subgroups of patients who were over age 75, had a history of stroke or transient ischemic attack, or weighed less than 60 kg. Prasugrel is therefore contraindicated in patients with a history of transient ischemic attack or stroke. Some suggest that a 5-mg dose can be used with caution (rather than the usual 10-mg dose) in patients over age 75 years or those who have low body weight.

The TRILOGY-ACS trial²⁵ compared prasugrel and clopidogrel in medically managed patients with high-risk non-ST-elevation ACS. It found no difference in the rates of the primary end points of cardiovascular death, myocardial infarction, or stroke at 1 year. In the prespecified subset of patients over age 75 years, the rate of bleeding end points was no higher with prasugrel 5 mg once daily than with clopidogrel.

Prasugrel’s half-life is 7 hours, and its peak antiplatelet effect is within 30 minutes after an oral dose, compared with 4 hours with clopidogrel. Therefore, if a patient with non-ST-elevation ACS is going to go to the catheterization laboratory soon, he or she should not receive prasugrel beforehand, and should receive it later only if the results of angiography indicate that CABG will not be needed urgently. This is an important consideration when using prasugrel, as the rate of surgery-related bleeding was four times higher than with clopidogrel. If possible, this drug should be withheld for at least 7 days before CABG.

Ticagrelor, a direct P2Y12 receptor inhibitor

Ticagrelor, a reversible direct inhibitor of the P2Y12 receptor, inhibits adenosine diphosphate-mediated activation and aggregation (Figure 3). It has a median time to peak concentration of 1.3 to 2 hours and a half-life of 9 hours.

The PLATO trial²⁶ enrolled 18,624 patients with ACS who were given either ticagrelor or clopidogrel in addition to standard therapy. At 12 months, the composite primary end point of myocardial infarction, death, or stroke had occurred in 16% fewer patients receiving ticagrelor than in the clopidogrel group. Analyzed separately, there were 16% fewer myocardial infarctions, 21% fewer cardiovascular deaths, and 22% fewer deaths from any cause, regardless of whether an invasive or conservative strategy was used, and with or without prior clopidogrel use. Fewer cases of stent thrombosis occurred in the ticagrelor group, and the rate of major bleeding was the same.

In a prospectively defined subgroup analysis,²⁷ ticagrelor was beneficial only in patients who received lower doses of aspirin (< 100 mg daily): the hazard ratio for the primary end point was 0.79 (95% confidence interval [CI] 0.71–0.88) in ticagrelor recipients who received low-dose aspirin and 1.45 (95% CI 1.01–2.09) in those who received high-dose aspirin.

Although this analysis is underpowered and controversial, the current evidence suggests that when used in combination with ticagrelor, the aspirin dose should be 81 mg.

Ticagrelor was also associated with a 19% higher incidence of non-CABG- or procedure-related major bleeding, more nonfatal and fatal intracranial bleeding, a higher incidence of dyspnea, and significantly more ventricular pauses.

Although ticagrelor carries no black-box warning about its use in patients with prior stroke or transient ischemic attack, the number of such patients in PLATO was small. Thus, caution should still be used in these patients.²⁸

Ticagrelor should preferably be discontinued 5 days before CABG.

Glycoprotein IIb/IIIa inhibitors: Eptifibatide, tirofiban, abciximab

Glycoprotein IIb/IIIa inhibitors are intravenous agents that act by inhibiting fibrinogen-and von Willebrand factor-mediated platelet-to-platelet cross-linkage, the final pathway of platelet aggregation (Figure 3).

Use of these agents in ACS has been decreasing, as evidence supporting their use was largely established before the era of dual antiplatelet therapy.

A meta-analysis29 of 46,374 patients with non-ST-elevation ACS found that routinely adding a glycoprotein IIb/IIIa inhibitor “upstream” as a third agent in patients receiving dual antiplatelet therapy bought only a modest (11%) reduction in death or myocardial infarction at 30 days, at the price of a 23% increase in major bleeding and no decrease in the overall rate of death. Roughly 70% of the patients were receiving dual antiplatelet therapy before cardiac catheterization.

These agents can be considered in high-risk ACS patients, such as those with ST-segment changes or elevated troponin concentrations, and in diabetic patients, on the assumption that these patients likely have a high intracoronary thrombus burden and are at higher risk of microvascular embolization.^6,30 They can also be considered at the time of primary percutaneous coronary intervention in selected patients receiving heparin.⁷

Eptifibatide

Eptifibatide is a small-molecule, short-acting glycoprotein IIb/IIIa inhibitor with a half-life of 2.5 hours. Its inhibition of platelet aggregation is reversible by stopping the drug infusion and is thought to be a result of dissociation of the drug from platelets.

The PURSUIT trial³¹ studied 10,948 patients presenting with non-ST-elevation ACS randomized to placebo, eptifibatide in a 180-μg/kg bolus followed by a 2.0-μg/kg/min infusion, or eptifibatide in a 180-μg/kg bolus followed by a 1.3-μg/kg/min infusion. Both eptifibatide groups had a 1.5% absolute reduction in the incidence of the primary end point of death or myocardial infarction, a benefit that was apparent at 96 hours and that persisted through 30 days. Bleeding was more common in the eptifibatide groups, but there was no increase in the rate of hemorrhagic stroke.

The ACUITY trial³² found that early use of eptifibatide or tirofiban had no effect on the primary outcome. (See the section below on bivalirudin for more information about the ACUITY trial.)

PARENTERAL ANTICOAGULANTS

Unfractionated heparin: A declining role

Heparin binds to antithrombin and induces a conformational change, causing rapid inhibition of factor IIa (thrombin), factor IXa, and factor Xa, thus preventing further thrombus propagation (Figure 4). An intravenous bolus of 60 units/kg produces a time to peak of 5 to 10 minutes and a half-life of 30 to 60 minutes.

Heparin can be reversed by giving protamine sulfate (1 mg per 100 units of heparin). For ACS, it is given in a bolus of 60 units/kg not exceeding 4,000 units, followed by an infusion of 12 units/kg/hour, with monitoring of the activated partial thromboplastin time every 6 hours with a goal value of 50 to 70 seconds or 1.5 to 2.5 times control.

Side effects include thrombocytopenia, heparin-induced thrombocytopenia (a distinct condition), and bleeding.

The use of unfractionated heparin was tested in ACS in the early 1990s. Oler et al³³ performed a meta-analysis of six randomized trials and found a 33% lower rate of death in patients treated with heparin in addition to aspirin in ACS, as well less reported ischemic pain.

Advantages of unfractionated heparin are that it has stood the test of time, is inexpensive, and can be rapidly reversed. The disadvantages are that it can have serious side effects, including heparin-induced thrombocytopenia, and is more likely to cause bleeding than the newer intravenous anticoagulants discussed below. Thus, its position as the main anticoagulant in ACS is being challenged.

Bivalirudin is a synthetic direct thrombin inhibitor of fluid-phase and clot-bound thrombin (Figure 4). It also inhibits platelets directly.

The ACUITY trial³² randomized 13,819 patients with moderate to high-risk ACS scheduled for invasive treatment into three treatment groups:

• Heparin (either unfractionated heparin or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor (either eptifibatide, tirofiban, or abciximab)
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

The bivalirudin-alone treatment was as sociated with noninferior rates of composite ischemia end points and significantly lower rates of major bleeding, adding up to a significant reduction in the net clinical outcome end point. An important caveat is that bivalirudin’s noninferiority was mostly in the group of patients already receiving a thienopyridine before angiography and percutaneous coronary intervention (RR 0.97 vs 1.27, P = .054). There was less major, nonmajor, minor, CABG-related, and non-CABG-related bleeding as well as need for transfusion in the bivalirudin-alone group, making bivalirudin monotherapy an attractive option in ACS patients with or without ST-segment elevation undergoing a percutaneous coronary intervention.^1,31

The ISAR-REACT trial³⁴ later compared bivalirudin alone vs unfractionated heparin and abciximab in patients with non-ST-elevation myocardial infarction undergoing percutaneous coronary intervention pretreated with aspirin and clopidogrel. The composite rate of ischemia was similar in the two treatment groups, with significantly lower rates of bleeding in the bivalirudin group.

HORIZONS-AMI³⁵ randomized 3,602 patients with ST-elevation myocardial infarction receiving aspirin and clopidogrel either to unfractionated heparin and a glycoprotein IIb/IIIa inhibitor or to bivalirudin. As in the ACUITY trial, there was no difference in ischemic end points and a 40% to 45% lower rate of major bleeding end points in the bivalirudin group, translating into an overall lower rate of death.

Enoxaparin, a low-molecular weight heparin

Enoxaparin is a low-molecular-weight heparin that inhibits factor IIa and factor Xa via antithrombin, roughly in a ratio of 1:3 (Figure 4). It has a time to peak effect of 10 minutes when given intravenously³⁶ and 3 to 5 hours when given subcutaneously.³⁷ Its half-life is 4.5 hours, but it is longer in patients with renal dysfunction, requiring dose adjustments in this population.

Its anticoagulant effect is partially reversible. If it is to be reversed between 0 and 8 hours after dosing, the recommended reversal regimen is 1 mg of protamine sulfate for every 1 mg of enoxaparin used. At 8 to 12 hours, it is 0.5 mg of protamine for every 1 mg of enoxaparin. After 12 hours, no protamine is required.

Compared with unfractionated heparin, enoxaparin has less plasma protein binding and a more consistent anticoagulant effect. Its high bioavailability also allows for subcutaneous dosing. Its greater anti-Xa activity inhibits thrombin generation more effectively, and it causes lower rates of thrombocytopenia and heparin-induced thrombocytopenia.

de Lemos et al³⁸ found that, in ACS patients in whom an early conservative approach of medical management was planned, enoxaparin was more efficacious than unfractionated heparin and caused a similar rate of bleeding.

Murphy et al,³⁹ in a meta-analysis of 12 trials in 49,088 ACS patients, also found that enoxaparin had a net clinical benefit compared with unfractionated heparin in reducing rates of myocardial infarction and death despite more bleeding.

The ESSENCE trial⁴⁰ compared enoxaparin vs unfractionated heparin in 3,171 patients with ACS. It found fewer ischemic events with enoxaparin in the early phase, more minor bleeding, but no increase in major bleeding.

The SYNERGY trial,⁴¹ in 10,027 patients with high-risk non-ST-elevation ACS undergoing percutaneous coronary intervention, compared subcutaneous enoxaparin with intravenous heparin. Enoxaparin was found to be noninferior to heparin but caused more bleeding, including major bleeding, drops in hemoglobin, and intracranial hemorrhage.

The EXTRACT-TIMI 25 trial.⁴² In patients with ST-elevation myocardial infarction, enoxaparin has been shown to be beneficial both in patients treated with fibrinolysis and in those who underwent primary percutaneous coronary intervention. The EXTRACT-TIMI 25 trial randomized 20,749 patients to receive either enoxaparin (an intravenous bolus and maintenance subcutaneous dosing based on renal function) or intravenous heparin in addition to thrombolysis within 6 hours of the diagnosis of ST-elevation myocardial infarction. Although the enoxaparin group had more bleeding end points, they had fewer primary and secondary efficacy end points, translating into an overall net clinical benefit in favor of enoxaparin.

The ATOLL trial⁴³ examined the use of enoxaparin (0.5 mg/kg intravenously) or unfractionated heparin in 910 patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (via the radial artery in 66% to 69%). Although there was a trend towards benefit in terms of the primary end point of death, myocardial infarction complications, procedure failure, and major bleeding favoring enoxaparin, it was not statistically significant (95% CI 0.68–1.01, P = .06).

However, there was a 37% to 42% lower rate of the secondary end point of death, recurrent myocardial infarction or ACS, or urgent target-vessel revascularization in the enoxaparin group, with a 40% reduction in death from any cause, death from a cardiac cause, or shock. The safety profiles of the two drugs were similar, and the net clinical benefit significantly favored enoxaparin.

Fondaparinux, a factor Xa inhibitor

Fondaparinux is a synthetic pentasaccharide that indirectly inhibits factor Xa through the action of antithrombin (Figure 4). After a 2.5-mg subcutaneous dose, it has a time to peak concentration of 2 hours and a half-life of 17 to 21 hours.

The OASIS-5 trial⁴⁴ compared fondaparinux and enoxaparin in 20,078 patients treated for non-ST-elevation ACS. Although the rates of death, myocardial infarction, and refractory ischemia at 9 days were similar for both drugs, the fondaparinux group had a significantly (almost 50%) lower rate of bleeding at 30 days, translating into significantly fewer deaths at 30 days. However, patients receiving fondaparinux who underwent percutaneous coronary intervention had a threefold higher rate of catheter-related thrombosis.

The OASIS-6 trial⁴⁵ compared fondaparinux vs usual care (placebo in those in whom unfractionated heparin was not indicated or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days) in 12,092 patients with ST-elevation myocardial infarction. There was a 1.5% absolute risk reduction in death and reinfarction without an increase in bleeding at 30 days, with trends persisting 6 months into the study. However, fondaparinux was not superior to heparin in the 3% of patients who underwent primary percutaneous coronary intervention. As in OASIS-5, there was more catheter-related thrombosis in the fondaparinux group.

Although the use of supplemental unfractionated heparin appears to have mitigated this risk, fondaparinux remains a less-than-ideal option in the era of primary percutaneous coronary intervention for ST-elevation myocardial infarction and has therefore found limited use in this group of patients. It should, however, be considered in patients for whom a conservative strategy is planned, especially if bleeding risk is deemed to be high.

ORAL ANTICOAGULANTS

Oral anticoagulants provide ischemic benefit in selected patients with ACS—at the price of a higher risk of significant bleeding.

Warfarin

Warfarin was investigated after myocardial infarction in the WARIS II,⁴⁶ CARS,⁴⁷ and CHAMP⁴⁸ trials.

WARIS II⁴⁶ looked at the use of aspirin alone, warfarin alone, and aspirin and warfarin in combination. The rates of the primary end points of stroke, nonfatal infarction, and death were lower in the warfarin group.

CARS⁴⁷ found no difference in the rate of the primary end point of fatal infarction, nonfatal ischemic stroke, or cardiovascular death with aspirin vs warfarin plus aspirin.

CHAMP⁴⁸ saw similar trends, ie, no difference in the rate of death, recurrent myocardial infarction, or stroke with warfarin plus aspirin vs aspirin alone.

All three studies showed increases in major bleeding with warfarin use.

Putting these trials into context, the significant net clinical benefit of dual antiplatelet therapy in the current era compared with the significant bleeding and questionable conflicting evidence supporting benefit with warfarin has limited its use in ACS patients.

Rivaroxaban, an oral factor Xa inhibitor

Rivaroxaban is a novel oral direct reversible factor Xa inhibitor.

The ATLAS ACS 2-TIMI 51 trial⁴⁹ found rivaroxaban 2.5 mg or 5 mg to yield a significantly lower rate of the primary outcome of cardiovascular death, myocardial infarction, ischemic stroke, and in-stent thrombosis compared with placebo, but significantly more major non-CABG bleeding and intracranial hemorrhage.

The dose used in this trial was much lower than the dose used in trials investigating the role of this drug in stroke prophylaxis in atrial fibrillation.

Apixaban, an oral factor Xa inhibitor

Apixaban is another direct factor Xa inhibitor.

The APPRAISE-2 trial⁵⁰ compared apixaban 5 mg twice daily vs placebo in ACS. There was no difference in the rate of cardiovascular death, myocardial infarction, or stroke, but there was significantly more bleeding in the apixaban group, prompting early termination of this study.

Dabigatran, an oral thrombin inhibitor

Dabigatran is an oral direct thrombin inhibitor.

The RE-DEEM trial⁵¹ compared four doses of dabigatran (50, 75, 110, and 150 mg twice daily) and placebo in ACS patients. The dabigatran groups had more major and minor bleeding, and the higher the dose, the higher the incidence of bleeding. In addition, the rates of ischemic end points were no lower with dabigatran, although this trial was not powered to show differences in clinical events.

REDUCING THE RISK OF BLEEDING

In the treatment of ACS, the benefits of restoring perfusion by preventing further propagation of thrombus and platelet aggregation come at a significant price of higher bleeding risk. This in turn increases the risk of death through various mechanisms, including shock, worsening ischemia, discontinuation of antiplatelet and anticoagulation therapy causing stent thrombosis, and anemia leading to transfusion, which propagates the underlying inflammatory milieu.⁵²

Giugliano and Braunwald⁵³ provide practical suggestions to reduce this risk, advising physicians to:

• Avoid inappropriately high dosing, particularly in patients with renal insufficiency
• Preferentially use agents that cause less bleeding (eg, bivalirudin, fondaparinux) without compromising anti-ischemic efficacy
• Minimize the concomitant use of other drugs that cause bleeding (eg, NSAIDs)
• Use drugs that protect against bleeding (eg, proton pump inhibitors) in patients at high risk
• Prevent access-site bleeding by using the radial artery, smaller sheaths, and appropriate sheath and closure device management. Indeed, the use of radial interventions in ACS has been shown to reduce access-site-related bleeding, even in patients at high risk.⁵⁴

The reduction in bleeding risk may provide future trials the opportunity to increase antithrombotic efficacy of different agents with goals of reducing ischemic end points.

Antiplatelet and anticoagulant drugs are a cornerstone of the medical treatment of acute coronary syndrome (ACS), reducing the rates of both morbidity and death.^1–4 However, reductions in ischemic events with these drugs have uniformly been accompanied by increases in bleeding complications, which reduce the net benefit.⁵ Thus, clinical research has been exploring ways to maximize the benefit while minimizing the risk.

Here, we review the guidelines and evidence supporting the use of antiplatelet and anticoagulant drugs in ACS.

ACUTE CORONARY SYNDROMES WITH OR WITHOUT ST ELEVATION

A key distinction when treating ACS is whether the electrocardiogram shows ST-segment elevation. In cases of non-ST-elevation ACS (ie, unstable angina or non-ST-elevation myocardial infarction), a second key question is whether the initial strategy will be invasive (with angiography performed urgently) or conservative (with angiography performed later). In ST-elevation myocardial infarction, another distinction is how perfusion is to be restored, ie, with primary percutaneous coronary intervention or with thrombolysis. All these questions affect the choice of antiplatelet and anticoagulant therapy.

Figure 1 and Figure 2 summarize the guidelines of the American College of Cardiology Foundation and American Heart Association.^1,2,6,7

ANTIPLATELET THERAPY

Aspirin for all

Aspirin irreversibly acetylates the enzyme cyclooxygenase-1, blocking intraplatelet formation of thromboxane A2 (Figure 3), a potent platelet aggregator and endothelial vasoconstrictor. Large clinical trials have confirmed that aspirin reduces morbidity and mortality rates by as much as 50% in patients with ACS.⁸

The ISIS-2 trial⁹ found that giving aspirin early in the emergency department significantly reduced the mortality rate.

The Antithrombotic Trialists’ Collaboration,¹⁰ in a meta-analysis of randomized controlled trials comparing different doses of aspirin in high-risk ACS patients, found no greater benefit for doses of aspirin higher than 162 mg per day when used long-term.

How to use. During an ACS, the patient should receive one dose of aspirin 325 mg (the standard high-dose pill in the United States). This dose should be chewed, as buccal absorption results in more rapid systemic effects.¹¹

Adapted from Storey RF. New developments in antiplatelet therapy. Eur Heart J Suppl 2008; 10(suppl D):D30-D37.

Thereafter, the patient should take 81 mg per day, continued indefinitely. The 81-mg dose also applies to patients who undergo a percutaneous coronary intervention with a drug-eluting stent.⁷ Previous recommendations called for higher doses, but studies have shown that higher doses pose a higher risk of bleeding without additional clinical benefit. The use of enteric-coated aspirin does not reduce this risk,¹² and its delayed release may in fact cause aspirin “pseudoresistance.”¹³

The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, as NSAIDs reversibly bind to platelets, thus preventing aspirin from binding.¹⁴ As aspirin washes out of the body, NSAIDs may then become unbound from platelets, leaving platelets activated.

P2Y12 receptor inhibitors: Clopidogrel, prasugrel, ticagrelor

These agents bind to P2Y12 receptors on platelets to inhibit adenosine diphosphate-mediated platelet activation (Figure 3). Clopidogrel and prasugrel are irreversible prodrugs, whereas ticagrelor binds reversibly.

Clopidogrel, a prodrug

Clopidogrel has a half-life of 8 hours and a time to peak concentration of 4 hours. Eighty-five percent of a dose is inactivated by gut esterases. The remainder is metabolized primarily by the cytochrome P4502C19 enzyme system into its active metabolite.

How to use. The recommended dosage is a 600-mg bolus early in the course of ACS. This is associated with a lower rate of cardiovascular events than a 300-mg dose,2,15 although no trial has rigorously compared 300-mg vs 600-mg doses using major clinical end points. In patients presenting with ACS who cannot tolerate aspirin because of hypersensitivity or major gastrointestinal contraindication, clopidogrel is an alternative.1

The CURE trial¹⁶ randomized 12,526 patients with non-ST-elevation ACS to receive clopidogrel or placebo in addition to standard therapy. Clopidogrel was associated with a 20% lower rate of cardiovascular death, myocardial infarction, or stroke in both low- and high-risk patients regardless of whether an invasive or conservative strategy was pursued.

However, patients who underwent coronary artery bypass grafting (CABG) had a 53% higher risk of bleeding (an absolute risk of 3.3%) if they received clopidogrel within 5 days of the surgery. This has led to the practice in some centers of delaying giving clopidogrel until after the coronary anatomy has been defined. This deprives the patient of the anti-ischemic benefits conferred by giving clopidogrel early and remains a contentious issue, with most suggesting that the risk-benefit ratio still favors giving clopidogrel early, before angiography, unless there is a high likelihood that surgery will ultimately be required.17 Alternatively, one could consider using a shorter-acting intravenous glycoprotein IIb/IIIa inhibitor such as eptifibatide as a “bridge” until a definitive reperfusion strategy is chosen.

Effect of CYP2C19 variants. The CLOVIS-2 study¹⁸ assessed the effects of genetic variants on the clopidogrel concentration in 106 patients who had had a myocardial infarction. The study confirmed that patients who carry certain variants of the CYP2C19 gene attain lower plasma concentrations of clopidogrel after receiving this drug.¹⁹ This accounts for its delayed onset of action as well as its variability in response in patients who have reduced expression or inhibition of this enzyme system. Doubling the standard dose in patients who carry these variants does not appear to provide clinical benefit.²⁰

Thus, the thought is emerging that one should consider using prasugrel or ticagrelor instead of clopidogrel in patients who have these polymorphisms, though this is yet to be backed by robust clinical evidence.

Possible interaction with proton pump inhibitors. Controversy exists about whether proton pump inhibitors inhibit clopidogrel’s action. Although the US Food and Drug Administration continues to warn against the concurrent use of omeprazole and clopidogrel,²¹ an analysis of the PLATO trial²² concluded that patients with ACS who were taking proton pump inhibitors were at higher risk of ischemic events regardless of whether they had been randomized to clopidogrel or ticagrelor (a drug that acts independently of the cytochrome P450 system). This observation suggests that patients on proton pump inhibitors are generally sicker and at higher risk of ischemic events regardless of the choice of antiplatelet therapy. The use of other gastroprotective agents did not appear to mitigate these risks.

Prasugrel: Faster metabolism to active drug

Prasugrel is an irreversible P2Y12 receptor antagonist (Figure 3) that is metabolized into its active metabolite faster and in a more predictable fashion than clopidogrel.²³

The TRITON-TIMI 38 study²⁴ included 13,608 ACS patients in whom an early invasive strategy was planned and who were pretreated with prasugrel or clopidogrel in addition to standard treatment. The rate of the primary efficacy end point of death, myocardial infarction, or stroke was 19% lower in the prasugrel group. In those who underwent percutaneous coronary intervention, the incidence of in-stent thrombosis was more than 50% lower in the prasugrel group regardless of whether bare metal stents or drug-eluting stents were used.

Greater platelet inhibition came at the price of a higher incidence of serious bleeding, particularly in the subgroups of patients who were over age 75, had a history of stroke or transient ischemic attack, or weighed less than 60 kg. Prasugrel is therefore contraindicated in patients with a history of transient ischemic attack or stroke. Some suggest that a 5-mg dose can be used with caution (rather than the usual 10-mg dose) in patients over age 75 years or those who have low body weight.

The TRILOGY-ACS trial²⁵ compared prasugrel and clopidogrel in medically managed patients with high-risk non-ST-elevation ACS. It found no difference in the rates of the primary end points of cardiovascular death, myocardial infarction, or stroke at 1 year. In the prespecified subset of patients over age 75 years, the rate of bleeding end points was no higher with prasugrel 5 mg once daily than with clopidogrel.

Prasugrel’s half-life is 7 hours, and its peak antiplatelet effect is within 30 minutes after an oral dose, compared with 4 hours with clopidogrel. Therefore, if a patient with non-ST-elevation ACS is going to go to the catheterization laboratory soon, he or she should not receive prasugrel beforehand, and should receive it later only if the results of angiography indicate that CABG will not be needed urgently. This is an important consideration when using prasugrel, as the rate of surgery-related bleeding was four times higher than with clopidogrel. If possible, this drug should be withheld for at least 7 days before CABG.

Ticagrelor, a direct P2Y12 receptor inhibitor

Ticagrelor, a reversible direct inhibitor of the P2Y12 receptor, inhibits adenosine diphosphate-mediated activation and aggregation (Figure 3). It has a median time to peak concentration of 1.3 to 2 hours and a half-life of 9 hours.

The PLATO trial²⁶ enrolled 18,624 patients with ACS who were given either ticagrelor or clopidogrel in addition to standard therapy. At 12 months, the composite primary end point of myocardial infarction, death, or stroke had occurred in 16% fewer patients receiving ticagrelor than in the clopidogrel group. Analyzed separately, there were 16% fewer myocardial infarctions, 21% fewer cardiovascular deaths, and 22% fewer deaths from any cause, regardless of whether an invasive or conservative strategy was used, and with or without prior clopidogrel use. Fewer cases of stent thrombosis occurred in the ticagrelor group, and the rate of major bleeding was the same.

In a prospectively defined subgroup analysis,²⁷ ticagrelor was beneficial only in patients who received lower doses of aspirin (< 100 mg daily): the hazard ratio for the primary end point was 0.79 (95% confidence interval [CI] 0.71–0.88) in ticagrelor recipients who received low-dose aspirin and 1.45 (95% CI 1.01–2.09) in those who received high-dose aspirin.

Although this analysis is underpowered and controversial, the current evidence suggests that when used in combination with ticagrelor, the aspirin dose should be 81 mg.

Ticagrelor was also associated with a 19% higher incidence of non-CABG- or procedure-related major bleeding, more nonfatal and fatal intracranial bleeding, a higher incidence of dyspnea, and significantly more ventricular pauses.

Although ticagrelor carries no black-box warning about its use in patients with prior stroke or transient ischemic attack, the number of such patients in PLATO was small. Thus, caution should still be used in these patients.²⁸

Ticagrelor should preferably be discontinued 5 days before CABG.

Glycoprotein IIb/IIIa inhibitors: Eptifibatide, tirofiban, abciximab

Glycoprotein IIb/IIIa inhibitors are intravenous agents that act by inhibiting fibrinogen-and von Willebrand factor-mediated platelet-to-platelet cross-linkage, the final pathway of platelet aggregation (Figure 3).

Use of these agents in ACS has been decreasing, as evidence supporting their use was largely established before the era of dual antiplatelet therapy.

A meta-analysis29 of 46,374 patients with non-ST-elevation ACS found that routinely adding a glycoprotein IIb/IIIa inhibitor “upstream” as a third agent in patients receiving dual antiplatelet therapy bought only a modest (11%) reduction in death or myocardial infarction at 30 days, at the price of a 23% increase in major bleeding and no decrease in the overall rate of death. Roughly 70% of the patients were receiving dual antiplatelet therapy before cardiac catheterization.

These agents can be considered in high-risk ACS patients, such as those with ST-segment changes or elevated troponin concentrations, and in diabetic patients, on the assumption that these patients likely have a high intracoronary thrombus burden and are at higher risk of microvascular embolization.^6,30 They can also be considered at the time of primary percutaneous coronary intervention in selected patients receiving heparin.⁷

Eptifibatide

Eptifibatide is a small-molecule, short-acting glycoprotein IIb/IIIa inhibitor with a half-life of 2.5 hours. Its inhibition of platelet aggregation is reversible by stopping the drug infusion and is thought to be a result of dissociation of the drug from platelets.

The PURSUIT trial³¹ studied 10,948 patients presenting with non-ST-elevation ACS randomized to placebo, eptifibatide in a 180-μg/kg bolus followed by a 2.0-μg/kg/min infusion, or eptifibatide in a 180-μg/kg bolus followed by a 1.3-μg/kg/min infusion. Both eptifibatide groups had a 1.5% absolute reduction in the incidence of the primary end point of death or myocardial infarction, a benefit that was apparent at 96 hours and that persisted through 30 days. Bleeding was more common in the eptifibatide groups, but there was no increase in the rate of hemorrhagic stroke.

The ACUITY trial³² found that early use of eptifibatide or tirofiban had no effect on the primary outcome. (See the section below on bivalirudin for more information about the ACUITY trial.)

PARENTERAL ANTICOAGULANTS

Unfractionated heparin: A declining role

Heparin binds to antithrombin and induces a conformational change, causing rapid inhibition of factor IIa (thrombin), factor IXa, and factor Xa, thus preventing further thrombus propagation (Figure 4). An intravenous bolus of 60 units/kg produces a time to peak of 5 to 10 minutes and a half-life of 30 to 60 minutes.

Heparin can be reversed by giving protamine sulfate (1 mg per 100 units of heparin). For ACS, it is given in a bolus of 60 units/kg not exceeding 4,000 units, followed by an infusion of 12 units/kg/hour, with monitoring of the activated partial thromboplastin time every 6 hours with a goal value of 50 to 70 seconds or 1.5 to 2.5 times control.

Side effects include thrombocytopenia, heparin-induced thrombocytopenia (a distinct condition), and bleeding.

The use of unfractionated heparin was tested in ACS in the early 1990s. Oler et al³³ performed a meta-analysis of six randomized trials and found a 33% lower rate of death in patients treated with heparin in addition to aspirin in ACS, as well less reported ischemic pain.

Advantages of unfractionated heparin are that it has stood the test of time, is inexpensive, and can be rapidly reversed. The disadvantages are that it can have serious side effects, including heparin-induced thrombocytopenia, and is more likely to cause bleeding than the newer intravenous anticoagulants discussed below. Thus, its position as the main anticoagulant in ACS is being challenged.

Bivalirudin is a synthetic direct thrombin inhibitor of fluid-phase and clot-bound thrombin (Figure 4). It also inhibits platelets directly.

The ACUITY trial³² randomized 13,819 patients with moderate to high-risk ACS scheduled for invasive treatment into three treatment groups:

• Heparin (either unfractionated heparin or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor (either eptifibatide, tirofiban, or abciximab)
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

The bivalirudin-alone treatment was as sociated with noninferior rates of composite ischemia end points and significantly lower rates of major bleeding, adding up to a significant reduction in the net clinical outcome end point. An important caveat is that bivalirudin’s noninferiority was mostly in the group of patients already receiving a thienopyridine before angiography and percutaneous coronary intervention (RR 0.97 vs 1.27, P = .054). There was less major, nonmajor, minor, CABG-related, and non-CABG-related bleeding as well as need for transfusion in the bivalirudin-alone group, making bivalirudin monotherapy an attractive option in ACS patients with or without ST-segment elevation undergoing a percutaneous coronary intervention.^1,31

The ISAR-REACT trial³⁴ later compared bivalirudin alone vs unfractionated heparin and abciximab in patients with non-ST-elevation myocardial infarction undergoing percutaneous coronary intervention pretreated with aspirin and clopidogrel. The composite rate of ischemia was similar in the two treatment groups, with significantly lower rates of bleeding in the bivalirudin group.

HORIZONS-AMI³⁵ randomized 3,602 patients with ST-elevation myocardial infarction receiving aspirin and clopidogrel either to unfractionated heparin and a glycoprotein IIb/IIIa inhibitor or to bivalirudin. As in the ACUITY trial, there was no difference in ischemic end points and a 40% to 45% lower rate of major bleeding end points in the bivalirudin group, translating into an overall lower rate of death.

Enoxaparin, a low-molecular weight heparin

Enoxaparin is a low-molecular-weight heparin that inhibits factor IIa and factor Xa via antithrombin, roughly in a ratio of 1:3 (Figure 4). It has a time to peak effect of 10 minutes when given intravenously³⁶ and 3 to 5 hours when given subcutaneously.³⁷ Its half-life is 4.5 hours, but it is longer in patients with renal dysfunction, requiring dose adjustments in this population.

Its anticoagulant effect is partially reversible. If it is to be reversed between 0 and 8 hours after dosing, the recommended reversal regimen is 1 mg of protamine sulfate for every 1 mg of enoxaparin used. At 8 to 12 hours, it is 0.5 mg of protamine for every 1 mg of enoxaparin. After 12 hours, no protamine is required.

Compared with unfractionated heparin, enoxaparin has less plasma protein binding and a more consistent anticoagulant effect. Its high bioavailability also allows for subcutaneous dosing. Its greater anti-Xa activity inhibits thrombin generation more effectively, and it causes lower rates of thrombocytopenia and heparin-induced thrombocytopenia.

de Lemos et al³⁸ found that, in ACS patients in whom an early conservative approach of medical management was planned, enoxaparin was more efficacious than unfractionated heparin and caused a similar rate of bleeding.

Murphy et al,³⁹ in a meta-analysis of 12 trials in 49,088 ACS patients, also found that enoxaparin had a net clinical benefit compared with unfractionated heparin in reducing rates of myocardial infarction and death despite more bleeding.

The ESSENCE trial⁴⁰ compared enoxaparin vs unfractionated heparin in 3,171 patients with ACS. It found fewer ischemic events with enoxaparin in the early phase, more minor bleeding, but no increase in major bleeding.

The SYNERGY trial,⁴¹ in 10,027 patients with high-risk non-ST-elevation ACS undergoing percutaneous coronary intervention, compared subcutaneous enoxaparin with intravenous heparin. Enoxaparin was found to be noninferior to heparin but caused more bleeding, including major bleeding, drops in hemoglobin, and intracranial hemorrhage.

The EXTRACT-TIMI 25 trial.⁴² In patients with ST-elevation myocardial infarction, enoxaparin has been shown to be beneficial both in patients treated with fibrinolysis and in those who underwent primary percutaneous coronary intervention. The EXTRACT-TIMI 25 trial randomized 20,749 patients to receive either enoxaparin (an intravenous bolus and maintenance subcutaneous dosing based on renal function) or intravenous heparin in addition to thrombolysis within 6 hours of the diagnosis of ST-elevation myocardial infarction. Although the enoxaparin group had more bleeding end points, they had fewer primary and secondary efficacy end points, translating into an overall net clinical benefit in favor of enoxaparin.

The ATOLL trial⁴³ examined the use of enoxaparin (0.5 mg/kg intravenously) or unfractionated heparin in 910 patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (via the radial artery in 66% to 69%). Although there was a trend towards benefit in terms of the primary end point of death, myocardial infarction complications, procedure failure, and major bleeding favoring enoxaparin, it was not statistically significant (95% CI 0.68–1.01, P = .06).

However, there was a 37% to 42% lower rate of the secondary end point of death, recurrent myocardial infarction or ACS, or urgent target-vessel revascularization in the enoxaparin group, with a 40% reduction in death from any cause, death from a cardiac cause, or shock. The safety profiles of the two drugs were similar, and the net clinical benefit significantly favored enoxaparin.

Fondaparinux, a factor Xa inhibitor

Fondaparinux is a synthetic pentasaccharide that indirectly inhibits factor Xa through the action of antithrombin (Figure 4). After a 2.5-mg subcutaneous dose, it has a time to peak concentration of 2 hours and a half-life of 17 to 21 hours.

The OASIS-5 trial⁴⁴ compared fondaparinux and enoxaparin in 20,078 patients treated for non-ST-elevation ACS. Although the rates of death, myocardial infarction, and refractory ischemia at 9 days were similar for both drugs, the fondaparinux group had a significantly (almost 50%) lower rate of bleeding at 30 days, translating into significantly fewer deaths at 30 days. However, patients receiving fondaparinux who underwent percutaneous coronary intervention had a threefold higher rate of catheter-related thrombosis.

The OASIS-6 trial⁴⁵ compared fondaparinux vs usual care (placebo in those in whom unfractionated heparin was not indicated or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days) in 12,092 patients with ST-elevation myocardial infarction. There was a 1.5% absolute risk reduction in death and reinfarction without an increase in bleeding at 30 days, with trends persisting 6 months into the study. However, fondaparinux was not superior to heparin in the 3% of patients who underwent primary percutaneous coronary intervention. As in OASIS-5, there was more catheter-related thrombosis in the fondaparinux group.

Although the use of supplemental unfractionated heparin appears to have mitigated this risk, fondaparinux remains a less-than-ideal option in the era of primary percutaneous coronary intervention for ST-elevation myocardial infarction and has therefore found limited use in this group of patients. It should, however, be considered in patients for whom a conservative strategy is planned, especially if bleeding risk is deemed to be high.

ORAL ANTICOAGULANTS

Oral anticoagulants provide ischemic benefit in selected patients with ACS—at the price of a higher risk of significant bleeding.

Warfarin

Warfarin was investigated after myocardial infarction in the WARIS II,⁴⁶ CARS,⁴⁷ and CHAMP⁴⁸ trials.

WARIS II⁴⁶ looked at the use of aspirin alone, warfarin alone, and aspirin and warfarin in combination. The rates of the primary end points of stroke, nonfatal infarction, and death were lower in the warfarin group.

CARS⁴⁷ found no difference in the rate of the primary end point of fatal infarction, nonfatal ischemic stroke, or cardiovascular death with aspirin vs warfarin plus aspirin.

CHAMP⁴⁸ saw similar trends, ie, no difference in the rate of death, recurrent myocardial infarction, or stroke with warfarin plus aspirin vs aspirin alone.

All three studies showed increases in major bleeding with warfarin use.

Putting these trials into context, the significant net clinical benefit of dual antiplatelet therapy in the current era compared with the significant bleeding and questionable conflicting evidence supporting benefit with warfarin has limited its use in ACS patients.

Rivaroxaban, an oral factor Xa inhibitor

Rivaroxaban is a novel oral direct reversible factor Xa inhibitor.

The ATLAS ACS 2-TIMI 51 trial⁴⁹ found rivaroxaban 2.5 mg or 5 mg to yield a significantly lower rate of the primary outcome of cardiovascular death, myocardial infarction, ischemic stroke, and in-stent thrombosis compared with placebo, but significantly more major non-CABG bleeding and intracranial hemorrhage.

The dose used in this trial was much lower than the dose used in trials investigating the role of this drug in stroke prophylaxis in atrial fibrillation.

Apixaban, an oral factor Xa inhibitor

Apixaban is another direct factor Xa inhibitor.

The APPRAISE-2 trial⁵⁰ compared apixaban 5 mg twice daily vs placebo in ACS. There was no difference in the rate of cardiovascular death, myocardial infarction, or stroke, but there was significantly more bleeding in the apixaban group, prompting early termination of this study.

Dabigatran, an oral thrombin inhibitor

Dabigatran is an oral direct thrombin inhibitor.

The RE-DEEM trial⁵¹ compared four doses of dabigatran (50, 75, 110, and 150 mg twice daily) and placebo in ACS patients. The dabigatran groups had more major and minor bleeding, and the higher the dose, the higher the incidence of bleeding. In addition, the rates of ischemic end points were no lower with dabigatran, although this trial was not powered to show differences in clinical events.

REDUCING THE RISK OF BLEEDING

In the treatment of ACS, the benefits of restoring perfusion by preventing further propagation of thrombus and platelet aggregation come at a significant price of higher bleeding risk. This in turn increases the risk of death through various mechanisms, including shock, worsening ischemia, discontinuation of antiplatelet and anticoagulation therapy causing stent thrombosis, and anemia leading to transfusion, which propagates the underlying inflammatory milieu.⁵²

Giugliano and Braunwald⁵³ provide practical suggestions to reduce this risk, advising physicians to:

• Avoid inappropriately high dosing, particularly in patients with renal insufficiency
• Preferentially use agents that cause less bleeding (eg, bivalirudin, fondaparinux) without compromising anti-ischemic efficacy
• Minimize the concomitant use of other drugs that cause bleeding (eg, NSAIDs)
• Use drugs that protect against bleeding (eg, proton pump inhibitors) in patients at high risk
• Prevent access-site bleeding by using the radial artery, smaller sheaths, and appropriate sheath and closure device management. Indeed, the use of radial interventions in ACS has been shown to reduce access-site-related bleeding, even in patients at high risk.⁵⁴

The reduction in bleeding risk may provide future trials the opportunity to increase antithrombotic efficacy of different agents with goals of reducing ischemic end points.

The decision should be individualized, taking into consideration the degree to which the thiazide increases the serum urate level, whether this increase can be managed without overly complicating the patient’s hypouricemic therapy, and, most importantly, what effect switching to another drug will have on the control of the patient’s hypertension. No study has directly addressed this issue.

My practice in most patients, for reasons I explain below, is to use a thiazide if it helps to control the blood pressure and to adjust the dose of the hypouricemic therapy as needed to reduce the serum urate to the desired level.

THIAZIDES REMAIN IMPORTANT IN ANTIHYPERTENSIVE THERAPY

Many patients with gout also have hypertension, perhaps due in part to the same hyperuricemia that caused their gouty arthritis. It is well documented that thiazide diuretics can raise the serum urate level.¹ In some studies² (but not all³), patients using thiazides had a higher incidence of gouty arthritis. Thus, it is reasonable to ask if we should avoid thiazides in patients with coexistent gout and hypertension.

Many hypertensive patients fail to reach their target blood pressures (although with the “looser” recommendations in the latest guidelines,⁴ we may appear to be doing a better job). The reasons for failing to reach target pressures are complex and many: physicians may simply not be aggressive enough in pursuing a target blood pressure; patients cannot tolerate the drugs or cannot afford the drugs; and many patients need two or more antihypertensive drugs to achieve adequate control. Thiazides are cheap and effective⁵ and work synergistically with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.⁶

Thus, in many patients, avoiding or discontinuing a thiazide may inhibit our ability to control their hypertension, which is a key contributor to cardiovascular events and chronic kidney injury in patients with gout. Since other diuretics (eg, loop diuretics, which can lower blood pressure but often require split doses) also raise the serum urate level, switching to one of them will not eliminate concern over hyperuricemia.

Thiazides and serum urate

Thiazides slightly increase the serum urate level and in a dose-dependent manner. At the doses commonly used in treating hypertension (12.5 or 25 mg once a day), hydrochlorothiazide increases the serum urate level by 0.8 mg/dL or less in patients with normal renal function, as shown in a number of older hypertension treatment trials and in a recent prospective study.¹ The effect of chlorthalidone is similar.

In patients with chronic gout treated with a xanthine oxidase inhibitor (allopurinol or febuxostat) to lower the serum urate to the American College of Rheumatology’s recommended target level⁷ of less than 6.0 mg/dL (or < 5 mg/dL in the British Rheumatology guidelines), this small elevation in serum urate is unlikely to negate the clinical efficacy of these drugs when dosing is optimized. Small studies have demonstrated a clinically insignificant pharmacodynamic interaction between thiazides and xanthine oxidase inhibitors.^8,9 When I add a thiazide to a patient’s regimen, I do not usually need to increase the dose of allopurinol significantly to keep the serum urate level below the desired target.

Switch antihypertensive therapy

Occasionally, in a patient with chronic gout and mild hypertension who has a serum urate level marginally above the estimated precipitation threshold of 6.7 mg/dL, it is reasonable to simply switch the thiazide to another antihypertensive, such as losartan. Losartan is a weak uricosuric and can lower the serum urate level slightly, possibly making the addition of another hypouricemic agent unnecessary, while still controlling the blood pressure with a single pill. This decision must be individualized, taking into consideration the efficacy and cost of the alternative antihypertensive drug, as well as the potential but as yet unproven cardiovascular and renal benefits of lowering the serum urate with a more potent hypouricemic to a degree not likely to be attained with losartan alone.

Continue thiazide, adjust gout therapy

Discontinuing a thiazide or switching to another antihypertensive drug may increase the cost and decrease the efficacy of hypertensive therapy. Continuing thiazide therapy and, if necessary, adjusting hypouricemic therapy will not worsen the control of the serum urate level or gouty arthritis, and in most patients will not complicate the management of gout.

ASPIRIN AND HYPERURICEMIA

In answer to a separate but related question, aspirin in low doses for cardioprotection (81 mg daily) also need not be stopped in patients with hyperuricemia or gout in an effort to better control the serum urate level. Low-dose aspirin increases the serum urate level by about 0.3 mg/dL. Since patients with gout have a higher risk of having cardiovascular disease, metabolic syndrome, and chronic kidney disease, many will benefit from low-dose aspirin therapy.

The decision should be individualized, taking into consideration the degree to which the thiazide increases the serum urate level, whether this increase can be managed without overly complicating the patient’s hypouricemic therapy, and, most importantly, what effect switching to another drug will have on the control of the patient’s hypertension. No study has directly addressed this issue.

My practice in most patients, for reasons I explain below, is to use a thiazide if it helps to control the blood pressure and to adjust the dose of the hypouricemic therapy as needed to reduce the serum urate to the desired level.

THIAZIDES REMAIN IMPORTANT IN ANTIHYPERTENSIVE THERAPY

Many patients with gout also have hypertension, perhaps due in part to the same hyperuricemia that caused their gouty arthritis. It is well documented that thiazide diuretics can raise the serum urate level.¹ In some studies² (but not all³), patients using thiazides had a higher incidence of gouty arthritis. Thus, it is reasonable to ask if we should avoid thiazides in patients with coexistent gout and hypertension.

Many hypertensive patients fail to reach their target blood pressures (although with the “looser” recommendations in the latest guidelines,⁴ we may appear to be doing a better job). The reasons for failing to reach target pressures are complex and many: physicians may simply not be aggressive enough in pursuing a target blood pressure; patients cannot tolerate the drugs or cannot afford the drugs; and many patients need two or more antihypertensive drugs to achieve adequate control. Thiazides are cheap and effective⁵ and work synergistically with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.⁶

Thus, in many patients, avoiding or discontinuing a thiazide may inhibit our ability to control their hypertension, which is a key contributor to cardiovascular events and chronic kidney injury in patients with gout. Since other diuretics (eg, loop diuretics, which can lower blood pressure but often require split doses) also raise the serum urate level, switching to one of them will not eliminate concern over hyperuricemia.

Thiazides and serum urate

Thiazides slightly increase the serum urate level and in a dose-dependent manner. At the doses commonly used in treating hypertension (12.5 or 25 mg once a day), hydrochlorothiazide increases the serum urate level by 0.8 mg/dL or less in patients with normal renal function, as shown in a number of older hypertension treatment trials and in a recent prospective study.¹ The effect of chlorthalidone is similar.

In patients with chronic gout treated with a xanthine oxidase inhibitor (allopurinol or febuxostat) to lower the serum urate to the American College of Rheumatology’s recommended target level⁷ of less than 6.0 mg/dL (or < 5 mg/dL in the British Rheumatology guidelines), this small elevation in serum urate is unlikely to negate the clinical efficacy of these drugs when dosing is optimized. Small studies have demonstrated a clinically insignificant pharmacodynamic interaction between thiazides and xanthine oxidase inhibitors.^8,9 When I add a thiazide to a patient’s regimen, I do not usually need to increase the dose of allopurinol significantly to keep the serum urate level below the desired target.

Switch antihypertensive therapy

Occasionally, in a patient with chronic gout and mild hypertension who has a serum urate level marginally above the estimated precipitation threshold of 6.7 mg/dL, it is reasonable to simply switch the thiazide to another antihypertensive, such as losartan. Losartan is a weak uricosuric and can lower the serum urate level slightly, possibly making the addition of another hypouricemic agent unnecessary, while still controlling the blood pressure with a single pill. This decision must be individualized, taking into consideration the efficacy and cost of the alternative antihypertensive drug, as well as the potential but as yet unproven cardiovascular and renal benefits of lowering the serum urate with a more potent hypouricemic to a degree not likely to be attained with losartan alone.

Continue thiazide, adjust gout therapy

Discontinuing a thiazide or switching to another antihypertensive drug may increase the cost and decrease the efficacy of hypertensive therapy. Continuing thiazide therapy and, if necessary, adjusting hypouricemic therapy will not worsen the control of the serum urate level or gouty arthritis, and in most patients will not complicate the management of gout.

ASPIRIN AND HYPERURICEMIA

In answer to a separate but related question, aspirin in low doses for cardioprotection (81 mg daily) also need not be stopped in patients with hyperuricemia or gout in an effort to better control the serum urate level. Low-dose aspirin increases the serum urate level by about 0.3 mg/dL. Since patients with gout have a higher risk of having cardiovascular disease, metabolic syndrome, and chronic kidney disease, many will benefit from low-dose aspirin therapy.

The decision should be individualized, taking into consideration the degree to which the thiazide increases the serum urate level, whether this increase can be managed without overly complicating the patient’s hypouricemic therapy, and, most importantly, what effect switching to another drug will have on the control of the patient’s hypertension. No study has directly addressed this issue.

My practice in most patients, for reasons I explain below, is to use a thiazide if it helps to control the blood pressure and to adjust the dose of the hypouricemic therapy as needed to reduce the serum urate to the desired level.

THIAZIDES REMAIN IMPORTANT IN ANTIHYPERTENSIVE THERAPY

Many patients with gout also have hypertension, perhaps due in part to the same hyperuricemia that caused their gouty arthritis. It is well documented that thiazide diuretics can raise the serum urate level.¹ In some studies² (but not all³), patients using thiazides had a higher incidence of gouty arthritis. Thus, it is reasonable to ask if we should avoid thiazides in patients with coexistent gout and hypertension.

Many hypertensive patients fail to reach their target blood pressures (although with the “looser” recommendations in the latest guidelines,⁴ we may appear to be doing a better job). The reasons for failing to reach target pressures are complex and many: physicians may simply not be aggressive enough in pursuing a target blood pressure; patients cannot tolerate the drugs or cannot afford the drugs; and many patients need two or more antihypertensive drugs to achieve adequate control. Thiazides are cheap and effective⁵ and work synergistically with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.⁶

Thus, in many patients, avoiding or discontinuing a thiazide may inhibit our ability to control their hypertension, which is a key contributor to cardiovascular events and chronic kidney injury in patients with gout. Since other diuretics (eg, loop diuretics, which can lower blood pressure but often require split doses) also raise the serum urate level, switching to one of them will not eliminate concern over hyperuricemia.

Thiazides and serum urate

Thiazides slightly increase the serum urate level and in a dose-dependent manner. At the doses commonly used in treating hypertension (12.5 or 25 mg once a day), hydrochlorothiazide increases the serum urate level by 0.8 mg/dL or less in patients with normal renal function, as shown in a number of older hypertension treatment trials and in a recent prospective study.¹ The effect of chlorthalidone is similar.

In patients with chronic gout treated with a xanthine oxidase inhibitor (allopurinol or febuxostat) to lower the serum urate to the American College of Rheumatology’s recommended target level⁷ of less than 6.0 mg/dL (or < 5 mg/dL in the British Rheumatology guidelines), this small elevation in serum urate is unlikely to negate the clinical efficacy of these drugs when dosing is optimized. Small studies have demonstrated a clinically insignificant pharmacodynamic interaction between thiazides and xanthine oxidase inhibitors.^8,9 When I add a thiazide to a patient’s regimen, I do not usually need to increase the dose of allopurinol significantly to keep the serum urate level below the desired target.

Switch antihypertensive therapy

Occasionally, in a patient with chronic gout and mild hypertension who has a serum urate level marginally above the estimated precipitation threshold of 6.7 mg/dL, it is reasonable to simply switch the thiazide to another antihypertensive, such as losartan. Losartan is a weak uricosuric and can lower the serum urate level slightly, possibly making the addition of another hypouricemic agent unnecessary, while still controlling the blood pressure with a single pill. This decision must be individualized, taking into consideration the efficacy and cost of the alternative antihypertensive drug, as well as the potential but as yet unproven cardiovascular and renal benefits of lowering the serum urate with a more potent hypouricemic to a degree not likely to be attained with losartan alone.

Continue thiazide, adjust gout therapy

Discontinuing a thiazide or switching to another antihypertensive drug may increase the cost and decrease the efficacy of hypertensive therapy. Continuing thiazide therapy and, if necessary, adjusting hypouricemic therapy will not worsen the control of the serum urate level or gouty arthritis, and in most patients will not complicate the management of gout.

ASPIRIN AND HYPERURICEMIA

In answer to a separate but related question, aspirin in low doses for cardioprotection (81 mg daily) also need not be stopped in patients with hyperuricemia or gout in an effort to better control the serum urate level. Low-dose aspirin increases the serum urate level by about 0.3 mg/dL. Since patients with gout have a higher risk of having cardiovascular disease, metabolic syndrome, and chronic kidney disease, many will benefit from low-dose aspirin therapy.

About 15 years ago, the first anti-tumor necrosis factor (anti-TNF) drugs received approval for treating Crohn disease and rheumatoid arthritis, and a new era of pharmacotherapy was born. A few years before that, I was at a meeting discussing the potential benefits and pitfalls of these new biologic therapies, and I opined that no one would pay for them on an ongoing basis unless they were amazingly effective—which was unlikely, as the drugs only affected a single cytokine. And if they were effective, they would undoubtedly be associated with a host of opportunistic infections. Given my predictive skills, it is no surprise that Warren Buffett rarely calls to ask my opinion.

Clearly, anti-TNF drugs are effective and have raised the bar for how we define successful response to therapy. But recent studies in early rheumatoid arthritis indicate that they may not be much better than traditional combination therapy or monotherapy with methotrexate if the methotrexate and the other drugs are given and tolerated at full dose. This is clearly not the case for other inflammatory diseases.

Anti-TNF drugs and other biologics are now part of the arsenal of most medical specialists, so outpatient internists and hospitalists increasingly encounter patients taking these drugs. Since patients with systemic inflammatory disease have an increased prevalence of cardiovascular disease, cardiologists are also seeing more patients taking these drugs. Thus, the overview by Hadam et al in this issue of the Journal on the risks of biologic therapies is relevant to many readers.

Almost all prescriptions and requests for insurance approval for these drugs are written by subspecialists familiar with their risks. But patients may ask their primary care physicians about the tests and vaccines recommended for those about to start anti-TNF therapy. Before starting anti-TNF therapy, all patients should be tested for previous exposure to tuberculosis and should be treated for latent tuberculosis if appropriate. Blocking TNF leads to a breakdown of the protective granulomatous inflammatory response that contains the mycobacteria and, as with corticosteroid treatment, results in reactivation of the disease. Interestingly, the reactivation is quite often not in the lungs. And since anti-TNF therapy dramatically blunts the inflammatory response, as does corticosteroid therapy, reactivation may appear as nonspecific malaise or may be misinterpreted as a flare in the underlying disease, and thus it may go undiagnosed. Patients should also be screened for exposure to hepatitis B virus. Vaccines, particularly live vaccines, are generally given if possible before starting anti-TNF therapy, and all patients on chronic therapy should get annual influenza vaccines.

Despite initial concerns about a dramatically increased risk of routine and opportunistic infections in patients on anti-TNF therapy, this has not been observed. Even in the perioperative setting, the increased risk of infection is modest. What has struck me, however, is the way these drugs, like steroids, blunt and mask the signs of infection. I have seen deep soft-tissue, intra-abdominal, and native and prosthetic joint infections go unsuspected for days or even weeks in the absence of significant fever, elevation in acute-phase markers, or dramatic local findings. We must be extra vigilant.

There is a fear of malignancy arising or recurring in patients on anti-TNF therapy. This fear is certainly promoted by the required black-box warning about the risk of lymphoma and other malignancies that these drugs carry. The evidence of a significant increase in risk of malignancies other than hepatosplenic T-cell lymphoma in children and nonmelanoma skin cancers is not strong and is likely slanted by an increased risk of certain malignancies associated with the underlying rheumatic disease and other previous therapies. Nonetheless, I am reluctant to use these drugs in patients with a history of melanoma.

We still have much to learn about these drugs. Why are specific agents more effective in some diseases than others? For example, etanercept treats rheumatoid arthritis but not Crohn disease. Also, we still do not know how they can elicit reversible demyelinating disorders or autoantibodies with or without associated drug-induced lupus syndromes. Even odder is the occurrence of psoriasis induced by anti-TNF drugs, despite their being used to treat psoriasis.

My initial skepticism regarding anti-TNF drugs was unjustified. They are being tested and used successfully in an increasing number of diseases. But we all need to increase our familiarity with their unique risks and somehow find a way to deal with their unique cost.

About 15 years ago, the first anti-tumor necrosis factor (anti-TNF) drugs received approval for treating Crohn disease and rheumatoid arthritis, and a new era of pharmacotherapy was born. A few years before that, I was at a meeting discussing the potential benefits and pitfalls of these new biologic therapies, and I opined that no one would pay for them on an ongoing basis unless they were amazingly effective—which was unlikely, as the drugs only affected a single cytokine. And if they were effective, they would undoubtedly be associated with a host of opportunistic infections. Given my predictive skills, it is no surprise that Warren Buffett rarely calls to ask my opinion.

Clearly, anti-TNF drugs are effective and have raised the bar for how we define successful response to therapy. But recent studies in early rheumatoid arthritis indicate that they may not be much better than traditional combination therapy or monotherapy with methotrexate if the methotrexate and the other drugs are given and tolerated at full dose. This is clearly not the case for other inflammatory diseases.

Anti-TNF drugs and other biologics are now part of the arsenal of most medical specialists, so outpatient internists and hospitalists increasingly encounter patients taking these drugs. Since patients with systemic inflammatory disease have an increased prevalence of cardiovascular disease, cardiologists are also seeing more patients taking these drugs. Thus, the overview by Hadam et al in this issue of the Journal on the risks of biologic therapies is relevant to many readers.

Almost all prescriptions and requests for insurance approval for these drugs are written by subspecialists familiar with their risks. But patients may ask their primary care physicians about the tests and vaccines recommended for those about to start anti-TNF therapy. Before starting anti-TNF therapy, all patients should be tested for previous exposure to tuberculosis and should be treated for latent tuberculosis if appropriate. Blocking TNF leads to a breakdown of the protective granulomatous inflammatory response that contains the mycobacteria and, as with corticosteroid treatment, results in reactivation of the disease. Interestingly, the reactivation is quite often not in the lungs. And since anti-TNF therapy dramatically blunts the inflammatory response, as does corticosteroid therapy, reactivation may appear as nonspecific malaise or may be misinterpreted as a flare in the underlying disease, and thus it may go undiagnosed. Patients should also be screened for exposure to hepatitis B virus. Vaccines, particularly live vaccines, are generally given if possible before starting anti-TNF therapy, and all patients on chronic therapy should get annual influenza vaccines.

Despite initial concerns about a dramatically increased risk of routine and opportunistic infections in patients on anti-TNF therapy, this has not been observed. Even in the perioperative setting, the increased risk of infection is modest. What has struck me, however, is the way these drugs, like steroids, blunt and mask the signs of infection. I have seen deep soft-tissue, intra-abdominal, and native and prosthetic joint infections go unsuspected for days or even weeks in the absence of significant fever, elevation in acute-phase markers, or dramatic local findings. We must be extra vigilant.

There is a fear of malignancy arising or recurring in patients on anti-TNF therapy. This fear is certainly promoted by the required black-box warning about the risk of lymphoma and other malignancies that these drugs carry. The evidence of a significant increase in risk of malignancies other than hepatosplenic T-cell lymphoma in children and nonmelanoma skin cancers is not strong and is likely slanted by an increased risk of certain malignancies associated with the underlying rheumatic disease and other previous therapies. Nonetheless, I am reluctant to use these drugs in patients with a history of melanoma.

We still have much to learn about these drugs. Why are specific agents more effective in some diseases than others? For example, etanercept treats rheumatoid arthritis but not Crohn disease. Also, we still do not know how they can elicit reversible demyelinating disorders or autoantibodies with or without associated drug-induced lupus syndromes. Even odder is the occurrence of psoriasis induced by anti-TNF drugs, despite their being used to treat psoriasis.

My initial skepticism regarding anti-TNF drugs was unjustified. They are being tested and used successfully in an increasing number of diseases. But we all need to increase our familiarity with their unique risks and somehow find a way to deal with their unique cost.

About 15 years ago, the first anti-tumor necrosis factor (anti-TNF) drugs received approval for treating Crohn disease and rheumatoid arthritis, and a new era of pharmacotherapy was born. A few years before that, I was at a meeting discussing the potential benefits and pitfalls of these new biologic therapies, and I opined that no one would pay for them on an ongoing basis unless they were amazingly effective—which was unlikely, as the drugs only affected a single cytokine. And if they were effective, they would undoubtedly be associated with a host of opportunistic infections. Given my predictive skills, it is no surprise that Warren Buffett rarely calls to ask my opinion.

Clearly, anti-TNF drugs are effective and have raised the bar for how we define successful response to therapy. But recent studies in early rheumatoid arthritis indicate that they may not be much better than traditional combination therapy or monotherapy with methotrexate if the methotrexate and the other drugs are given and tolerated at full dose. This is clearly not the case for other inflammatory diseases.

Anti-TNF drugs and other biologics are now part of the arsenal of most medical specialists, so outpatient internists and hospitalists increasingly encounter patients taking these drugs. Since patients with systemic inflammatory disease have an increased prevalence of cardiovascular disease, cardiologists are also seeing more patients taking these drugs. Thus, the overview by Hadam et al in this issue of the Journal on the risks of biologic therapies is relevant to many readers.

Almost all prescriptions and requests for insurance approval for these drugs are written by subspecialists familiar with their risks. But patients may ask their primary care physicians about the tests and vaccines recommended for those about to start anti-TNF therapy. Before starting anti-TNF therapy, all patients should be tested for previous exposure to tuberculosis and should be treated for latent tuberculosis if appropriate. Blocking TNF leads to a breakdown of the protective granulomatous inflammatory response that contains the mycobacteria and, as with corticosteroid treatment, results in reactivation of the disease. Interestingly, the reactivation is quite often not in the lungs. And since anti-TNF therapy dramatically blunts the inflammatory response, as does corticosteroid therapy, reactivation may appear as nonspecific malaise or may be misinterpreted as a flare in the underlying disease, and thus it may go undiagnosed. Patients should also be screened for exposure to hepatitis B virus. Vaccines, particularly live vaccines, are generally given if possible before starting anti-TNF therapy, and all patients on chronic therapy should get annual influenza vaccines.

Despite initial concerns about a dramatically increased risk of routine and opportunistic infections in patients on anti-TNF therapy, this has not been observed. Even in the perioperative setting, the increased risk of infection is modest. What has struck me, however, is the way these drugs, like steroids, blunt and mask the signs of infection. I have seen deep soft-tissue, intra-abdominal, and native and prosthetic joint infections go unsuspected for days or even weeks in the absence of significant fever, elevation in acute-phase markers, or dramatic local findings. We must be extra vigilant.

There is a fear of malignancy arising or recurring in patients on anti-TNF therapy. This fear is certainly promoted by the required black-box warning about the risk of lymphoma and other malignancies that these drugs carry. The evidence of a significant increase in risk of malignancies other than hepatosplenic T-cell lymphoma in children and nonmelanoma skin cancers is not strong and is likely slanted by an increased risk of certain malignancies associated with the underlying rheumatic disease and other previous therapies. Nonetheless, I am reluctant to use these drugs in patients with a history of melanoma.

We still have much to learn about these drugs. Why are specific agents more effective in some diseases than others? For example, etanercept treats rheumatoid arthritis but not Crohn disease. Also, we still do not know how they can elicit reversible demyelinating disorders or autoantibodies with or without associated drug-induced lupus syndromes. Even odder is the occurrence of psoriasis induced by anti-TNF drugs, despite their being used to treat psoriasis.

My initial skepticism regarding anti-TNF drugs was unjustified. They are being tested and used successfully in an increasing number of diseases. But we all need to increase our familiarity with their unique risks and somehow find a way to deal with their unique cost.

Biologic agents such as those that block tumor necrosis factor (TNF) alpha have revolutionized the treatment of autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease, dramatically improving disease control and quality of life. In addition, they have made true disease remission possible in some cases.

However, as with any new therapy, a variety of side effects must be considered.

WHAT ARE BIOLOGIC AGENTS?

Biologic agents are genetically engineered drugs manufactured or synthesized in vitro from molecules such as proteins, genes, and antibodies present in living organisms. By targeting specific molecular components of the inflammatory cascade, including cytokines, these drugs alter certain aspects of the body’s inflammatory response in autoimmune diseases. Because TNF inhibitors are the most widely used biologic agents in the United States, this review will focus on them.

TNF INHIBITORS

TNF inhibitors suppress the inflammatory cascade by inactivating TNF alpha, a cytokine that promotes inflammation in the intestine, synovial tissue, and other sites.^1,2

Several TNF inhibitors are available. Etanercept and infliximab were the first two to receive US Food and Drug Administration (FDA) approval, and they are extensively used. Etanercept, a soluble TNF receptor given subcutaneously, was approved for treating rheumatoid arthritis in 1998. Infliximab, a chimeric monoclonal antibody (75% human and 25% mouse protein sequence) given intravenously, received FDA approval for treating Crohn disease in 1998 and for rheumatoid arthritis in 1999. Other anti-TNF agents with varying properties are also available.

Table 1 lists anti-TNF agents approved for treating rheumatoid arthritis and inflammatory bowel disease. These are chronic, relapsing diseases that significantly and dramatically reduce quality of life, especially when they are poorly controlled.^3,4 Untreated disease has been associated with malignancy, infection, pregnancy loss, and malnutrition.^5–8 TNF inhibitors are aimed at patients who have moderate to severe disease or for whom previous treatments have failed, to help them achieve and maintain steroid-free remission. However, use of these agents is tempered by the risk of potentially serious side effects.

Special thought should also be given to the direct costs of the drugs (up to $30,000 per year, not counting the cost of their administration) and to the indirect costs such as time away from work to receive treatment. These are major considerations in some cases, and patients should be selected carefully for treatment with these drugs.

BEFORE STARTING THERAPY

Before starting anti-TNF therapy, several steps can reduce the risk of serious adverse events.

Take a focused history

The clinical history should include inquiries about previous bacterial, fungal, and tuberculosis infections or exposure; diabetes; and other immunocompromised states that increase the risk of acquiring potentially life-threatening infections.

Details of particular geographic areas of residence, occupational exposures, and social history should be sought. These include history of incarceration (which may put patients at risk of tuberculosis) and residence in the Ohio River valley or in the southwestern or midwestern United States (which may increase the risk of histoplasmosis, coccidioidomycosis, and other fungal infections).

Bring vaccinations up to date

Age-appropriate vaccinations should be discussed and given, ideally before starting therapy. These include influenza vaccine every year and tetanus boosters every 10 years for all and, as appropriate, varicella, human papillomavirus, and pneumococcal vaccinations. The US Centers for Disease Control and Prevention recommend an additional dose of the pneumococcal vaccine if more than 5 years have elapsed since the first one, and many clinicians opt to give it every 5 years.

In general, live-attenuated vaccines, including the intranasal influenza vaccine, are contraindicated in patients taking biologic agents.⁹ For patients at high risk of exposure or infection, it may be reasonable to hold the biologic agent for a period of time, vaccinate, and resume the biologic agent a month later.

Recent data suggest that the varicella zoster vaccine may be safely given to older patients with immune-mediated diseases such as rheumatoid arthritis and inflammatory bowel disease taking biologic agents.¹⁰ New guidelines from the American College of Rheumatology recommend age-appropriate vaccines for rheumatoid arthritis patients age 60 and older before biologic treatments are started. Case-by-case discussion with the subspecialist and the patient is recommended.

Screen for chronic infections

Tuberculosis screening with a purified protein derivative test or an interferon-gamma-release (Quantiferon) assay followed by chest radiography in patients with a positive test is mandatory before giving a TNF inhibitor.

Hepatitis B virus status should be determined before starting anti-TNF therapy.¹¹

Hepatitis B vaccination has been recommended for patients with inflammatory bowel disease, but no clear recommendation exists for patients with rheumatic disease. Patients with inflammatory bowel disease tend to have low rates of response to hepatitis B vaccination^12,13; possible reasons include their lack of an appropriate innate immune response to infectious agents, malnutrition, surgery, older age, and immunosuppressive drugs.¹⁴ An accelerated vaccination protocol with recombinant hepatitis B vaccine (Energix-B) in a double dose at 0, 1, and 2 months has been shown to improve response rates.¹⁵

Whenever possible, it may be better to vaccinate patients before starting immunosuppressive therapy, and to check postvaccination titers to ensure adequate response.

A full physical examination with special attention to skin rashes should be performed. This may serve as a baseline to assist early detection of new rashes associated with anti-TNF therapy.

A baseline complete blood cell count and complete metabolic panel should be routinely obtained before starting therapy (and thereafter at the discretion of the physician). In conjunction with follow-up tests, they can help detect an unexpected decrease in white blood cell count or abnormal results on the liver panel.¹⁶ These baseline and follow-up tests are generally performed by the subspecialist, and the results are shared with the primary care physician.

Table 2 summarizes key information to be sought before starting a patient on a TNF inhibitor.

ADVERSE EFFECTS OF ANTI-TNF DRUGS

Infusion reactions, infections, cardiac arrhythmias, demyelinating disorders, skin infections, and malignancies have been reported with anti-TNF therapy. The relative frequencies of these adverse events are summarized in Table 3.^17–22

NONINFECTIOUS COMPLICATIONS OF TNF INHIBITORS

Injection site reactions

When anti-TNF agents are given subcutaneously, injection site reactions are common (occurring in up to 40% of patients) and are considered minor.¹¹ Reactions, including significant pain, typically occur within the first few months of therapy. They can last 2 to 5 days but rarely warrant stopping therapy. Treatment with ice and an antihistamine is almost always sufficient to control symptoms.

Infusion reactions with infliximab

Infliximab can cause both acute and delayed infusion reactions. Acute reactions can occur up to 24 hours after infusion but usually appear within 10 minutes of administration and are handled by the infusion suite staff. They range from the severe immunoglobulin E-mediated type I reaction, manifesting with hypotension, bronchospasm, and urticaria, to the milder anaphylactoid-type reaction, which constitutes the majority.^23–25

While most primary care physicians will not encounter an acute reaction, family doctors and emergency room physicians may encounter delayed reactions, which can develop 1 to 14 days after infusion. These reactions usually resemble serum sickness and present with joint pain, fatigue, myalgia, and fever. But, unlike classic serum sickness, these reactions are generally not associated with a rash.

With nonspecific symptoms, the diagnosis may be easy to overlook. However, establishing this diagnosis is important because repeat therapy may result in a more severe reaction upon reexposure to the drug.

Once diagnosed, these reactions can be treated symptomatically with a combination of acetaminophen and diphenhydramine after discussion between the primary care physician and subspecialist.^23,24

Autoimmune syndromes

Several studies have reported a small percentage of patients treated with anti-TNF agents who develop paradoxical autoimmune conditions. These range from asymptomatic immunologic alterations, including the formation of antinuclear antibodies and antibodies to double-stranded DNA, to life-threatening systemic autoimmune diseases.^26,27

Autoimmune diseases associated with anti-TNF treatment include a lupus-like syndrome, vasculitides, and psoriatic skin lesions. These syndromes warrant stopping the inciting drug and, on occasion, giving corticosteroids. Most cases arise between 1 month and 1 year of starting treatment, and almost 75% resolve completely after the anti-TNF therapy is stopped.²⁶

Interestingly, anti-TNF agents are approved for treating psoriasis and psoriatic arthritis, but psoriasis has paradoxically developed in patients being treated with these drugs for other autoimmune diseases. The FDA has reviewed 69 cases of new-onset psoriasis with anti-TNF therapy, including 17 pustular and 15 palmoplantar cases. The 12 most severe cases resulted in hospitalization, and symptoms resolved in most after treatment cessation.²⁸

Fiorino et al²⁹ counted 18 reported cases of psoriasis induced by anti-TNF therapy in patients with inflammatory bowel disease and concluded that it is rare. Harrison et al³⁰ reported similar findings in patients with rheumatoid arthritis, with an increased incidence rate of 1.04 per 1,000 person-years. New-onset psoriasis was most common in patients treated with adalimumab. An example of the rash is seen in Figure 1.

CARDIOVASCULAR SIDE EFFECTS

Cardiovascular side effects of anti-TNF agents range from nonspecific and asymptomatic arrhythmias to worsening of heart failure.

Circulating levels of TNF are increased in patients with heart failure, and studies have evaluated the effects of TNF inhibition with infliximab on cardiac function and overall survival.^31,32 The combined risk of death from any cause or hospitalization from heart failure was significantly higher in the infliximab groups, and the effects persisted for up to 5 months after stopping therapy.

Other studies^22,33 have evaluated the effects of infliximab and etanercept on cardiac function and overall survival. Results showed possible exacerbation of heart failure with etanercept and increased risk of death with infliximab in patients with New York Heart Association (NYHA) class III or IV heart failure and left ventricular ejection fractions less than 35%.

Case reports have also described patients with worsening or new-onset heart failure on TNF inhibitors, including patients younger than 50 years and without identifiable cardiovascular risk factors.

Data analyses^31,34,35 from large clinical registries have reported no significant increase in heart failure attributable to TNF inhibitors. However, we have concerns about the methodology of these analyses.

Currently, anti-TNF therapy is contraindicated in patients with NYHA class III or IV heart failure. Data are inconclusive for patients with class I or II heart failure. Baseline echocardiography and cardiology consultation can be considered, with close monitoring and avoidance of high doses of TNF inhibitors. If heart failure develops in a patient on anti-TNF therapy, the drug should be discontinued and the patient should be evaluated further.³⁶

DEMYELINATING DISEASE, INCLUDING MULTIPLE SCLEROSIS

Anti-TNF agents have been associated with the onset or exacerbation of clinical symptoms and radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis.^37–40 Mohan et al³⁸ identified 19 cases of demyelinating events occurring after administration of anti-TNF agents in early 2001. In most cases, symptoms improved or resolved after therapy was stopped.

Optic neuritis,^41,42 bilateral optic neuropathy,⁴³ and aseptic meningitis⁴⁴ have also been reported, but these have occurred only rarely.

How common are these effects? Postmarketing surveillance in patients with rheumatoid arthritis yields an estimated incidence of demyelinating disorders of 1 per 1,000 patient-years with adalimumab therapy.⁴⁵ Complicating the assessment is an observed slight increase in risk of demyelinating conditions associated with inflammatory bowel disease.

Symptoms that should heighten the physician’s suspicion of this adverse effect include confusion, paresthesias, and ataxia. Patients on anti-TNF therapy who develop new visual symptoms should be checked for painless visual loss as a sign of early demyelinating disease.

Although data that conclusively link anti-TNF agents to multiple sclerosis are lacking, these drugs should not be initiated in patients who have a history of demyelinating disease, and treatment should be stopped promptly if the diagnosis is suspected.

MALIGNANCY

Whether anti-TNF therapy is directly linked to development of malignancies is difficult to determine. There are many confounding factors, including the risk of malignancy in underlying inflammatory disease and the concomitant use of other medications such as thiopurines, which have a known association with lymphoma.⁴⁶

The incidence of lymphoma is twice as high in rheumatoid arthritis patients as in the general population.⁴⁷ The risk is higher in those with more aggressive joint disease—the subset of rheumatoid arthritis patients who are more likely to be given anti-TNF agents.⁵

In patients with inflammatory bowel disease, the risk of cholangiocarcinoma is four times higher, and the risk of small-bowel adenocarcinoma is 16 to 18 times higher, but no increased risk of lymphoma has been identified in this population.^48,49

Data from six clinical trials of infliximab, including a long-term study of its safety in Crohn disease, suggest it poses no increase in overall risk of malignancy.^50–52 Similar results have been reported in patients with other rheumatic diseases.⁸ Information on this topic is constantly evolving, and studies range from case series to clinical trials to large patient registries.

The decision to use a TNF inhibitor should be based on the patient’s clinical picture and risk factors. Discussion of the risks and benefits of therapy with the patient should be clearly documented.

Non-Hodgkin lymphoma

Evidence about the risk of lymphoma with anti-TNF use is mixed, as up to two-thirds of patients on anti-TNF therapy have received concomitant nonbiologic immunosuppressive medications, making it difficult to determine the true risk from the biologic agents alone.⁵³ Current evidence both supports^9,53–56 and refutes^7,55,57–60 the idea that anti-TNF agents increase lymphoma risk.

In patients with inflammatory bowel disease, several population-based studies have not shown a clear increase in lymphoma risk with anti-TNF use.^56,59,60 Pedersen et al,⁶¹ in a meta-analysis of eight studies, confirmed these findings by showing no overall lymphoma risk in patients with inflammatory bowel disease.

However, a Canadian population-based study found a statistically significant increase in non-Hodgkin lymphoma in males with Crohn disease, with an incidence ratio of 3.63 (95% confidence interval [CI] 1.53–8.62).⁶¹ Additionally, Siegel et al⁶² found a significantly higher risk (6.1 cases per 10,000 patients) in patients treated with anti-TNF agents and thiopurines than in the general population (1.9 cases per 10,000 people). Although the difference was statistically significant, the overall risk is still very low.

Patients with rheumatoid arthritis seem to have a risk of lymphoma two to three times higher than in the general population. However, large population-based studies have not shown a statistically significant increase in the risk of lymphoma with anti-TNF therapy.⁶³

Hepatosplenic T-cell lymphoma is a rare subtype of peripheral T-cell non-Hodgkin lymphoma; 25 cases have been reported in patients receiving anti-TNF therapy.⁶⁴ Although the risk is extremely low (< 0.05%), physicians must carefully consider the risks and benefits of combination therapy, especially in young male patients with inflammatory bowel disease, since death is the usual outcome of this disease.^65–67

Skin cancers

Wolfe and Michaud⁸ evaluated malignancy risk in rheumatoid arthritis patients being treated with biologic agents, including TNF inhibitors, using a large longitudinal database. These data were compared with those of the US Surveillance, Epidemiology, and End-Results (SEER) national database. No increase in the overall cancer rate was seen in rheumatoid arthritis patients (standardized incidence ratio [SIR] 1.0, 95% CI 1.0–1.1).

However, melanoma was more common in rheumatoid arthritis patients compared with SEER rates (SIR 1.7, 95% CI 1.3–2.3).⁸ In addition, biologic therapy was associated with a higher (but not statistically significant) risk of melanoma (odds ratio [OR] 2.3, 95% CI 0.9–5.4) and a higher risk of nonmelanoma skin cancer (OR 1.5, 95% CI 1.2–1.8), but not of other types of cancer.⁸

INFECTION

Patients on anti-TNF therapy are at a higher risk of infection, ranging from minor to life-threatening bacterial infections, and including the reactivation of granulomatous and fungal infections. More importantly, these agents are similar to steroids in blunting signs of infection, which may delay diagnosis and treatment.

The management of infection in patients on anti-TNF medications varies from case to case. In general, patients with a minor infection that does not require hospitalization or intravenous antibiotics can continue the biologic therapy while taking oral antibiotics. TNF inhibitors must be held in the event of a major infection.

Consultation with an infectious disease specialist is recommended, especially in complex cases.

Bacterial infections

An increased risk of minor bacterial infections such as urinary tract and respiratory infections has been well documented in several randomized control trials of anti-TNF agents, though other studies have shown no such increase in risk.^33,51–59

The threshold for using antibiotics for a suspected bacterial infection is somewhat shifted in favor of treatment in patients on anti-TNF therapy. The reason is twofold: as previously noted, infections may be worse than they appear, because anti-TNF drugs can mask the signs and symptoms of a serious infection, and in patients on these drugs, an untreated bacterial infection may rapidly become life-threatening.

In general, broad-spectrum antibiotics are not warranted unless the source of infection is unclear or the patient is in danger of hemodynamic compromise.

Opportunistic infections

The association of anti-TNF agents with opportunistic infections could be viewed as an extension of their normal and intended therapeutic activity as potent immunosuppressive agents.⁶⁸ Rheumatoid arthritis and inflammatory bowel disease are usually associated with conditions and situations that predispose patients to opportunistic infections, such as decreased immune response, malnutrition or malabsorption, surgeries, and concomitant immunosuppressive medications.⁷ Combination therapy with other immunosuppressive drugs and older age appear to markedly increase the risk of opportunistic infections, including mycobacterial and fungal infections, in patients with inflammatory bowel disease.⁷

Overall, opportunistic infections represent a measurable risk of anti-TNF therapy, and awareness and vigilance are important, especially in areas where opportunistic infections such as histoplasmosis and coccidiomycosis are endemic.⁵⁰ Furthermore, physicians must be aware of the higher risk of opportunistic infections when multiple immunosuppressive drugs are used concurrently.

Anti-TNF agents increase the risk of de novo granulomatous infections and of reactivating such infections. Granuloma formation and intracellular destruction of mycobacteria depend on TNF. TNF is important in maintaining the anatomic integrity of granulomas where these organisms have been sequestered, and blocking TNF leads to breakdown of granulomas and release of virulent organisms.^69,70

TNF inhibitors increase the risk of reactivation of latent tuberculosis infection. The risk is greater with infliximab and adalimumab than with etanercept,^71,72 and it has been described with certolizumab.⁷⁴ Study results are varied thus far but show a risk of tuberculosis reactivation five to 30 times higher than in the general population, with tremendous variability in risk depending on background rates of previous exposure.

The absence of typical tuberculosis symptoms further complicates care in these cases. Fever, weight loss, and night sweats tend to be TNF-mediated and are therefore masked by anti-TNF agents, leading to atypical presentations. In addition, active tuberculosis infection associated with TNF inhibitors is more likely to involve extrapulmonary sites such as the skin and musculoskeletal system and to be disseminated at presentation.

A paradoxical worsening of tuberculosis symptoms may also be seen in patients with latent tuberculosis reactivation, especially after discontinuing anti-TNF therapy. This is thought to result from an immune reconstitution inflammatory syndrome.

The pretreatment evaluation should include a history of risk factors, a physical examination, and either a tuberculin skin test or an interferon-gamma-release assay. Interferon-gamma-release assays are particularly helpful in patients who have received bacille Calmette-Guérin vaccination. In patients who test positive or have been exposed, tuberculosis treatment should begin 4 weeks before starting anti-TNF therapy, though the optimal timing of antituberculosis agents is still controversial.^74–77

If tuberculosis develops in a patient on anti-TNF therapy, he or she should receive antituberculosis drugs. Anti-TNF therapy should be stopped and should be resumed after 2 months only if no other treatment option is available.⁷⁵

Invasive opportunistic fungal infections

Invasive opportunistic fungal infections have been reported with anti-TNF therapy, including histoplasmosis and coccidioidomycosis.^78–80 Most patients who had histoplasmosis were treated with other immunosuppressive therapies and resided in or were raised near the Ohio or Mississippi River valleys, where this disease is endemic. Similarly, most cases of coccidioidomycosis were in endemic areas of Arizona, California, and Nevada, and patients on concomitant immunosuppressive therapy.⁷⁸

Currently, there is no evidence to recommend obtaining Histoplasma capsulatum or Coccidioides immitis serologies before initiating anti-TNF therapy in patients in endemic areas.⁸¹ However, patients must be instructed to seek medical attention quickly for pulmonary or febrile illnesses.

Viral hepatitis infections

The data on hepatitis B and hepatitis C in patients on biologic therapies are mostly limited to case reports.

Hepatitis B. A small prospective study from Spain followed the liver biochemistry tests and hepatitis B status of 80 patients with Crohn disease treated with infliximab. Of three patients who were chronic hepatitis B carriers before starting infliximab, two experienced reactivation of hepatitis B after discontinuing infliximab, and one ultimately died. The third patient was treated with lamivudine concurrently with infliximab without clinical or biochemical changes during or after therapy.⁸²

Similar findings were observed in two patients with rheumatoid arthritis on treatment with infliximab. One of the patients required liver transplantation, and both were treated with lamivudine, resulting in normalization of liver function test results.^83,84

Recent reviews indicate that despite these findings, hepatitis B reactivation after anti-TNF withdrawal may not be common.⁸⁵ There are limited data on hepatitis B reactivation and associated liver dysfunction in patients with inflammatory bowel disease treated with immunosuppressants. In a retrospective multicenter trial by Loras et al⁸⁶ in patients with inflammatory bowel disease who had viral hepatitis, 36% of patients positive for hepatitis B surface antigen developed liver dysfunction, and six patients developed liver failure. In that study, treatment with more than two immunosuppressants was an independent predictor of hepatitis B reactivation.

Prolonged immunosuppression (longer than 3 months) has also been identified as an independent predictor of liver dysfunction (OR 3.06; 95% 95% CI 1.02–9.16).⁸⁷

The European Association for the Study of the Liver and the American Association for the Study of Liver Diseases recommend starting lamivudine before chemotherapy or immunomodulator or immunosuppressive therapy in hepatitis B virus carriers and continuing preventive treatment for at least 6 months after stopping immunomodulating drugs. Lamivudine at a dose of 100 mg/day may reduce the risk of reactivation of hepatitis B.^88–90 Tenofovir and entecavir may be useful alternatives in patients with hepatitis B who have never received nucleoside analogues. Hepatitis B reactivation did not occur in any of the 16 patients who received preventive entecavir treatment while receiving immunosuppressive treatments.^89,91

In patients receiving immunosuppressive therapy, hepatitis B reactivation is associated with significant morbidity and mortality. Although risk factors for reactivation of hepatitis B virus infection have been identified, we recommend preventive treatment for all carriers positive for hepatitis B surface antigen. This should be done regardless of the number, type, and dosage of immunosuppressants and regardless of hepatitis B virus DNA levels.⁹⁰

The frequency of hepatitis B and hepatitis C infection in patients with Crohn disease has been reported to be as high as 24%. The high incidence is thought to be secondary to multiple blood transfusions and surgeries.⁹² The use of biologic agents, including anti-TNF agents, in chronic hepatitis B virus- or hepatitis C virus-infected patients can lead to enhanced viral replication and hepatitis exacerbation.

Although active viral replication can occur during treatment with biologic agents, reactivation or exacerbation can also occur after the anti-TNF agent is stopped.⁸² This finding has prompted the recommendation that all candidates for biologic therapy be tested for hepatitis B immunization status, followed by immunization in nonimmune patients before starting anti-TNF therapy.^93,94

Hepatitis C. There are no guidelines that adequately address the use of anti-TNF agents in patients with chronic hepatitis C infection.

Several small retrospective studies in rheumatoid arthritis patients with hepatitis C have shown that TNF inhibitors can be safely used without worsening liver function tests or changing the viral load.^95–98 This is reassuring and provides the subspecialist with another treatment option, as other therapies such as disease-modifying antirheumatic drugs and steroids are known to aggravate viral hepatitis and increase the risk of viremia.⁹⁶

Although small retrospective studies and one large randomized double-blind placebo-controlled trial have shown TNF inhibitors to be relatively safe in rheumatoid arthritis patients with hepatitis C, their use in these patients should be considered only with caution if they have evidence of hepatic synthetic dysfunction (eg, hypoalbuminemia, thrombocytopenia, increased international normalized ratio). The American College of Rheumatology recommends avoiding TNF inhibitors in Child-Pugh classes B and C.⁹⁹

PREGNANCY

Physicians caring for patients with rheumatoid arthritis and inflammatory bowel disease must be aware of how these diseases affect fecundity and fertility and how the medications can affect conception and pregnancy. Many patients have difficulty conceiving while their autoimmune disease is active, and better disease control may improve fecundity and result in unanticipated pregnancy. Patients should be advised of the need for contraception if pregnancy is ill-advised or undesired.

Many patients seek advice about teratogenicity before conceiving, or seek guidance about rheumatoid arthritis and inflammatory bowel disease treatment while pregnant.

Several studies have reported a higher risk of adverse pregnancy outcomes in patients with rheumatoid arthritis and inflammatory bowel disease than in the general population.^99–105 In inflammatory bowel disease, the odds of a premature delivery or having a low-birth-weight child are twice as high as in the normal population.^100,103 Higher rates of cesarean delivery and stillbirth have also been reported. The main predisposing factor appears to be the disease activity at the time of conception, as active disease seems to be linked to adverse pregnancy outcomes.

Treatment with anti-TNF agents may rapidly achieve and maintain remission, raising the question of the safety of continued anti-TNF use during pregnancy. The FDA classifies anti-TNF agents as category B drugs, as animal studies have not demonstrated fetal risk, and no well-controlled prospective study has yet been conducted with pregnant women.

In an observational study, Schnitzler et al¹⁰⁵ assessed the outcomes of 42 pregnancies in 35 patients with inflammatory bowel disease receiving either infliximab or adalimumab during pregnancy, compared with 56 pregnancies in 45 healthy patients without inflammatory bowel disease. There was no statistical difference in abortion rates between patients receiving anti-TNF agents and healthy women without inflammatory bowel disease (21% vs 14%, P = .4234). There was also no significant difference observed in birth weight, birth length, or cranial circumference of the children between the two groups. However, pregnancies with direct exposure to anti-TNF agents resulted in a higher frequency of premature delivery (25% vs 6%, P = .023).

Similar results were noted from the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool, or TREAT, registry, as well as from a large systematic review by Vinet et al¹⁰⁶ and case reports of rheumatoid arthritis and inflammatory bowel disease in women exposed to anti-TNF agents during pregnancy.

In addition, results from a recent systematic review of 38 studies of anti-TNF use and fetal risk, with a total of 437 women (189 on infliximab, 230 on adalimumab, 18 on certolizumab pegol), showed similar results.¹⁰⁷ In pregnancies exposed to anti-TNF agents, the rates of congenital abnormalities (3.4%), fetal deaths (8.5%), and preterm births (2.7%) were similar to those in the general population.

For patients in disease remission on TNF inhibitors, it is reasonable to continue these agents during pregnancy after careful discussion with the patient. Fetal safety and infant immunization response after delivery are the primary concerns in these cases.

Both infliximab and adalimumab cross the placenta and remain detectable in the baby’s circulation 4 months (for adalimumab) to 6 months (for infliximab) after delivery. It is currently recommended that infliximab be stopped at 32 weeks of gestation for the remainder of the pregnancy and that adalimumab be stopped at 34 to 36 weeks, given a planned 40-week gestation.

Certolizumab does not cross the placenta in significant amounts and should be continued throughout pregnancy; drug levels in infants were shown to be less than 2 μg/mL, even when dosed the week of delivery.^108–112

TAKE-HOME POINTS

• All health care providers of patients with rheumatoid arthritis and inflammatory bowel disease should be familiar with anti-TNF agents used in treating these diseases.
• The benefits of controlling the disease far outweigh the risks of therapy when used appropriately.
• Care of these patients should be multidisciplinary, with clear communication between primary care physician and specialist.
• Patient education and monitoring combined with prompt communication between primary care physician and specialist are key.

Biologic agents such as those that block tumor necrosis factor (TNF) alpha have revolutionized the treatment of autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease, dramatically improving disease control and quality of life. In addition, they have made true disease remission possible in some cases.

However, as with any new therapy, a variety of side effects must be considered.

WHAT ARE BIOLOGIC AGENTS?

Biologic agents are genetically engineered drugs manufactured or synthesized in vitro from molecules such as proteins, genes, and antibodies present in living organisms. By targeting specific molecular components of the inflammatory cascade, including cytokines, these drugs alter certain aspects of the body’s inflammatory response in autoimmune diseases. Because TNF inhibitors are the most widely used biologic agents in the United States, this review will focus on them.

TNF INHIBITORS

TNF inhibitors suppress the inflammatory cascade by inactivating TNF alpha, a cytokine that promotes inflammation in the intestine, synovial tissue, and other sites.^1,2

Several TNF inhibitors are available. Etanercept and infliximab were the first two to receive US Food and Drug Administration (FDA) approval, and they are extensively used. Etanercept, a soluble TNF receptor given subcutaneously, was approved for treating rheumatoid arthritis in 1998. Infliximab, a chimeric monoclonal antibody (75% human and 25% mouse protein sequence) given intravenously, received FDA approval for treating Crohn disease in 1998 and for rheumatoid arthritis in 1999. Other anti-TNF agents with varying properties are also available.

Table 1 lists anti-TNF agents approved for treating rheumatoid arthritis and inflammatory bowel disease. These are chronic, relapsing diseases that significantly and dramatically reduce quality of life, especially when they are poorly controlled.^3,4 Untreated disease has been associated with malignancy, infection, pregnancy loss, and malnutrition.^5–8 TNF inhibitors are aimed at patients who have moderate to severe disease or for whom previous treatments have failed, to help them achieve and maintain steroid-free remission. However, use of these agents is tempered by the risk of potentially serious side effects.

Special thought should also be given to the direct costs of the drugs (up to $30,000 per year, not counting the cost of their administration) and to the indirect costs such as time away from work to receive treatment. These are major considerations in some cases, and patients should be selected carefully for treatment with these drugs.

BEFORE STARTING THERAPY

Before starting anti-TNF therapy, several steps can reduce the risk of serious adverse events.

Take a focused history

The clinical history should include inquiries about previous bacterial, fungal, and tuberculosis infections or exposure; diabetes; and other immunocompromised states that increase the risk of acquiring potentially life-threatening infections.

Details of particular geographic areas of residence, occupational exposures, and social history should be sought. These include history of incarceration (which may put patients at risk of tuberculosis) and residence in the Ohio River valley or in the southwestern or midwestern United States (which may increase the risk of histoplasmosis, coccidioidomycosis, and other fungal infections).

Bring vaccinations up to date

Age-appropriate vaccinations should be discussed and given, ideally before starting therapy. These include influenza vaccine every year and tetanus boosters every 10 years for all and, as appropriate, varicella, human papillomavirus, and pneumococcal vaccinations. The US Centers for Disease Control and Prevention recommend an additional dose of the pneumococcal vaccine if more than 5 years have elapsed since the first one, and many clinicians opt to give it every 5 years.

In general, live-attenuated vaccines, including the intranasal influenza vaccine, are contraindicated in patients taking biologic agents.⁹ For patients at high risk of exposure or infection, it may be reasonable to hold the biologic agent for a period of time, vaccinate, and resume the biologic agent a month later.

Recent data suggest that the varicella zoster vaccine may be safely given to older patients with immune-mediated diseases such as rheumatoid arthritis and inflammatory bowel disease taking biologic agents.¹⁰ New guidelines from the American College of Rheumatology recommend age-appropriate vaccines for rheumatoid arthritis patients age 60 and older before biologic treatments are started. Case-by-case discussion with the subspecialist and the patient is recommended.

Screen for chronic infections

Tuberculosis screening with a purified protein derivative test or an interferon-gamma-release (Quantiferon) assay followed by chest radiography in patients with a positive test is mandatory before giving a TNF inhibitor.

Hepatitis B virus status should be determined before starting anti-TNF therapy.¹¹

Hepatitis B vaccination has been recommended for patients with inflammatory bowel disease, but no clear recommendation exists for patients with rheumatic disease. Patients with inflammatory bowel disease tend to have low rates of response to hepatitis B vaccination^12,13; possible reasons include their lack of an appropriate innate immune response to infectious agents, malnutrition, surgery, older age, and immunosuppressive drugs.¹⁴ An accelerated vaccination protocol with recombinant hepatitis B vaccine (Energix-B) in a double dose at 0, 1, and 2 months has been shown to improve response rates.¹⁵

Whenever possible, it may be better to vaccinate patients before starting immunosuppressive therapy, and to check postvaccination titers to ensure adequate response.

A full physical examination with special attention to skin rashes should be performed. This may serve as a baseline to assist early detection of new rashes associated with anti-TNF therapy.

A baseline complete blood cell count and complete metabolic panel should be routinely obtained before starting therapy (and thereafter at the discretion of the physician). In conjunction with follow-up tests, they can help detect an unexpected decrease in white blood cell count or abnormal results on the liver panel.¹⁶ These baseline and follow-up tests are generally performed by the subspecialist, and the results are shared with the primary care physician.

Table 2 summarizes key information to be sought before starting a patient on a TNF inhibitor.

ADVERSE EFFECTS OF ANTI-TNF DRUGS

Infusion reactions, infections, cardiac arrhythmias, demyelinating disorders, skin infections, and malignancies have been reported with anti-TNF therapy. The relative frequencies of these adverse events are summarized in Table 3.^17–22

NONINFECTIOUS COMPLICATIONS OF TNF INHIBITORS

Injection site reactions

When anti-TNF agents are given subcutaneously, injection site reactions are common (occurring in up to 40% of patients) and are considered minor.¹¹ Reactions, including significant pain, typically occur within the first few months of therapy. They can last 2 to 5 days but rarely warrant stopping therapy. Treatment with ice and an antihistamine is almost always sufficient to control symptoms.

Infusion reactions with infliximab

Infliximab can cause both acute and delayed infusion reactions. Acute reactions can occur up to 24 hours after infusion but usually appear within 10 minutes of administration and are handled by the infusion suite staff. They range from the severe immunoglobulin E-mediated type I reaction, manifesting with hypotension, bronchospasm, and urticaria, to the milder anaphylactoid-type reaction, which constitutes the majority.^23–25

While most primary care physicians will not encounter an acute reaction, family doctors and emergency room physicians may encounter delayed reactions, which can develop 1 to 14 days after infusion. These reactions usually resemble serum sickness and present with joint pain, fatigue, myalgia, and fever. But, unlike classic serum sickness, these reactions are generally not associated with a rash.

With nonspecific symptoms, the diagnosis may be easy to overlook. However, establishing this diagnosis is important because repeat therapy may result in a more severe reaction upon reexposure to the drug.

Once diagnosed, these reactions can be treated symptomatically with a combination of acetaminophen and diphenhydramine after discussion between the primary care physician and subspecialist.^23,24

Autoimmune syndromes

Several studies have reported a small percentage of patients treated with anti-TNF agents who develop paradoxical autoimmune conditions. These range from asymptomatic immunologic alterations, including the formation of antinuclear antibodies and antibodies to double-stranded DNA, to life-threatening systemic autoimmune diseases.^26,27

Autoimmune diseases associated with anti-TNF treatment include a lupus-like syndrome, vasculitides, and psoriatic skin lesions. These syndromes warrant stopping the inciting drug and, on occasion, giving corticosteroids. Most cases arise between 1 month and 1 year of starting treatment, and almost 75% resolve completely after the anti-TNF therapy is stopped.²⁶

Interestingly, anti-TNF agents are approved for treating psoriasis and psoriatic arthritis, but psoriasis has paradoxically developed in patients being treated with these drugs for other autoimmune diseases. The FDA has reviewed 69 cases of new-onset psoriasis with anti-TNF therapy, including 17 pustular and 15 palmoplantar cases. The 12 most severe cases resulted in hospitalization, and symptoms resolved in most after treatment cessation.²⁸

Fiorino et al²⁹ counted 18 reported cases of psoriasis induced by anti-TNF therapy in patients with inflammatory bowel disease and concluded that it is rare. Harrison et al³⁰ reported similar findings in patients with rheumatoid arthritis, with an increased incidence rate of 1.04 per 1,000 person-years. New-onset psoriasis was most common in patients treated with adalimumab. An example of the rash is seen in Figure 1.

CARDIOVASCULAR SIDE EFFECTS

Cardiovascular side effects of anti-TNF agents range from nonspecific and asymptomatic arrhythmias to worsening of heart failure.

Circulating levels of TNF are increased in patients with heart failure, and studies have evaluated the effects of TNF inhibition with infliximab on cardiac function and overall survival.^31,32 The combined risk of death from any cause or hospitalization from heart failure was significantly higher in the infliximab groups, and the effects persisted for up to 5 months after stopping therapy.

Other studies^22,33 have evaluated the effects of infliximab and etanercept on cardiac function and overall survival. Results showed possible exacerbation of heart failure with etanercept and increased risk of death with infliximab in patients with New York Heart Association (NYHA) class III or IV heart failure and left ventricular ejection fractions less than 35%.

Case reports have also described patients with worsening or new-onset heart failure on TNF inhibitors, including patients younger than 50 years and without identifiable cardiovascular risk factors.

Data analyses^31,34,35 from large clinical registries have reported no significant increase in heart failure attributable to TNF inhibitors. However, we have concerns about the methodology of these analyses.

Currently, anti-TNF therapy is contraindicated in patients with NYHA class III or IV heart failure. Data are inconclusive for patients with class I or II heart failure. Baseline echocardiography and cardiology consultation can be considered, with close monitoring and avoidance of high doses of TNF inhibitors. If heart failure develops in a patient on anti-TNF therapy, the drug should be discontinued and the patient should be evaluated further.³⁶

DEMYELINATING DISEASE, INCLUDING MULTIPLE SCLEROSIS

Anti-TNF agents have been associated with the onset or exacerbation of clinical symptoms and radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis.^37–40 Mohan et al³⁸ identified 19 cases of demyelinating events occurring after administration of anti-TNF agents in early 2001. In most cases, symptoms improved or resolved after therapy was stopped.

Optic neuritis,^41,42 bilateral optic neuropathy,⁴³ and aseptic meningitis⁴⁴ have also been reported, but these have occurred only rarely.

How common are these effects? Postmarketing surveillance in patients with rheumatoid arthritis yields an estimated incidence of demyelinating disorders of 1 per 1,000 patient-years with adalimumab therapy.⁴⁵ Complicating the assessment is an observed slight increase in risk of demyelinating conditions associated with inflammatory bowel disease.

Symptoms that should heighten the physician’s suspicion of this adverse effect include confusion, paresthesias, and ataxia. Patients on anti-TNF therapy who develop new visual symptoms should be checked for painless visual loss as a sign of early demyelinating disease.

Although data that conclusively link anti-TNF agents to multiple sclerosis are lacking, these drugs should not be initiated in patients who have a history of demyelinating disease, and treatment should be stopped promptly if the diagnosis is suspected.

MALIGNANCY

Whether anti-TNF therapy is directly linked to development of malignancies is difficult to determine. There are many confounding factors, including the risk of malignancy in underlying inflammatory disease and the concomitant use of other medications such as thiopurines, which have a known association with lymphoma.⁴⁶

The incidence of lymphoma is twice as high in rheumatoid arthritis patients as in the general population.⁴⁷ The risk is higher in those with more aggressive joint disease—the subset of rheumatoid arthritis patients who are more likely to be given anti-TNF agents.⁵

In patients with inflammatory bowel disease, the risk of cholangiocarcinoma is four times higher, and the risk of small-bowel adenocarcinoma is 16 to 18 times higher, but no increased risk of lymphoma has been identified in this population.^48,49

Data from six clinical trials of infliximab, including a long-term study of its safety in Crohn disease, suggest it poses no increase in overall risk of malignancy.^50–52 Similar results have been reported in patients with other rheumatic diseases.⁸ Information on this topic is constantly evolving, and studies range from case series to clinical trials to large patient registries.

The decision to use a TNF inhibitor should be based on the patient’s clinical picture and risk factors. Discussion of the risks and benefits of therapy with the patient should be clearly documented.

Non-Hodgkin lymphoma

Evidence about the risk of lymphoma with anti-TNF use is mixed, as up to two-thirds of patients on anti-TNF therapy have received concomitant nonbiologic immunosuppressive medications, making it difficult to determine the true risk from the biologic agents alone.⁵³ Current evidence both supports^9,53–56 and refutes^7,55,57–60 the idea that anti-TNF agents increase lymphoma risk.

In patients with inflammatory bowel disease, several population-based studies have not shown a clear increase in lymphoma risk with anti-TNF use.^56,59,60 Pedersen et al,⁶¹ in a meta-analysis of eight studies, confirmed these findings by showing no overall lymphoma risk in patients with inflammatory bowel disease.

However, a Canadian population-based study found a statistically significant increase in non-Hodgkin lymphoma in males with Crohn disease, with an incidence ratio of 3.63 (95% confidence interval [CI] 1.53–8.62).⁶¹ Additionally, Siegel et al⁶² found a significantly higher risk (6.1 cases per 10,000 patients) in patients treated with anti-TNF agents and thiopurines than in the general population (1.9 cases per 10,000 people). Although the difference was statistically significant, the overall risk is still very low.

Patients with rheumatoid arthritis seem to have a risk of lymphoma two to three times higher than in the general population. However, large population-based studies have not shown a statistically significant increase in the risk of lymphoma with anti-TNF therapy.⁶³

Hepatosplenic T-cell lymphoma is a rare subtype of peripheral T-cell non-Hodgkin lymphoma; 25 cases have been reported in patients receiving anti-TNF therapy.⁶⁴ Although the risk is extremely low (< 0.05%), physicians must carefully consider the risks and benefits of combination therapy, especially in young male patients with inflammatory bowel disease, since death is the usual outcome of this disease.^65–67

Skin cancers

Wolfe and Michaud⁸ evaluated malignancy risk in rheumatoid arthritis patients being treated with biologic agents, including TNF inhibitors, using a large longitudinal database. These data were compared with those of the US Surveillance, Epidemiology, and End-Results (SEER) national database. No increase in the overall cancer rate was seen in rheumatoid arthritis patients (standardized incidence ratio [SIR] 1.0, 95% CI 1.0–1.1).

However, melanoma was more common in rheumatoid arthritis patients compared with SEER rates (SIR 1.7, 95% CI 1.3–2.3).⁸ In addition, biologic therapy was associated with a higher (but not statistically significant) risk of melanoma (odds ratio [OR] 2.3, 95% CI 0.9–5.4) and a higher risk of nonmelanoma skin cancer (OR 1.5, 95% CI 1.2–1.8), but not of other types of cancer.⁸

INFECTION

Patients on anti-TNF therapy are at a higher risk of infection, ranging from minor to life-threatening bacterial infections, and including the reactivation of granulomatous and fungal infections. More importantly, these agents are similar to steroids in blunting signs of infection, which may delay diagnosis and treatment.

The management of infection in patients on anti-TNF medications varies from case to case. In general, patients with a minor infection that does not require hospitalization or intravenous antibiotics can continue the biologic therapy while taking oral antibiotics. TNF inhibitors must be held in the event of a major infection.

Consultation with an infectious disease specialist is recommended, especially in complex cases.

Bacterial infections

An increased risk of minor bacterial infections such as urinary tract and respiratory infections has been well documented in several randomized control trials of anti-TNF agents, though other studies have shown no such increase in risk.^33,51–59

The threshold for using antibiotics for a suspected bacterial infection is somewhat shifted in favor of treatment in patients on anti-TNF therapy. The reason is twofold: as previously noted, infections may be worse than they appear, because anti-TNF drugs can mask the signs and symptoms of a serious infection, and in patients on these drugs, an untreated bacterial infection may rapidly become life-threatening.

In general, broad-spectrum antibiotics are not warranted unless the source of infection is unclear or the patient is in danger of hemodynamic compromise.

Opportunistic infections

The association of anti-TNF agents with opportunistic infections could be viewed as an extension of their normal and intended therapeutic activity as potent immunosuppressive agents.⁶⁸ Rheumatoid arthritis and inflammatory bowel disease are usually associated with conditions and situations that predispose patients to opportunistic infections, such as decreased immune response, malnutrition or malabsorption, surgeries, and concomitant immunosuppressive medications.⁷ Combination therapy with other immunosuppressive drugs and older age appear to markedly increase the risk of opportunistic infections, including mycobacterial and fungal infections, in patients with inflammatory bowel disease.⁷

Overall, opportunistic infections represent a measurable risk of anti-TNF therapy, and awareness and vigilance are important, especially in areas where opportunistic infections such as histoplasmosis and coccidiomycosis are endemic.⁵⁰ Furthermore, physicians must be aware of the higher risk of opportunistic infections when multiple immunosuppressive drugs are used concurrently.

Anti-TNF agents increase the risk of de novo granulomatous infections and of reactivating such infections. Granuloma formation and intracellular destruction of mycobacteria depend on TNF. TNF is important in maintaining the anatomic integrity of granulomas where these organisms have been sequestered, and blocking TNF leads to breakdown of granulomas and release of virulent organisms.^69,70

TNF inhibitors increase the risk of reactivation of latent tuberculosis infection. The risk is greater with infliximab and adalimumab than with etanercept,^71,72 and it has been described with certolizumab.⁷⁴ Study results are varied thus far but show a risk of tuberculosis reactivation five to 30 times higher than in the general population, with tremendous variability in risk depending on background rates of previous exposure.

The absence of typical tuberculosis symptoms further complicates care in these cases. Fever, weight loss, and night sweats tend to be TNF-mediated and are therefore masked by anti-TNF agents, leading to atypical presentations. In addition, active tuberculosis infection associated with TNF inhibitors is more likely to involve extrapulmonary sites such as the skin and musculoskeletal system and to be disseminated at presentation.

A paradoxical worsening of tuberculosis symptoms may also be seen in patients with latent tuberculosis reactivation, especially after discontinuing anti-TNF therapy. This is thought to result from an immune reconstitution inflammatory syndrome.

The pretreatment evaluation should include a history of risk factors, a physical examination, and either a tuberculin skin test or an interferon-gamma-release assay. Interferon-gamma-release assays are particularly helpful in patients who have received bacille Calmette-Guérin vaccination. In patients who test positive or have been exposed, tuberculosis treatment should begin 4 weeks before starting anti-TNF therapy, though the optimal timing of antituberculosis agents is still controversial.^74–77

If tuberculosis develops in a patient on anti-TNF therapy, he or she should receive antituberculosis drugs. Anti-TNF therapy should be stopped and should be resumed after 2 months only if no other treatment option is available.⁷⁵

Invasive opportunistic fungal infections

Invasive opportunistic fungal infections have been reported with anti-TNF therapy, including histoplasmosis and coccidioidomycosis.^78–80 Most patients who had histoplasmosis were treated with other immunosuppressive therapies and resided in or were raised near the Ohio or Mississippi River valleys, where this disease is endemic. Similarly, most cases of coccidioidomycosis were in endemic areas of Arizona, California, and Nevada, and patients on concomitant immunosuppressive therapy.⁷⁸

Currently, there is no evidence to recommend obtaining Histoplasma capsulatum or Coccidioides immitis serologies before initiating anti-TNF therapy in patients in endemic areas.⁸¹ However, patients must be instructed to seek medical attention quickly for pulmonary or febrile illnesses.

Viral hepatitis infections

The data on hepatitis B and hepatitis C in patients on biologic therapies are mostly limited to case reports.

Hepatitis B. A small prospective study from Spain followed the liver biochemistry tests and hepatitis B status of 80 patients with Crohn disease treated with infliximab. Of three patients who were chronic hepatitis B carriers before starting infliximab, two experienced reactivation of hepatitis B after discontinuing infliximab, and one ultimately died. The third patient was treated with lamivudine concurrently with infliximab without clinical or biochemical changes during or after therapy.⁸²

Similar findings were observed in two patients with rheumatoid arthritis on treatment with infliximab. One of the patients required liver transplantation, and both were treated with lamivudine, resulting in normalization of liver function test results.^83,84

Recent reviews indicate that despite these findings, hepatitis B reactivation after anti-TNF withdrawal may not be common.⁸⁵ There are limited data on hepatitis B reactivation and associated liver dysfunction in patients with inflammatory bowel disease treated with immunosuppressants. In a retrospective multicenter trial by Loras et al⁸⁶ in patients with inflammatory bowel disease who had viral hepatitis, 36% of patients positive for hepatitis B surface antigen developed liver dysfunction, and six patients developed liver failure. In that study, treatment with more than two immunosuppressants was an independent predictor of hepatitis B reactivation.

Prolonged immunosuppression (longer than 3 months) has also been identified as an independent predictor of liver dysfunction (OR 3.06; 95% 95% CI 1.02–9.16).⁸⁷

The European Association for the Study of the Liver and the American Association for the Study of Liver Diseases recommend starting lamivudine before chemotherapy or immunomodulator or immunosuppressive therapy in hepatitis B virus carriers and continuing preventive treatment for at least 6 months after stopping immunomodulating drugs. Lamivudine at a dose of 100 mg/day may reduce the risk of reactivation of hepatitis B.^88–90 Tenofovir and entecavir may be useful alternatives in patients with hepatitis B who have never received nucleoside analogues. Hepatitis B reactivation did not occur in any of the 16 patients who received preventive entecavir treatment while receiving immunosuppressive treatments.^89,91

In patients receiving immunosuppressive therapy, hepatitis B reactivation is associated with significant morbidity and mortality. Although risk factors for reactivation of hepatitis B virus infection have been identified, we recommend preventive treatment for all carriers positive for hepatitis B surface antigen. This should be done regardless of the number, type, and dosage of immunosuppressants and regardless of hepatitis B virus DNA levels.⁹⁰

The frequency of hepatitis B and hepatitis C infection in patients with Crohn disease has been reported to be as high as 24%. The high incidence is thought to be secondary to multiple blood transfusions and surgeries.⁹² The use of biologic agents, including anti-TNF agents, in chronic hepatitis B virus- or hepatitis C virus-infected patients can lead to enhanced viral replication and hepatitis exacerbation.

Although active viral replication can occur during treatment with biologic agents, reactivation or exacerbation can also occur after the anti-TNF agent is stopped.⁸² This finding has prompted the recommendation that all candidates for biologic therapy be tested for hepatitis B immunization status, followed by immunization in nonimmune patients before starting anti-TNF therapy.^93,94

Hepatitis C. There are no guidelines that adequately address the use of anti-TNF agents in patients with chronic hepatitis C infection.

Several small retrospective studies in rheumatoid arthritis patients with hepatitis C have shown that TNF inhibitors can be safely used without worsening liver function tests or changing the viral load.^95–98 This is reassuring and provides the subspecialist with another treatment option, as other therapies such as disease-modifying antirheumatic drugs and steroids are known to aggravate viral hepatitis and increase the risk of viremia.⁹⁶

Although small retrospective studies and one large randomized double-blind placebo-controlled trial have shown TNF inhibitors to be relatively safe in rheumatoid arthritis patients with hepatitis C, their use in these patients should be considered only with caution if they have evidence of hepatic synthetic dysfunction (eg, hypoalbuminemia, thrombocytopenia, increased international normalized ratio). The American College of Rheumatology recommends avoiding TNF inhibitors in Child-Pugh classes B and C.⁹⁹

PREGNANCY

Physicians caring for patients with rheumatoid arthritis and inflammatory bowel disease must be aware of how these diseases affect fecundity and fertility and how the medications can affect conception and pregnancy. Many patients have difficulty conceiving while their autoimmune disease is active, and better disease control may improve fecundity and result in unanticipated pregnancy. Patients should be advised of the need for contraception if pregnancy is ill-advised or undesired.

Many patients seek advice about teratogenicity before conceiving, or seek guidance about rheumatoid arthritis and inflammatory bowel disease treatment while pregnant.

Several studies have reported a higher risk of adverse pregnancy outcomes in patients with rheumatoid arthritis and inflammatory bowel disease than in the general population.^99–105 In inflammatory bowel disease, the odds of a premature delivery or having a low-birth-weight child are twice as high as in the normal population.^100,103 Higher rates of cesarean delivery and stillbirth have also been reported. The main predisposing factor appears to be the disease activity at the time of conception, as active disease seems to be linked to adverse pregnancy outcomes.

Treatment with anti-TNF agents may rapidly achieve and maintain remission, raising the question of the safety of continued anti-TNF use during pregnancy. The FDA classifies anti-TNF agents as category B drugs, as animal studies have not demonstrated fetal risk, and no well-controlled prospective study has yet been conducted with pregnant women.

In an observational study, Schnitzler et al¹⁰⁵ assessed the outcomes of 42 pregnancies in 35 patients with inflammatory bowel disease receiving either infliximab or adalimumab during pregnancy, compared with 56 pregnancies in 45 healthy patients without inflammatory bowel disease. There was no statistical difference in abortion rates between patients receiving anti-TNF agents and healthy women without inflammatory bowel disease (21% vs 14%, P = .4234). There was also no significant difference observed in birth weight, birth length, or cranial circumference of the children between the two groups. However, pregnancies with direct exposure to anti-TNF agents resulted in a higher frequency of premature delivery (25% vs 6%, P = .023).

Similar results were noted from the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool, or TREAT, registry, as well as from a large systematic review by Vinet et al¹⁰⁶ and case reports of rheumatoid arthritis and inflammatory bowel disease in women exposed to anti-TNF agents during pregnancy.

In addition, results from a recent systematic review of 38 studies of anti-TNF use and fetal risk, with a total of 437 women (189 on infliximab, 230 on adalimumab, 18 on certolizumab pegol), showed similar results.¹⁰⁷ In pregnancies exposed to anti-TNF agents, the rates of congenital abnormalities (3.4%), fetal deaths (8.5%), and preterm births (2.7%) were similar to those in the general population.

For patients in disease remission on TNF inhibitors, it is reasonable to continue these agents during pregnancy after careful discussion with the patient. Fetal safety and infant immunization response after delivery are the primary concerns in these cases.

Both infliximab and adalimumab cross the placenta and remain detectable in the baby’s circulation 4 months (for adalimumab) to 6 months (for infliximab) after delivery. It is currently recommended that infliximab be stopped at 32 weeks of gestation for the remainder of the pregnancy and that adalimumab be stopped at 34 to 36 weeks, given a planned 40-week gestation.

Certolizumab does not cross the placenta in significant amounts and should be continued throughout pregnancy; drug levels in infants were shown to be less than 2 μg/mL, even when dosed the week of delivery.^108–112

TAKE-HOME POINTS

• All health care providers of patients with rheumatoid arthritis and inflammatory bowel disease should be familiar with anti-TNF agents used in treating these diseases.
• The benefits of controlling the disease far outweigh the risks of therapy when used appropriately.
• Care of these patients should be multidisciplinary, with clear communication between primary care physician and specialist.
• Patient education and monitoring combined with prompt communication between primary care physician and specialist are key.

Biologic agents such as those that block tumor necrosis factor (TNF) alpha have revolutionized the treatment of autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease, dramatically improving disease control and quality of life. In addition, they have made true disease remission possible in some cases.

However, as with any new therapy, a variety of side effects must be considered.

WHAT ARE BIOLOGIC AGENTS?

Biologic agents are genetically engineered drugs manufactured or synthesized in vitro from molecules such as proteins, genes, and antibodies present in living organisms. By targeting specific molecular components of the inflammatory cascade, including cytokines, these drugs alter certain aspects of the body’s inflammatory response in autoimmune diseases. Because TNF inhibitors are the most widely used biologic agents in the United States, this review will focus on them.

TNF INHIBITORS

TNF inhibitors suppress the inflammatory cascade by inactivating TNF alpha, a cytokine that promotes inflammation in the intestine, synovial tissue, and other sites.^1,2

Several TNF inhibitors are available. Etanercept and infliximab were the first two to receive US Food and Drug Administration (FDA) approval, and they are extensively used. Etanercept, a soluble TNF receptor given subcutaneously, was approved for treating rheumatoid arthritis in 1998. Infliximab, a chimeric monoclonal antibody (75% human and 25% mouse protein sequence) given intravenously, received FDA approval for treating Crohn disease in 1998 and for rheumatoid arthritis in 1999. Other anti-TNF agents with varying properties are also available.

Table 1 lists anti-TNF agents approved for treating rheumatoid arthritis and inflammatory bowel disease. These are chronic, relapsing diseases that significantly and dramatically reduce quality of life, especially when they are poorly controlled.^3,4 Untreated disease has been associated with malignancy, infection, pregnancy loss, and malnutrition.^5–8 TNF inhibitors are aimed at patients who have moderate to severe disease or for whom previous treatments have failed, to help them achieve and maintain steroid-free remission. However, use of these agents is tempered by the risk of potentially serious side effects.

Special thought should also be given to the direct costs of the drugs (up to $30,000 per year, not counting the cost of their administration) and to the indirect costs such as time away from work to receive treatment. These are major considerations in some cases, and patients should be selected carefully for treatment with these drugs.

BEFORE STARTING THERAPY

Before starting anti-TNF therapy, several steps can reduce the risk of serious adverse events.

Take a focused history

The clinical history should include inquiries about previous bacterial, fungal, and tuberculosis infections or exposure; diabetes; and other immunocompromised states that increase the risk of acquiring potentially life-threatening infections.

Details of particular geographic areas of residence, occupational exposures, and social history should be sought. These include history of incarceration (which may put patients at risk of tuberculosis) and residence in the Ohio River valley or in the southwestern or midwestern United States (which may increase the risk of histoplasmosis, coccidioidomycosis, and other fungal infections).

Bring vaccinations up to date

Age-appropriate vaccinations should be discussed and given, ideally before starting therapy. These include influenza vaccine every year and tetanus boosters every 10 years for all and, as appropriate, varicella, human papillomavirus, and pneumococcal vaccinations. The US Centers for Disease Control and Prevention recommend an additional dose of the pneumococcal vaccine if more than 5 years have elapsed since the first one, and many clinicians opt to give it every 5 years.

In general, live-attenuated vaccines, including the intranasal influenza vaccine, are contraindicated in patients taking biologic agents.⁹ For patients at high risk of exposure or infection, it may be reasonable to hold the biologic agent for a period of time, vaccinate, and resume the biologic agent a month later.

Recent data suggest that the varicella zoster vaccine may be safely given to older patients with immune-mediated diseases such as rheumatoid arthritis and inflammatory bowel disease taking biologic agents.¹⁰ New guidelines from the American College of Rheumatology recommend age-appropriate vaccines for rheumatoid arthritis patients age 60 and older before biologic treatments are started. Case-by-case discussion with the subspecialist and the patient is recommended.

Screen for chronic infections

Tuberculosis screening with a purified protein derivative test or an interferon-gamma-release (Quantiferon) assay followed by chest radiography in patients with a positive test is mandatory before giving a TNF inhibitor.

Hepatitis B virus status should be determined before starting anti-TNF therapy.¹¹

Hepatitis B vaccination has been recommended for patients with inflammatory bowel disease, but no clear recommendation exists for patients with rheumatic disease. Patients with inflammatory bowel disease tend to have low rates of response to hepatitis B vaccination^12,13; possible reasons include their lack of an appropriate innate immune response to infectious agents, malnutrition, surgery, older age, and immunosuppressive drugs.¹⁴ An accelerated vaccination protocol with recombinant hepatitis B vaccine (Energix-B) in a double dose at 0, 1, and 2 months has been shown to improve response rates.¹⁵

Whenever possible, it may be better to vaccinate patients before starting immunosuppressive therapy, and to check postvaccination titers to ensure adequate response.

A full physical examination with special attention to skin rashes should be performed. This may serve as a baseline to assist early detection of new rashes associated with anti-TNF therapy.

A baseline complete blood cell count and complete metabolic panel should be routinely obtained before starting therapy (and thereafter at the discretion of the physician). In conjunction with follow-up tests, they can help detect an unexpected decrease in white blood cell count or abnormal results on the liver panel.¹⁶ These baseline and follow-up tests are generally performed by the subspecialist, and the results are shared with the primary care physician.

Table 2 summarizes key information to be sought before starting a patient on a TNF inhibitor.

ADVERSE EFFECTS OF ANTI-TNF DRUGS

Infusion reactions, infections, cardiac arrhythmias, demyelinating disorders, skin infections, and malignancies have been reported with anti-TNF therapy. The relative frequencies of these adverse events are summarized in Table 3.^17–22

NONINFECTIOUS COMPLICATIONS OF TNF INHIBITORS

Injection site reactions

When anti-TNF agents are given subcutaneously, injection site reactions are common (occurring in up to 40% of patients) and are considered minor.¹¹ Reactions, including significant pain, typically occur within the first few months of therapy. They can last 2 to 5 days but rarely warrant stopping therapy. Treatment with ice and an antihistamine is almost always sufficient to control symptoms.

Infusion reactions with infliximab

Infliximab can cause both acute and delayed infusion reactions. Acute reactions can occur up to 24 hours after infusion but usually appear within 10 minutes of administration and are handled by the infusion suite staff. They range from the severe immunoglobulin E-mediated type I reaction, manifesting with hypotension, bronchospasm, and urticaria, to the milder anaphylactoid-type reaction, which constitutes the majority.^23–25

While most primary care physicians will not encounter an acute reaction, family doctors and emergency room physicians may encounter delayed reactions, which can develop 1 to 14 days after infusion. These reactions usually resemble serum sickness and present with joint pain, fatigue, myalgia, and fever. But, unlike classic serum sickness, these reactions are generally not associated with a rash.

With nonspecific symptoms, the diagnosis may be easy to overlook. However, establishing this diagnosis is important because repeat therapy may result in a more severe reaction upon reexposure to the drug.

Once diagnosed, these reactions can be treated symptomatically with a combination of acetaminophen and diphenhydramine after discussion between the primary care physician and subspecialist.^23,24

Autoimmune syndromes

Several studies have reported a small percentage of patients treated with anti-TNF agents who develop paradoxical autoimmune conditions. These range from asymptomatic immunologic alterations, including the formation of antinuclear antibodies and antibodies to double-stranded DNA, to life-threatening systemic autoimmune diseases.^26,27

Autoimmune diseases associated with anti-TNF treatment include a lupus-like syndrome, vasculitides, and psoriatic skin lesions. These syndromes warrant stopping the inciting drug and, on occasion, giving corticosteroids. Most cases arise between 1 month and 1 year of starting treatment, and almost 75% resolve completely after the anti-TNF therapy is stopped.²⁶

Interestingly, anti-TNF agents are approved for treating psoriasis and psoriatic arthritis, but psoriasis has paradoxically developed in patients being treated with these drugs for other autoimmune diseases. The FDA has reviewed 69 cases of new-onset psoriasis with anti-TNF therapy, including 17 pustular and 15 palmoplantar cases. The 12 most severe cases resulted in hospitalization, and symptoms resolved in most after treatment cessation.²⁸

Fiorino et al²⁹ counted 18 reported cases of psoriasis induced by anti-TNF therapy in patients with inflammatory bowel disease and concluded that it is rare. Harrison et al³⁰ reported similar findings in patients with rheumatoid arthritis, with an increased incidence rate of 1.04 per 1,000 person-years. New-onset psoriasis was most common in patients treated with adalimumab. An example of the rash is seen in Figure 1.

CARDIOVASCULAR SIDE EFFECTS

Cardiovascular side effects of anti-TNF agents range from nonspecific and asymptomatic arrhythmias to worsening of heart failure.

Circulating levels of TNF are increased in patients with heart failure, and studies have evaluated the effects of TNF inhibition with infliximab on cardiac function and overall survival.^31,32 The combined risk of death from any cause or hospitalization from heart failure was significantly higher in the infliximab groups, and the effects persisted for up to 5 months after stopping therapy.

Other studies^22,33 have evaluated the effects of infliximab and etanercept on cardiac function and overall survival. Results showed possible exacerbation of heart failure with etanercept and increased risk of death with infliximab in patients with New York Heart Association (NYHA) class III or IV heart failure and left ventricular ejection fractions less than 35%.

Case reports have also described patients with worsening or new-onset heart failure on TNF inhibitors, including patients younger than 50 years and without identifiable cardiovascular risk factors.

Data analyses^31,34,35 from large clinical registries have reported no significant increase in heart failure attributable to TNF inhibitors. However, we have concerns about the methodology of these analyses.

Currently, anti-TNF therapy is contraindicated in patients with NYHA class III or IV heart failure. Data are inconclusive for patients with class I or II heart failure. Baseline echocardiography and cardiology consultation can be considered, with close monitoring and avoidance of high doses of TNF inhibitors. If heart failure develops in a patient on anti-TNF therapy, the drug should be discontinued and the patient should be evaluated further.³⁶

DEMYELINATING DISEASE, INCLUDING MULTIPLE SCLEROSIS

Anti-TNF agents have been associated with the onset or exacerbation of clinical symptoms and radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis.^37–40 Mohan et al³⁸ identified 19 cases of demyelinating events occurring after administration of anti-TNF agents in early 2001. In most cases, symptoms improved or resolved after therapy was stopped.

Optic neuritis,^41,42 bilateral optic neuropathy,⁴³ and aseptic meningitis⁴⁴ have also been reported, but these have occurred only rarely.

How common are these effects? Postmarketing surveillance in patients with rheumatoid arthritis yields an estimated incidence of demyelinating disorders of 1 per 1,000 patient-years with adalimumab therapy.⁴⁵ Complicating the assessment is an observed slight increase in risk of demyelinating conditions associated with inflammatory bowel disease.

Symptoms that should heighten the physician’s suspicion of this adverse effect include confusion, paresthesias, and ataxia. Patients on anti-TNF therapy who develop new visual symptoms should be checked for painless visual loss as a sign of early demyelinating disease.

Although data that conclusively link anti-TNF agents to multiple sclerosis are lacking, these drugs should not be initiated in patients who have a history of demyelinating disease, and treatment should be stopped promptly if the diagnosis is suspected.

MALIGNANCY

Whether anti-TNF therapy is directly linked to development of malignancies is difficult to determine. There are many confounding factors, including the risk of malignancy in underlying inflammatory disease and the concomitant use of other medications such as thiopurines, which have a known association with lymphoma.⁴⁶

The incidence of lymphoma is twice as high in rheumatoid arthritis patients as in the general population.⁴⁷ The risk is higher in those with more aggressive joint disease—the subset of rheumatoid arthritis patients who are more likely to be given anti-TNF agents.⁵

In patients with inflammatory bowel disease, the risk of cholangiocarcinoma is four times higher, and the risk of small-bowel adenocarcinoma is 16 to 18 times higher, but no increased risk of lymphoma has been identified in this population.^48,49

Data from six clinical trials of infliximab, including a long-term study of its safety in Crohn disease, suggest it poses no increase in overall risk of malignancy.^50–52 Similar results have been reported in patients with other rheumatic diseases.⁸ Information on this topic is constantly evolving, and studies range from case series to clinical trials to large patient registries.

The decision to use a TNF inhibitor should be based on the patient’s clinical picture and risk factors. Discussion of the risks and benefits of therapy with the patient should be clearly documented.

Non-Hodgkin lymphoma

Evidence about the risk of lymphoma with anti-TNF use is mixed, as up to two-thirds of patients on anti-TNF therapy have received concomitant nonbiologic immunosuppressive medications, making it difficult to determine the true risk from the biologic agents alone.⁵³ Current evidence both supports^9,53–56 and refutes^7,55,57–60 the idea that anti-TNF agents increase lymphoma risk.

In patients with inflammatory bowel disease, several population-based studies have not shown a clear increase in lymphoma risk with anti-TNF use.^56,59,60 Pedersen et al,⁶¹ in a meta-analysis of eight studies, confirmed these findings by showing no overall lymphoma risk in patients with inflammatory bowel disease.

However, a Canadian population-based study found a statistically significant increase in non-Hodgkin lymphoma in males with Crohn disease, with an incidence ratio of 3.63 (95% confidence interval [CI] 1.53–8.62).⁶¹ Additionally, Siegel et al⁶² found a significantly higher risk (6.1 cases per 10,000 patients) in patients treated with anti-TNF agents and thiopurines than in the general population (1.9 cases per 10,000 people). Although the difference was statistically significant, the overall risk is still very low.

Patients with rheumatoid arthritis seem to have a risk of lymphoma two to three times higher than in the general population. However, large population-based studies have not shown a statistically significant increase in the risk of lymphoma with anti-TNF therapy.⁶³

Hepatosplenic T-cell lymphoma is a rare subtype of peripheral T-cell non-Hodgkin lymphoma; 25 cases have been reported in patients receiving anti-TNF therapy.⁶⁴ Although the risk is extremely low (< 0.05%), physicians must carefully consider the risks and benefits of combination therapy, especially in young male patients with inflammatory bowel disease, since death is the usual outcome of this disease.^65–67

Skin cancers

Wolfe and Michaud⁸ evaluated malignancy risk in rheumatoid arthritis patients being treated with biologic agents, including TNF inhibitors, using a large longitudinal database. These data were compared with those of the US Surveillance, Epidemiology, and End-Results (SEER) national database. No increase in the overall cancer rate was seen in rheumatoid arthritis patients (standardized incidence ratio [SIR] 1.0, 95% CI 1.0–1.1).

However, melanoma was more common in rheumatoid arthritis patients compared with SEER rates (SIR 1.7, 95% CI 1.3–2.3).⁸ In addition, biologic therapy was associated with a higher (but not statistically significant) risk of melanoma (odds ratio [OR] 2.3, 95% CI 0.9–5.4) and a higher risk of nonmelanoma skin cancer (OR 1.5, 95% CI 1.2–1.8), but not of other types of cancer.⁸

INFECTION

Patients on anti-TNF therapy are at a higher risk of infection, ranging from minor to life-threatening bacterial infections, and including the reactivation of granulomatous and fungal infections. More importantly, these agents are similar to steroids in blunting signs of infection, which may delay diagnosis and treatment.

The management of infection in patients on anti-TNF medications varies from case to case. In general, patients with a minor infection that does not require hospitalization or intravenous antibiotics can continue the biologic therapy while taking oral antibiotics. TNF inhibitors must be held in the event of a major infection.

Consultation with an infectious disease specialist is recommended, especially in complex cases.

Bacterial infections

An increased risk of minor bacterial infections such as urinary tract and respiratory infections has been well documented in several randomized control trials of anti-TNF agents, though other studies have shown no such increase in risk.^33,51–59

The threshold for using antibiotics for a suspected bacterial infection is somewhat shifted in favor of treatment in patients on anti-TNF therapy. The reason is twofold: as previously noted, infections may be worse than they appear, because anti-TNF drugs can mask the signs and symptoms of a serious infection, and in patients on these drugs, an untreated bacterial infection may rapidly become life-threatening.

In general, broad-spectrum antibiotics are not warranted unless the source of infection is unclear or the patient is in danger of hemodynamic compromise.

Opportunistic infections

The association of anti-TNF agents with opportunistic infections could be viewed as an extension of their normal and intended therapeutic activity as potent immunosuppressive agents.⁶⁸ Rheumatoid arthritis and inflammatory bowel disease are usually associated with conditions and situations that predispose patients to opportunistic infections, such as decreased immune response, malnutrition or malabsorption, surgeries, and concomitant immunosuppressive medications.⁷ Combination therapy with other immunosuppressive drugs and older age appear to markedly increase the risk of opportunistic infections, including mycobacterial and fungal infections, in patients with inflammatory bowel disease.⁷

Overall, opportunistic infections represent a measurable risk of anti-TNF therapy, and awareness and vigilance are important, especially in areas where opportunistic infections such as histoplasmosis and coccidiomycosis are endemic.⁵⁰ Furthermore, physicians must be aware of the higher risk of opportunistic infections when multiple immunosuppressive drugs are used concurrently.

Anti-TNF agents increase the risk of de novo granulomatous infections and of reactivating such infections. Granuloma formation and intracellular destruction of mycobacteria depend on TNF. TNF is important in maintaining the anatomic integrity of granulomas where these organisms have been sequestered, and blocking TNF leads to breakdown of granulomas and release of virulent organisms.^69,70

TNF inhibitors increase the risk of reactivation of latent tuberculosis infection. The risk is greater with infliximab and adalimumab than with etanercept,^71,72 and it has been described with certolizumab.⁷⁴ Study results are varied thus far but show a risk of tuberculosis reactivation five to 30 times higher than in the general population, with tremendous variability in risk depending on background rates of previous exposure.

The absence of typical tuberculosis symptoms further complicates care in these cases. Fever, weight loss, and night sweats tend to be TNF-mediated and are therefore masked by anti-TNF agents, leading to atypical presentations. In addition, active tuberculosis infection associated with TNF inhibitors is more likely to involve extrapulmonary sites such as the skin and musculoskeletal system and to be disseminated at presentation.

A paradoxical worsening of tuberculosis symptoms may also be seen in patients with latent tuberculosis reactivation, especially after discontinuing anti-TNF therapy. This is thought to result from an immune reconstitution inflammatory syndrome.

The pretreatment evaluation should include a history of risk factors, a physical examination, and either a tuberculin skin test or an interferon-gamma-release assay. Interferon-gamma-release assays are particularly helpful in patients who have received bacille Calmette-Guérin vaccination. In patients who test positive or have been exposed, tuberculosis treatment should begin 4 weeks before starting anti-TNF therapy, though the optimal timing of antituberculosis agents is still controversial.^74–77

If tuberculosis develops in a patient on anti-TNF therapy, he or she should receive antituberculosis drugs. Anti-TNF therapy should be stopped and should be resumed after 2 months only if no other treatment option is available.⁷⁵

Invasive opportunistic fungal infections

Invasive opportunistic fungal infections have been reported with anti-TNF therapy, including histoplasmosis and coccidioidomycosis.^78–80 Most patients who had histoplasmosis were treated with other immunosuppressive therapies and resided in or were raised near the Ohio or Mississippi River valleys, where this disease is endemic. Similarly, most cases of coccidioidomycosis were in endemic areas of Arizona, California, and Nevada, and patients on concomitant immunosuppressive therapy.⁷⁸

Currently, there is no evidence to recommend obtaining Histoplasma capsulatum or Coccidioides immitis serologies before initiating anti-TNF therapy in patients in endemic areas.⁸¹ However, patients must be instructed to seek medical attention quickly for pulmonary or febrile illnesses.

Viral hepatitis infections

The data on hepatitis B and hepatitis C in patients on biologic therapies are mostly limited to case reports.

Hepatitis B. A small prospective study from Spain followed the liver biochemistry tests and hepatitis B status of 80 patients with Crohn disease treated with infliximab. Of three patients who were chronic hepatitis B carriers before starting infliximab, two experienced reactivation of hepatitis B after discontinuing infliximab, and one ultimately died. The third patient was treated with lamivudine concurrently with infliximab without clinical or biochemical changes during or after therapy.⁸²

Similar findings were observed in two patients with rheumatoid arthritis on treatment with infliximab. One of the patients required liver transplantation, and both were treated with lamivudine, resulting in normalization of liver function test results.^83,84

Recent reviews indicate that despite these findings, hepatitis B reactivation after anti-TNF withdrawal may not be common.⁸⁵ There are limited data on hepatitis B reactivation and associated liver dysfunction in patients with inflammatory bowel disease treated with immunosuppressants. In a retrospective multicenter trial by Loras et al⁸⁶ in patients with inflammatory bowel disease who had viral hepatitis, 36% of patients positive for hepatitis B surface antigen developed liver dysfunction, and six patients developed liver failure. In that study, treatment with more than two immunosuppressants was an independent predictor of hepatitis B reactivation.

Prolonged immunosuppression (longer than 3 months) has also been identified as an independent predictor of liver dysfunction (OR 3.06; 95% 95% CI 1.02–9.16).⁸⁷

The European Association for the Study of the Liver and the American Association for the Study of Liver Diseases recommend starting lamivudine before chemotherapy or immunomodulator or immunosuppressive therapy in hepatitis B virus carriers and continuing preventive treatment for at least 6 months after stopping immunomodulating drugs. Lamivudine at a dose of 100 mg/day may reduce the risk of reactivation of hepatitis B.^88–90 Tenofovir and entecavir may be useful alternatives in patients with hepatitis B who have never received nucleoside analogues. Hepatitis B reactivation did not occur in any of the 16 patients who received preventive entecavir treatment while receiving immunosuppressive treatments.^89,91

In patients receiving immunosuppressive therapy, hepatitis B reactivation is associated with significant morbidity and mortality. Although risk factors for reactivation of hepatitis B virus infection have been identified, we recommend preventive treatment for all carriers positive for hepatitis B surface antigen. This should be done regardless of the number, type, and dosage of immunosuppressants and regardless of hepatitis B virus DNA levels.⁹⁰

The frequency of hepatitis B and hepatitis C infection in patients with Crohn disease has been reported to be as high as 24%. The high incidence is thought to be secondary to multiple blood transfusions and surgeries.⁹² The use of biologic agents, including anti-TNF agents, in chronic hepatitis B virus- or hepatitis C virus-infected patients can lead to enhanced viral replication and hepatitis exacerbation.

Although active viral replication can occur during treatment with biologic agents, reactivation or exacerbation can also occur after the anti-TNF agent is stopped.⁸² This finding has prompted the recommendation that all candidates for biologic therapy be tested for hepatitis B immunization status, followed by immunization in nonimmune patients before starting anti-TNF therapy.^93,94

Hepatitis C. There are no guidelines that adequately address the use of anti-TNF agents in patients with chronic hepatitis C infection.

Several small retrospective studies in rheumatoid arthritis patients with hepatitis C have shown that TNF inhibitors can be safely used without worsening liver function tests or changing the viral load.^95–98 This is reassuring and provides the subspecialist with another treatment option, as other therapies such as disease-modifying antirheumatic drugs and steroids are known to aggravate viral hepatitis and increase the risk of viremia.⁹⁶

Although small retrospective studies and one large randomized double-blind placebo-controlled trial have shown TNF inhibitors to be relatively safe in rheumatoid arthritis patients with hepatitis C, their use in these patients should be considered only with caution if they have evidence of hepatic synthetic dysfunction (eg, hypoalbuminemia, thrombocytopenia, increased international normalized ratio). The American College of Rheumatology recommends avoiding TNF inhibitors in Child-Pugh classes B and C.⁹⁹

PREGNANCY

Physicians caring for patients with rheumatoid arthritis and inflammatory bowel disease must be aware of how these diseases affect fecundity and fertility and how the medications can affect conception and pregnancy. Many patients have difficulty conceiving while their autoimmune disease is active, and better disease control may improve fecundity and result in unanticipated pregnancy. Patients should be advised of the need for contraception if pregnancy is ill-advised or undesired.

Many patients seek advice about teratogenicity before conceiving, or seek guidance about rheumatoid arthritis and inflammatory bowel disease treatment while pregnant.

Several studies have reported a higher risk of adverse pregnancy outcomes in patients with rheumatoid arthritis and inflammatory bowel disease than in the general population.^99–105 In inflammatory bowel disease, the odds of a premature delivery or having a low-birth-weight child are twice as high as in the normal population.^100,103 Higher rates of cesarean delivery and stillbirth have also been reported. The main predisposing factor appears to be the disease activity at the time of conception, as active disease seems to be linked to adverse pregnancy outcomes.

Treatment with anti-TNF agents may rapidly achieve and maintain remission, raising the question of the safety of continued anti-TNF use during pregnancy. The FDA classifies anti-TNF agents as category B drugs, as animal studies have not demonstrated fetal risk, and no well-controlled prospective study has yet been conducted with pregnant women.

In an observational study, Schnitzler et al¹⁰⁵ assessed the outcomes of 42 pregnancies in 35 patients with inflammatory bowel disease receiving either infliximab or adalimumab during pregnancy, compared with 56 pregnancies in 45 healthy patients without inflammatory bowel disease. There was no statistical difference in abortion rates between patients receiving anti-TNF agents and healthy women without inflammatory bowel disease (21% vs 14%, P = .4234). There was also no significant difference observed in birth weight, birth length, or cranial circumference of the children between the two groups. However, pregnancies with direct exposure to anti-TNF agents resulted in a higher frequency of premature delivery (25% vs 6%, P = .023).

Similar results were noted from the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool, or TREAT, registry, as well as from a large systematic review by Vinet et al¹⁰⁶ and case reports of rheumatoid arthritis and inflammatory bowel disease in women exposed to anti-TNF agents during pregnancy.

In addition, results from a recent systematic review of 38 studies of anti-TNF use and fetal risk, with a total of 437 women (189 on infliximab, 230 on adalimumab, 18 on certolizumab pegol), showed similar results.¹⁰⁷ In pregnancies exposed to anti-TNF agents, the rates of congenital abnormalities (3.4%), fetal deaths (8.5%), and preterm births (2.7%) were similar to those in the general population.

For patients in disease remission on TNF inhibitors, it is reasonable to continue these agents during pregnancy after careful discussion with the patient. Fetal safety and infant immunization response after delivery are the primary concerns in these cases.

Both infliximab and adalimumab cross the placenta and remain detectable in the baby’s circulation 4 months (for adalimumab) to 6 months (for infliximab) after delivery. It is currently recommended that infliximab be stopped at 32 weeks of gestation for the remainder of the pregnancy and that adalimumab be stopped at 34 to 36 weeks, given a planned 40-week gestation.

Certolizumab does not cross the placenta in significant amounts and should be continued throughout pregnancy; drug levels in infants were shown to be less than 2 μg/mL, even when dosed the week of delivery.^108–112

TAKE-HOME POINTS

• All health care providers of patients with rheumatoid arthritis and inflammatory bowel disease should be familiar with anti-TNF agents used in treating these diseases.
• The benefits of controlling the disease far outweigh the risks of therapy when used appropriately.
• Care of these patients should be multidisciplinary, with clear communication between primary care physician and specialist.
• Patient education and monitoring combined with prompt communication between primary care physician and specialist are key.