Percutaneous coronary intervention for acute coronary syndromes has evolved, and so, hand in hand, has antiplatelet therapy. With the advent of clopidogrel and newer agents, several studies demonstrated the benefits of dual antiplatelet therapy in preventing major vascular ischemic complications. The findings culminated in a guideline recommendation for at least 12 months of dual antiplatelet therapy after placement of a drug-eluting stent, when feasible—a class I recommendation (treatment should be given), level of evidence B (limited populations evaluated).^1,2 But extending dual antiplatelet therapy beyond 12 months had no strong favorable evidence until the recent Dual Antiplatelet Therapy (DAPT) study³ shed light on this topic.

Here, we review the evidence thus far on the optimal duration of dual antiplatelet therapy in the secondary prevention of coronary artery disease.

PLATELETS IN ACUTE CORONARY SYNDROMES AND STENT THROMBOSIS

Acute coronary syndromes begin with fissuring or ulceration of a vulnerable atherosclerotic plaque, followed by thrombosis and occlusion, mediated by platelet adhesion, activation, and aggregation (Figure 1). Transient occlusion results in unstable angina or non-ST-elevation myocardial infarction, while total occlusion usually results in ST-elevation myocardial infarction.

Platelet aggregation is prominent among the mechanisms leading to stent thrombosis and vaso-occlusive ischemic complications after percutaneous coronary intervention. Thus, antiplatelet agents play a vital role in both primary and secondary prevention of cardiovascular events.^4–6

Adhesion, activation, and aggregation

Adhesion. Disruption of the vascular endothelium as a result of vulnerable plaque fissuring or ulceration exposes subendothelial thrombogenic collagen and von Willebrand factor to blood. Collagen engages platelets through their glycoprotein (GP) Ia, IIa, and VI receptors, and von Willebrand factor binds platelets through the GP Ib-IX-V receptor.

Activation. Once platelets adhere to the subendothelium, they undergo a conformational change and become activated. Simultaneous release of various autocrine and paracrine mediators including adenosine diphosphate, serotonin, epinephrine, thromboxane, and various ligand-receptor interactions all contribute to the activation cascade.  Adenosine diphosphate binds to the platelet receptor P2Y₁, leading to an increase in intracellular calcium, and it binds to P2Y₁₂, leading to a decrease in cyclic adenosine monophosphate, both of which cause GP IIb/IIIa receptor activation. Thromboxane A₂ released by platelets by cyclo-oxygenase 1 binds to alpha or beta variant receptors and contributes to GP IIb/IIIa activation through elevation of intracellular calcium levels.

Aggregation and thrombosis. Exposure of tissue factor to plasma following plaque rupture activates the coagulation cascade via the extrinsic pathway, which generates thrombin, a powerful platelet activator that causes thrombus formation via fibrin. Thrombin binds to protease-activated receptors PAR-1 and PAR-4 on platelets, causing an increase in intracellular calcium and a decrease in cyclic adenosine monophosphate with subsequent GP IIb/IIIa activation. GP IIb/IIIa facilitates platelet aggregation by binding to fibrinogen and forming a stable platelet thrombus.

In the early stages of thrombus formation, platelets predominate (“white” thrombi); further organization with fibrin results in older “red” thrombi. The stages of thrombi vary in non-ST-elevation and ST-elevation myocardial infarction and are prognostic markers of death.^4–8

PERCUTANEOUS INTERVENTION, RESTENOSIS, AND STENT THROMBOSIS

Percutaneous coronary intervention, the preferred means of revascularization for many patients, is performed emergently in patients with ST-elevation myocardial infarction, urgently in those with acute coronary syndromes without ST elevation, and electively in those with stable ischemic symptoms.

Percutaneous revascularization techniques have evolved from balloon angioplasty to bare-metal stents to drug-eluting stents, but each of these procedures has been associated with a periprocedural and postprocedural risk of thrombosis.

Balloon angioplasty was associated with vascular intimal injury, inciting elastic vascular recoil and smooth muscle cell proliferation leading to restenosis.

Bare-metal stents reduced the restenosis rate by eliminating vascular recoil, although restenosis still occurred within the stent because of neointimal proliferation of vascular smooth muscle cells. This was an important limitation, as both acute and subacute stent thrombosis were refractory to aggressive anticoagulation regimens that were associated with major bleeding complications and longer hospital length of stay. Stenting became mainstream practice only after the ISAR⁹ and STARS¹⁰ trials showed that dual antiplatelet therapy controlled stent thrombosis.

Drug-eluting stents coated with anti-proliferative and anti-inflammatory polymers markedly reduced in-stent restenosis rates by suppressing the initial vascular smooth-muscle proliferative response. However, they were still associated with late and very late stent thrombosis with incomplete endothelialization, even up to 40 months after implantation. Proposed mechanisms include incomplete stent apposition and inflammatory hypersensitivity reactions to the polymer coating. Incomplete stent apposition associated with low-velocity blood flow at the junction of the stent strut and vessel wall, together with delayed endothelialization, promotes platelet adhesion and aggregation, followed by thrombus formation.¹¹

Second-generation drug-eluting stents have thinner struts and more biocompatible polymers and are thought to favor more complete re-endothelialization, reducing the rates of stent thrombosis.^8,12,13

Predictors of early stent thrombosis

The Dutch Stent Thrombosis Registry and other studies looked at risk factors for stent thrombosis.^14,15

Procedure-related factors included:

• Stent undersizing
• Residual uncovered dissections after angioplasty
• Longer stents
• Low flow after angioplasty (< 3 on the 0–3 Thrombolysis in Myocardial Infarction [TIMI] scale).

Lesion-related factors included:

• Intermediate coronary artery disease both proximal and distal to the culprit lesions
• Bifurcation lesions.

Patient-related factors included:

• Low left ventricular ejection fraction
• Diabetes mellitus
• Peripheral arterial disease
Premature discontinuation of clopidogrel.

ANTIPLATELET AGENTS: MECHANISM OF ACTION

Various pathways play synergistic roles in platelet activation and aggregation and thrombus formation, and different antiplatelet agents inhibit these specific pathways, thus complementing each other and having additive effects (Figure 2, Table 1).^5,16–21

Aspirin inhibits cyclo-oxygenase 1

Cyclo-oxygenase 1, found in platelets, endothelial cells, and other cells, catalyzes the conversion of arachidonic acid to thromboxane A₂. Aspirin irreversibly inhibits cyclo-oxygenase 1 by acetylating its serine residue, preventing formation of thromboxane A₂ and preventing platelet activation and aggregation.

P2Y₁₂ ADP receptor antagonists

Clopidogrel and prasugrel are thienopyridine agents that irreversibly inhibit the P2Y₁₂ receptor, thereby preventing binding of adenosine diphosphate and the subsequent platelet activation-aggregation cascade. They are both prodrugs and require conversion by cytochrome P450 enzymes to active metabolites. Prasugrel is 10 times more potent than clopidogrel due to more efficient formation of its active metabolite, and it achieves a comparable effect on platelet inhibition 30 minutes faster than the peak effect of clopidogrel at 6 hours. The overall peak inhibitory effect of prasugrel is twice that of clopidogrel.²²

Ticagrelor, a cyclopentyl-triazolo-pyrimidine, directly and reversibly inhibits the P2Y₁₂ ADP receptor. Unlike clopidogrel and prasugrel, it does not need to be converted to an active metabolite, and it noncompetitively inhibits P2Y₁₂ at a site different from the adenosine diphosphate binding site.²³ Like prasugrel, ticagrelor inhibits platelet function more rapidly and more completely than clopidogrel.

Cangrelor, an intravenously administered analogue of adenosine triphosphate, reversibly inhibits the P2Y₁₂ receptor. It has undergone phase 3 trials but is not yet approved for clinical use.²⁴

WHY DUAL ANTIPLATELET THERAPY?

Aspirin is good, clopidogrel is better

Aspirin has a well-validated role in both primary and secondary prevention of coronary and noncoronary atherosclerotic vascular disease.

The CAPRIE trial found clopidogrel monotherapy to be superior to aspirin monotherapy in patients with established atherosclerotic vascular disease.²⁵

After stenting, short-term dual therapy is better than short-term warfarin

Thrombotic complications in the early postprocedural period were a major limitation of stenting, and existing anticoagulation regimens were ineffective in preventing them.^26,27

The ISAR trial studied the benefit of combined antiplatelet vs anticoagulant therapy after stent placement. Patients randomized to receive combined aspirin plus ticlopidine (an early P2Y₁₂ inhibitor) had significantly lower rates of primary cardiac, hemorrhagic, and vascular events at 30 days.⁹ Two other trials confirmed this finding.^28,29

STARS¹⁰ also confirmed the benefit of aspirin and ticlopidine after stenting. Patients were randomly assigned to aspirin alone, aspirin plus warfarin, or aspirin plus ticlopidine after stent placement. The rate of stent thrombosis at 30 days was significantly lower in the dual antiplatelet group than in the other two groups. The dual antiplatelet group had a higher rate of bleeding than the aspirin-alone group, but the rate was similar to that of the aspirin-plus-warfarin group.

Long-term dual antiplatelet therapy is beneficial in several situations

ISAR and STARS were landmark trials that showed stent thrombosis could be reduced by dual antiplatelet therapy for a 30-day period. However, the long-term role of dual antiplatelet therapy was still unknown.

The CURE trial^30–32 randomized patients presenting with acute coronary syndromes without ST elevation to receive clopidogrel plus aspirin or placebo plus aspirin for 3 to 12 months. The rate of the primary end point (cardiac death, nonfatal myocardial infarction, or stroke) was significantly lower in the clopidogrel-plus-aspirin group. A similar benefit of dual antiplatelet therapy was seen in the subgroup of patients who underwent percutaneous coronary intervention. Both pretreatment with clopidogrel plus aspirin for a median of 10 days prior to percutaneous intervention and continuing it for a mean of 9 months reduced major adverse cardiovascular events.

The CREDO trial²⁰ found that the combination of clopidogrel and aspirin significantly reduced the incidence of death, myocardial infarction, or stroke at 1 year after percutaneous coronary intervention. A subgroup of patients in this trial who had a longer pretreatment interval with a loading clopidogrel dose showed a benefit at 28 days, which was not as evident with a shorter loading dose interval.

The CLARITY-TIMI 28 trial^33,34 showed the advantage of adding clopidogrel to aspirin in patients receiving fibrinolytic therapy for ST-elevation myocardial infarction. Adding clopidogrel both improved the patency of the infarct-related artery and reduced ischemic complications. In patients who subsequently underwent percutaneous coronary intervention and stenting, clopidogrel pretreatment was associated with a significant decrease in ischemic complications before and after the procedure. There was no significant increase in bleeding complications in either group.

COMMIT/CCS 2³⁵ also showed the benefit of dual antiplatelet therapy in patients with ST-elevation myocardial infarction. Clopidogrel added to aspirin during the short-term in-hospital or postdischarge treatment period significantly reduced a composite end point of reinfarction, death, or stroke as well as death from any cause.

The CHARISMA trial^36–38 aimed to determine if patients who were more stable (ie, no recent acute coronary syndrome event or percutaneous coronary intervention) would benefit. Overall, CHARISMA showed no benefit of adding clopidogrel to aspirin compared with aspirin alone in a broad population of patients with established vascular disease (secondary prevention) or risk factors for vascular disease (primary prevention).

But importantly, though no benefit was seen in the primary prevention group, the large subgroup of patients with established atherosclerotic vascular disease (12,153 of the 15,603 patients in the trial) did benefit from dual antiplatelet therapy.^36,37 This subgroup showed an overall reduction in absolute risk of 1.5% (relative risk 0.88, P = .046) over a median follow-up of 27.6 months. This benefit was even more apparent in the 9,478 patients with prior myocardial infarction, stroke, or peripheral artery disease, for whom the relative risk reduction was 17.1% (P = .01) and the reduction in absolute risk 1.5%.³⁸

These results are comparable to the 2% absolute risk reduction in the CURE trial for similar end points over 9 months. In both studies, there was no significant increase in the risk of major bleeding or intracranial bleeding in the clopidogrel-plus-aspirin groups, although minor bleeding was increased by dual antiplatelet therapy.

The rate of severe bleeding, which was the primary safety end point in CHARISMA, was not significantly different in the clopidogrel-plus-aspirin group compared with the placebo-plus-aspirin group (relative risk 1.25, 95% CI 0.97–1.61, P = .09).

Thus, although the CHARISMA findings were negative overall, the positive finding observed in the predominant subgroup of patients with established vascular disease can therefore be considered supportive of the results of the subsequent trials discussed below.

The PEGASUS-TIMI 54 trial³⁹ studied the benefit of adding ticagrelor (60 or 90 mg) to low-dose aspirin in patients with stable coronary artery disease who had had a myocardial infarction 1 to 3 years earlier.

Confirming the results of the CHARISMA subgroup analysis, the incidence of the ischemic primary efficacy end point (a composite of cardiovascular death, myocardial infarction, and stroke) was significantly lower in both groups receiving ticagrelor plus aspirin compared with those receiving placebo plus aspirin. The Kaplan-Meier rate at 3 years for the ticagrelor 90 mg-plus-aspirin group was 7.85% vs 9.04% for the placebo-plus-aspirin group (hazard ratio 0.85, 95% confidence interval [CI] 0.75–0.96, P = .008). The rate for the ticagrelor 60 mg-plus-aspirin group was 7.77% vs 9.04% for the placebo-plus-aspirin group (hazard ratio 0.84, 95% CI 0.74–0.95, P = .004).

The rates of all TIMI major and minor bleeding, as well as bleeding requiring transfusion or discontinuation of the study drug, were significantly higher in both ticagrelor dosing groups than in the placebo group (P < .01 for both groups vs placebo). The rates of fatal bleeding and nonfatal intracranial hemorrhage were not significantly higher. Although there was an overall reduction in ischemic end points with the addition of ticagrelor, there was also a significantly higher incidence of bleeding in this group.

Comment. Thus, with or without percutaneous coronary intervention in acute coronary syndrome as well as in stable coronary artery disease, dual antiplatelet therapy was shown to improve outcomes and decrease ischemic complications compared with aspirin alone. It provided benefit in the setting of acute coronary syndrome (in the CURE trial) and percutaneous coronary intervention (in the CREDO trial) for up to 1 year.

Major questions remained to be addressed:

• Do the results of CREDO, which was performed before the current interventional era and the use of drug-eluting stents, reflect outcomes after current interventional practice?
• Could shorter periods of dual antiplatelet therapy be sufficient, especially with newer stents with less risk of late thrombosis?
• Does the benefit of dual antiplatelet therapy extend beyond the 1-year time period tested in those trials to date?

RECOMMENDATIONS FOR DOSING

The American College of Cardiology Foundation/American Heart Association guidelines for dosing of antiplatelet agents for non-ST-elevation myocardial infarction are summarized in Table 2, and those for ST-elevation myocardial infarction are summarized in Table 3.^1,2

WOULD SHORTER THERAPY AFTER STENTING WORK AS WELL?

The American College of Cardiology Foundation/American Heart Association currently recommend dual antiplatelet therapy for at least 12 months after drug-eluting stent placement, with shorter courses appropriate for patients who develop excessive bleeding complications or who are at high risk of bleeding.

Four trials (Table 4) evaluated whether shorter durations of dual antiplatelet therapy would suffice: SECURITY,⁴⁰ EXCELLENT,⁴¹ OPTIMIZE,⁴² and RESET.⁴³ All of them showed that short-duration therapy was not inferior to standard-duration therapy.⁴⁴ These studies were comparable in that:

• Patients were randomized at the time of percutaneous coronary intervention or within 24 hours of it.
• Most patients received a second-generation drug-eluting stent, with the following exceptions: in EXCELLENT,⁴¹ one-fourth of patients received a Cypher first-generation drug-eluting stent, and in RESET,⁴³ approximately one-fourth of the patients received a sirolimus-eluting stent in the standard-duration group for short lesions. Those patients with longer lesions in the RESET standard-duration group received an evero­limus drug-eluting stent.
• The second antiplatelet added to aspirin in all studies was clopidogrel, with the exception of the SECURITY trial, in which fewer than 2% of patients received ticagrelor or prasugrel.⁴⁰
• All the trials except RESET excluded patients who had had a myocardial infarction within 72 hours, and thus most patients studied had a lower risk profile.
• All of the trials sought to study noninferiority of short- vs standard-duration dual antiplatelet therapy, defined as the occurrence of a primary end point at 1 year (a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, target vessel failure or revascularization, or bleeding).

Their low-risk patient populations and infrequent end points rendered these studies underpowered to make definitive conclusions about the relative efficacy of 6-months vs 12-months of dual antiplatelet therapy.

WOULD LONGER THERAPY BE BETTER?

The PRODIGY trial⁴⁵ assessed durations of dual antiplatelet therapy both shorter and longer than the conventional 1 year, randomizing patients undergoing placement of a bare-metal stent, first-generation drug-eluting stent, or second-generation drug-eluting stent to receive aspirin and clopidogrel for either 6 months or 24 months. The study showed no significant difference in primary outcomes in the short- or long-duration groups.

Other trials that compared the standard 12 months of dual antiplatelet therapy with extended duration beyond 12 months were DAPT,³ ARCTIC-Interruption,⁴⁶ and DES-LATE.⁴⁷ The trials were comparable in that:

• All patients were randomized after completing 12 months of dual antiplatelet therapy following drug-eluting stent placement.
• All patients who were included had been free of major cardiac ischemic events or bleeding during the 12 months following stent placement.
• The primary aim of all three studies was to compare primary end points in groups receiving aspirin alone vs extended dual antiplatelet therapy. The primary end point was a composite of death due to a cardiovascular cause, nonfatal myocardial infarction, stroke, or stent thrombosis.
• The principal safety end point was bleeding.

Although the two earlier studies (ARCTIC-Interruption and DES-LATE) did not show any benefit of extended dual antiplatelet therapy compared with the standard 12-month duration, the recent DAPT study did.

The DAPT study

The DAPT study³ was an international, multicenter, placebo-controlled, double-blind randomized trial designed to examine the benefit of dual antiplatelet therapy beyond 1 year in a patient population large enough to provide definitive assessment of benefit and risk.

A total of 9,961 patients who received drug-eluting stents were randomized after 12 months of dual antiplatelet therapy to receive either a thienopyridine (clopidogrel or prasugrel) plus aspirin or placebo plus aspirin. They were followed for an additional 18 months. The coprimary efficacy end points were stent thrombosis and a composite of death, myocardial infarction, or stroke, while the primary safety end point was moderate or severe bleeding. The patients were also observed from months 30 to 33 on aspirin alone after stopping the thienopyridine.

Results. Longer therapy substantially reduced the risks of stent thrombosis (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.17–0.48) and the composite ischemic end point (HR 0.71, 95% CI 0.59–0.85). Follow-up during the 3-month thienopyridine discontinuation phase starting at 30 months revealed convergence of the ischemic event-rate curves in the two groups, which suggested that continuing dual antiplatelet therapy beyond 30 months might have been beneficial. Myocardial infarction unrelated to stent thrombosis accounted for 55% of the treatment benefit of dual antiplatelet therapy.

The risk of bleeding was higher in the thienopyridine group during the treatment period (2.5% vs 1.6%, P = .001). There was also a higher rate of noncardiovascular mortality in the thienopyridine group, although this difference may have been due to chance.^3,48

Why were the results different?

All three trials included first- and second-generation drug-eluting stents, with different proportions in different trials. In ARCTIC-Interruption,⁴⁶ 43% of the patients in the continuation group had a first-generation stent, as did 64% of the patients in the dual antiplatelet group of DES-LATE.⁴⁷ In the DAPT trial,³ 38% of the patients in the longer-duration arm had a first-generation stent, and in 26% of cases it was a paclitaxel-eluting stent.

Only clopidogrel was used as the second antiplatelet agent in DES-LATE, whereas prasugrel was used in 10% of patients in ARCTIC-Interruption and 35% in DAPT.

Yet none of these differences seem to explain the differences in outcome among the studies. ARCTIC-Interruption and DES-LATE did not show any benefit of continued dual antiplatelet therapy beyond 12 months. DAPT showed benefit of extended therapy with prasugrel or with clopidogrel, and with first-generation or second-generation drug-eluting stents. The most likely explanation for the different results was that DAPT was the only trial sufficiently powered to definitively assess the end points, including stent thrombosis.

A balance between ischemic efficacy and bleeding risk is the major consideration with any antithrombotic and antiplatelet therapy. In the three largest trials we discussed (the vascular disease subgroups of CHARISMA,³⁸ PEGASUS,³⁹ and DAPT³), comparison of the prespecified efficacy and safety end points of each trial suggests that dual antiplatelet therapy has a net benefit, particularly given the irreversible nature of ischemic end points.

In CHARISMA,³⁸ 60 cardiovascular deaths, myocardial infarctions, or strokes were prevented per year per 10,000 patients treated, at the cost of 28 excess moderate bleeding events.

In PEGASUS,³⁹ 42 cardiovascular deaths, myocardial infarctions, or strokes were prevented, at the cost of 79 excess bleeding events requiring transfusion.

In DAPT (a selected population who had tolerated dual antiplatelet therapy for 1 year), 106 deaths, myocardial infarctions, or stroke events were prevented, at the cost of 47 excess moderate bleeding events^.3

Indirect comparisons between trials are problematic, given different end point definitions, populations, and background therapies. But their results suggest that less-intensive inhibition with clopidogrel as the second antiplatelet long-term (as in CHARISMA) may provide the best balance of benefit vs risk.

BALANCING RISK AND BENEFIT

The evidence is unequivocal that dual antiplatelet therapy suppresses coronary ischemic complications resulting from thrombosis at sites of spontaneous plaque rupture following acute coronary syndromes or mechanical plaque disruption and foreign body implantation associated with percutaneous coronary intervention.

Three large-scale trials (DAPT,³ PEGASUS,³⁹ and the secondary prevention subgroup of CHARISMA³⁸) showed that the protective effect of dual antiplatelet therapy continues with prolonged therapy in patients who have experienced an acute coronary syndrome event or have received a drug-eluting stent. That benefit seems to be due to the action of these therapies on the culprit vessel (the one that caused the acute coronary syndrome or the site of stenting), as well as nonculprit arteries, emphasizing that dual antiplatelet therapy protects against atherosclerosis progression and future plaque rupture events.

For the durations studied in the longest trials thus far, 30 months (DAPT³) and 36 months (PEGASUS³⁹), event curves continue to diverge, indicating that the advantage of dual antiplatelet therapy may persist for an indefinite period of time. Thus, indefinite therapy with dual antiplatelet agents can be supported, particularly in patients with advanced coronary artery disease or those who have had multiple coronary events.

We believe that the balance of evidence suggests that smaller studies that failed to show a benefit of longer-term therapy were underpowered to do so.

The ischemic protection is associated with the adverse effect of increased bleeding risk. Unfortunately, there has been little success in guiding dual antiplatelet therapy based on ischemic vs bleeding risk, in part because the same factors that predict risk of ischemic complications seem to predict increased susceptibility to bleeding. Nevertheless, indirect comparisons between studies suggest that for longer-term therapy clopidogrel may be superior to ticagrelor or prasugrel: the absolute excess bleeding risk with dual antiplatelet therapy vs aspirin in the CHARISMA secondary prevention subgroup was less than that in PEGASUS, with similar absolute reductions in ischemic events. So while the TRITON-TIMI 38²² and PLATO²³ trials support the superiority of prasugrel or ticagrelor over clopidogrel for the first year after acute coronary syndrome, subsequent years of therapy may best be provided with clopidogrel.

Some patients may have identifiable factors that place them at very high risk of bleeding—need for surgical procedures, need for anticoagulation, or occurrence of bleeding complications or excessive “nuisance bleeding.” In those patients, the data suggest that dual antiplatelet therapy could be discontinued after 6 months, or perhaps even 3 months in the highest bleeding risk circumstances after second-generation drug-eluting stent placement.

WOEST⁴⁹ was an open-label randomized controlled trial that studied the safety of antiplatelet regimens in patients on anticoagulation requiring percutaneous coronary interventions. Patients were randomized to double therapy with anticoagulant and clopidogrel vs triple therapy with additional aspirin following percutaneous coronary intervention. The primary end point was bleeding events within 1 year. Clopidogrel without aspirin was associated with significantly fewer bleeding events compared with triple therapy, with no increase in adverse ischemic events. The strategy tested in the WOEST trial seems reasonable in the specific group of patients who require ongoing anticoagulant therapy after drug-eluting stent placement, recognizing that the trial was somewhat underpowered to make definitive conclusions, particularly in patients at high risk for stent thrombosis.

Based on the results of PEGASUS and the CHARISMA subgroup with established ischemic burden, in which dual antiplatelet therapy was started after an interruption following the index coronary event, it is also reasonable to restart long-term dual antiplatelet therapy in patients who require interruption for short-term indications such as a surgical procedure.            

Percutaneous coronary intervention for acute coronary syndromes has evolved, and so, hand in hand, has antiplatelet therapy. With the advent of clopidogrel and newer agents, several studies demonstrated the benefits of dual antiplatelet therapy in preventing major vascular ischemic complications. The findings culminated in a guideline recommendation for at least 12 months of dual antiplatelet therapy after placement of a drug-eluting stent, when feasible—a class I recommendation (treatment should be given), level of evidence B (limited populations evaluated).^1,2 But extending dual antiplatelet therapy beyond 12 months had no strong favorable evidence until the recent Dual Antiplatelet Therapy (DAPT) study³ shed light on this topic.

Here, we review the evidence thus far on the optimal duration of dual antiplatelet therapy in the secondary prevention of coronary artery disease.

PLATELETS IN ACUTE CORONARY SYNDROMES AND STENT THROMBOSIS

Acute coronary syndromes begin with fissuring or ulceration of a vulnerable atherosclerotic plaque, followed by thrombosis and occlusion, mediated by platelet adhesion, activation, and aggregation (Figure 1). Transient occlusion results in unstable angina or non-ST-elevation myocardial infarction, while total occlusion usually results in ST-elevation myocardial infarction.

Platelet aggregation is prominent among the mechanisms leading to stent thrombosis and vaso-occlusive ischemic complications after percutaneous coronary intervention. Thus, antiplatelet agents play a vital role in both primary and secondary prevention of cardiovascular events.^4–6

Adhesion, activation, and aggregation

Adhesion. Disruption of the vascular endothelium as a result of vulnerable plaque fissuring or ulceration exposes subendothelial thrombogenic collagen and von Willebrand factor to blood. Collagen engages platelets through their glycoprotein (GP) Ia, IIa, and VI receptors, and von Willebrand factor binds platelets through the GP Ib-IX-V receptor.

Activation. Once platelets adhere to the subendothelium, they undergo a conformational change and become activated. Simultaneous release of various autocrine and paracrine mediators including adenosine diphosphate, serotonin, epinephrine, thromboxane, and various ligand-receptor interactions all contribute to the activation cascade.  Adenosine diphosphate binds to the platelet receptor P2Y₁, leading to an increase in intracellular calcium, and it binds to P2Y₁₂, leading to a decrease in cyclic adenosine monophosphate, both of which cause GP IIb/IIIa receptor activation. Thromboxane A₂ released by platelets by cyclo-oxygenase 1 binds to alpha or beta variant receptors and contributes to GP IIb/IIIa activation through elevation of intracellular calcium levels.

Aggregation and thrombosis. Exposure of tissue factor to plasma following plaque rupture activates the coagulation cascade via the extrinsic pathway, which generates thrombin, a powerful platelet activator that causes thrombus formation via fibrin. Thrombin binds to protease-activated receptors PAR-1 and PAR-4 on platelets, causing an increase in intracellular calcium and a decrease in cyclic adenosine monophosphate with subsequent GP IIb/IIIa activation. GP IIb/IIIa facilitates platelet aggregation by binding to fibrinogen and forming a stable platelet thrombus.

In the early stages of thrombus formation, platelets predominate (“white” thrombi); further organization with fibrin results in older “red” thrombi. The stages of thrombi vary in non-ST-elevation and ST-elevation myocardial infarction and are prognostic markers of death.^4–8

PERCUTANEOUS INTERVENTION, RESTENOSIS, AND STENT THROMBOSIS

Percutaneous coronary intervention, the preferred means of revascularization for many patients, is performed emergently in patients with ST-elevation myocardial infarction, urgently in those with acute coronary syndromes without ST elevation, and electively in those with stable ischemic symptoms.

Percutaneous revascularization techniques have evolved from balloon angioplasty to bare-metal stents to drug-eluting stents, but each of these procedures has been associated with a periprocedural and postprocedural risk of thrombosis.

Balloon angioplasty was associated with vascular intimal injury, inciting elastic vascular recoil and smooth muscle cell proliferation leading to restenosis.

Bare-metal stents reduced the restenosis rate by eliminating vascular recoil, although restenosis still occurred within the stent because of neointimal proliferation of vascular smooth muscle cells. This was an important limitation, as both acute and subacute stent thrombosis were refractory to aggressive anticoagulation regimens that were associated with major bleeding complications and longer hospital length of stay. Stenting became mainstream practice only after the ISAR⁹ and STARS¹⁰ trials showed that dual antiplatelet therapy controlled stent thrombosis.

Drug-eluting stents coated with anti-proliferative and anti-inflammatory polymers markedly reduced in-stent restenosis rates by suppressing the initial vascular smooth-muscle proliferative response. However, they were still associated with late and very late stent thrombosis with incomplete endothelialization, even up to 40 months after implantation. Proposed mechanisms include incomplete stent apposition and inflammatory hypersensitivity reactions to the polymer coating. Incomplete stent apposition associated with low-velocity blood flow at the junction of the stent strut and vessel wall, together with delayed endothelialization, promotes platelet adhesion and aggregation, followed by thrombus formation.¹¹

Second-generation drug-eluting stents have thinner struts and more biocompatible polymers and are thought to favor more complete re-endothelialization, reducing the rates of stent thrombosis.^8,12,13

Predictors of early stent thrombosis

The Dutch Stent Thrombosis Registry and other studies looked at risk factors for stent thrombosis.^14,15

Procedure-related factors included:

• Stent undersizing
• Residual uncovered dissections after angioplasty
• Longer stents
• Low flow after angioplasty (< 3 on the 0–3 Thrombolysis in Myocardial Infarction [TIMI] scale).

Lesion-related factors included:

• Intermediate coronary artery disease both proximal and distal to the culprit lesions
• Bifurcation lesions.

Patient-related factors included:

• Low left ventricular ejection fraction
• Diabetes mellitus
• Peripheral arterial disease
Premature discontinuation of clopidogrel.

ANTIPLATELET AGENTS: MECHANISM OF ACTION

Various pathways play synergistic roles in platelet activation and aggregation and thrombus formation, and different antiplatelet agents inhibit these specific pathways, thus complementing each other and having additive effects (Figure 2, Table 1).^5,16–21

Aspirin inhibits cyclo-oxygenase 1

Cyclo-oxygenase 1, found in platelets, endothelial cells, and other cells, catalyzes the conversion of arachidonic acid to thromboxane A₂. Aspirin irreversibly inhibits cyclo-oxygenase 1 by acetylating its serine residue, preventing formation of thromboxane A₂ and preventing platelet activation and aggregation.

P2Y₁₂ ADP receptor antagonists

Clopidogrel and prasugrel are thienopyridine agents that irreversibly inhibit the P2Y₁₂ receptor, thereby preventing binding of adenosine diphosphate and the subsequent platelet activation-aggregation cascade. They are both prodrugs and require conversion by cytochrome P450 enzymes to active metabolites. Prasugrel is 10 times more potent than clopidogrel due to more efficient formation of its active metabolite, and it achieves a comparable effect on platelet inhibition 30 minutes faster than the peak effect of clopidogrel at 6 hours. The overall peak inhibitory effect of prasugrel is twice that of clopidogrel.²²

Ticagrelor, a cyclopentyl-triazolo-pyrimidine, directly and reversibly inhibits the P2Y₁₂ ADP receptor. Unlike clopidogrel and prasugrel, it does not need to be converted to an active metabolite, and it noncompetitively inhibits P2Y₁₂ at a site different from the adenosine diphosphate binding site.²³ Like prasugrel, ticagrelor inhibits platelet function more rapidly and more completely than clopidogrel.

Cangrelor, an intravenously administered analogue of adenosine triphosphate, reversibly inhibits the P2Y₁₂ receptor. It has undergone phase 3 trials but is not yet approved for clinical use.²⁴

WHY DUAL ANTIPLATELET THERAPY?

Aspirin is good, clopidogrel is better

Aspirin has a well-validated role in both primary and secondary prevention of coronary and noncoronary atherosclerotic vascular disease.

The CAPRIE trial found clopidogrel monotherapy to be superior to aspirin monotherapy in patients with established atherosclerotic vascular disease.²⁵

After stenting, short-term dual therapy is better than short-term warfarin

Thrombotic complications in the early postprocedural period were a major limitation of stenting, and existing anticoagulation regimens were ineffective in preventing them.^26,27

The ISAR trial studied the benefit of combined antiplatelet vs anticoagulant therapy after stent placement. Patients randomized to receive combined aspirin plus ticlopidine (an early P2Y₁₂ inhibitor) had significantly lower rates of primary cardiac, hemorrhagic, and vascular events at 30 days.⁹ Two other trials confirmed this finding.^28,29

STARS¹⁰ also confirmed the benefit of aspirin and ticlopidine after stenting. Patients were randomly assigned to aspirin alone, aspirin plus warfarin, or aspirin plus ticlopidine after stent placement. The rate of stent thrombosis at 30 days was significantly lower in the dual antiplatelet group than in the other two groups. The dual antiplatelet group had a higher rate of bleeding than the aspirin-alone group, but the rate was similar to that of the aspirin-plus-warfarin group.

Long-term dual antiplatelet therapy is beneficial in several situations

ISAR and STARS were landmark trials that showed stent thrombosis could be reduced by dual antiplatelet therapy for a 30-day period. However, the long-term role of dual antiplatelet therapy was still unknown.

The CURE trial^30–32 randomized patients presenting with acute coronary syndromes without ST elevation to receive clopidogrel plus aspirin or placebo plus aspirin for 3 to 12 months. The rate of the primary end point (cardiac death, nonfatal myocardial infarction, or stroke) was significantly lower in the clopidogrel-plus-aspirin group. A similar benefit of dual antiplatelet therapy was seen in the subgroup of patients who underwent percutaneous coronary intervention. Both pretreatment with clopidogrel plus aspirin for a median of 10 days prior to percutaneous intervention and continuing it for a mean of 9 months reduced major adverse cardiovascular events.

The CREDO trial²⁰ found that the combination of clopidogrel and aspirin significantly reduced the incidence of death, myocardial infarction, or stroke at 1 year after percutaneous coronary intervention. A subgroup of patients in this trial who had a longer pretreatment interval with a loading clopidogrel dose showed a benefit at 28 days, which was not as evident with a shorter loading dose interval.

The CLARITY-TIMI 28 trial^33,34 showed the advantage of adding clopidogrel to aspirin in patients receiving fibrinolytic therapy for ST-elevation myocardial infarction. Adding clopidogrel both improved the patency of the infarct-related artery and reduced ischemic complications. In patients who subsequently underwent percutaneous coronary intervention and stenting, clopidogrel pretreatment was associated with a significant decrease in ischemic complications before and after the procedure. There was no significant increase in bleeding complications in either group.

COMMIT/CCS 2³⁵ also showed the benefit of dual antiplatelet therapy in patients with ST-elevation myocardial infarction. Clopidogrel added to aspirin during the short-term in-hospital or postdischarge treatment period significantly reduced a composite end point of reinfarction, death, or stroke as well as death from any cause.

The CHARISMA trial^36–38 aimed to determine if patients who were more stable (ie, no recent acute coronary syndrome event or percutaneous coronary intervention) would benefit. Overall, CHARISMA showed no benefit of adding clopidogrel to aspirin compared with aspirin alone in a broad population of patients with established vascular disease (secondary prevention) or risk factors for vascular disease (primary prevention).

But importantly, though no benefit was seen in the primary prevention group, the large subgroup of patients with established atherosclerotic vascular disease (12,153 of the 15,603 patients in the trial) did benefit from dual antiplatelet therapy.^36,37 This subgroup showed an overall reduction in absolute risk of 1.5% (relative risk 0.88, P = .046) over a median follow-up of 27.6 months. This benefit was even more apparent in the 9,478 patients with prior myocardial infarction, stroke, or peripheral artery disease, for whom the relative risk reduction was 17.1% (P = .01) and the reduction in absolute risk 1.5%.³⁸

These results are comparable to the 2% absolute risk reduction in the CURE trial for similar end points over 9 months. In both studies, there was no significant increase in the risk of major bleeding or intracranial bleeding in the clopidogrel-plus-aspirin groups, although minor bleeding was increased by dual antiplatelet therapy.

The rate of severe bleeding, which was the primary safety end point in CHARISMA, was not significantly different in the clopidogrel-plus-aspirin group compared with the placebo-plus-aspirin group (relative risk 1.25, 95% CI 0.97–1.61, P = .09).

Thus, although the CHARISMA findings were negative overall, the positive finding observed in the predominant subgroup of patients with established vascular disease can therefore be considered supportive of the results of the subsequent trials discussed below.

The PEGASUS-TIMI 54 trial³⁹ studied the benefit of adding ticagrelor (60 or 90 mg) to low-dose aspirin in patients with stable coronary artery disease who had had a myocardial infarction 1 to 3 years earlier.

Confirming the results of the CHARISMA subgroup analysis, the incidence of the ischemic primary efficacy end point (a composite of cardiovascular death, myocardial infarction, and stroke) was significantly lower in both groups receiving ticagrelor plus aspirin compared with those receiving placebo plus aspirin. The Kaplan-Meier rate at 3 years for the ticagrelor 90 mg-plus-aspirin group was 7.85% vs 9.04% for the placebo-plus-aspirin group (hazard ratio 0.85, 95% confidence interval [CI] 0.75–0.96, P = .008). The rate for the ticagrelor 60 mg-plus-aspirin group was 7.77% vs 9.04% for the placebo-plus-aspirin group (hazard ratio 0.84, 95% CI 0.74–0.95, P = .004).

The rates of all TIMI major and minor bleeding, as well as bleeding requiring transfusion or discontinuation of the study drug, were significantly higher in both ticagrelor dosing groups than in the placebo group (P < .01 for both groups vs placebo). The rates of fatal bleeding and nonfatal intracranial hemorrhage were not significantly higher. Although there was an overall reduction in ischemic end points with the addition of ticagrelor, there was also a significantly higher incidence of bleeding in this group.

Comment. Thus, with or without percutaneous coronary intervention in acute coronary syndrome as well as in stable coronary artery disease, dual antiplatelet therapy was shown to improve outcomes and decrease ischemic complications compared with aspirin alone. It provided benefit in the setting of acute coronary syndrome (in the CURE trial) and percutaneous coronary intervention (in the CREDO trial) for up to 1 year.

Major questions remained to be addressed:

• Do the results of CREDO, which was performed before the current interventional era and the use of drug-eluting stents, reflect outcomes after current interventional practice?
• Could shorter periods of dual antiplatelet therapy be sufficient, especially with newer stents with less risk of late thrombosis?
• Does the benefit of dual antiplatelet therapy extend beyond the 1-year time period tested in those trials to date?

RECOMMENDATIONS FOR DOSING

The American College of Cardiology Foundation/American Heart Association guidelines for dosing of antiplatelet agents for non-ST-elevation myocardial infarction are summarized in Table 2, and those for ST-elevation myocardial infarction are summarized in Table 3.^1,2

WOULD SHORTER THERAPY AFTER STENTING WORK AS WELL?

The American College of Cardiology Foundation/American Heart Association currently recommend dual antiplatelet therapy for at least 12 months after drug-eluting stent placement, with shorter courses appropriate for patients who develop excessive bleeding complications or who are at high risk of bleeding.

Four trials (Table 4) evaluated whether shorter durations of dual antiplatelet therapy would suffice: SECURITY,⁴⁰ EXCELLENT,⁴¹ OPTIMIZE,⁴² and RESET.⁴³ All of them showed that short-duration therapy was not inferior to standard-duration therapy.⁴⁴ These studies were comparable in that:

• Patients were randomized at the time of percutaneous coronary intervention or within 24 hours of it.
• Most patients received a second-generation drug-eluting stent, with the following exceptions: in EXCELLENT,⁴¹ one-fourth of patients received a Cypher first-generation drug-eluting stent, and in RESET,⁴³ approximately one-fourth of the patients received a sirolimus-eluting stent in the standard-duration group for short lesions. Those patients with longer lesions in the RESET standard-duration group received an evero­limus drug-eluting stent.
• The second antiplatelet added to aspirin in all studies was clopidogrel, with the exception of the SECURITY trial, in which fewer than 2% of patients received ticagrelor or prasugrel.⁴⁰
• All the trials except RESET excluded patients who had had a myocardial infarction within 72 hours, and thus most patients studied had a lower risk profile.
• All of the trials sought to study noninferiority of short- vs standard-duration dual antiplatelet therapy, defined as the occurrence of a primary end point at 1 year (a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, target vessel failure or revascularization, or bleeding).

Their low-risk patient populations and infrequent end points rendered these studies underpowered to make definitive conclusions about the relative efficacy of 6-months vs 12-months of dual antiplatelet therapy.

WOULD LONGER THERAPY BE BETTER?

The PRODIGY trial⁴⁵ assessed durations of dual antiplatelet therapy both shorter and longer than the conventional 1 year, randomizing patients undergoing placement of a bare-metal stent, first-generation drug-eluting stent, or second-generation drug-eluting stent to receive aspirin and clopidogrel for either 6 months or 24 months. The study showed no significant difference in primary outcomes in the short- or long-duration groups.

Other trials that compared the standard 12 months of dual antiplatelet therapy with extended duration beyond 12 months were DAPT,³ ARCTIC-Interruption,⁴⁶ and DES-LATE.⁴⁷ The trials were comparable in that:

• All patients were randomized after completing 12 months of dual antiplatelet therapy following drug-eluting stent placement.
• All patients who were included had been free of major cardiac ischemic events or bleeding during the 12 months following stent placement.
• The primary aim of all three studies was to compare primary end points in groups receiving aspirin alone vs extended dual antiplatelet therapy. The primary end point was a composite of death due to a cardiovascular cause, nonfatal myocardial infarction, stroke, or stent thrombosis.
• The principal safety end point was bleeding.

Although the two earlier studies (ARCTIC-Interruption and DES-LATE) did not show any benefit of extended dual antiplatelet therapy compared with the standard 12-month duration, the recent DAPT study did.

The DAPT study

The DAPT study³ was an international, multicenter, placebo-controlled, double-blind randomized trial designed to examine the benefit of dual antiplatelet therapy beyond 1 year in a patient population large enough to provide definitive assessment of benefit and risk.

A total of 9,961 patients who received drug-eluting stents were randomized after 12 months of dual antiplatelet therapy to receive either a thienopyridine (clopidogrel or prasugrel) plus aspirin or placebo plus aspirin. They were followed for an additional 18 months. The coprimary efficacy end points were stent thrombosis and a composite of death, myocardial infarction, or stroke, while the primary safety end point was moderate or severe bleeding. The patients were also observed from months 30 to 33 on aspirin alone after stopping the thienopyridine.

Results. Longer therapy substantially reduced the risks of stent thrombosis (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.17–0.48) and the composite ischemic end point (HR 0.71, 95% CI 0.59–0.85). Follow-up during the 3-month thienopyridine discontinuation phase starting at 30 months revealed convergence of the ischemic event-rate curves in the two groups, which suggested that continuing dual antiplatelet therapy beyond 30 months might have been beneficial. Myocardial infarction unrelated to stent thrombosis accounted for 55% of the treatment benefit of dual antiplatelet therapy.

The risk of bleeding was higher in the thienopyridine group during the treatment period (2.5% vs 1.6%, P = .001). There was also a higher rate of noncardiovascular mortality in the thienopyridine group, although this difference may have been due to chance.^3,48

Why were the results different?

All three trials included first- and second-generation drug-eluting stents, with different proportions in different trials. In ARCTIC-Interruption,⁴⁶ 43% of the patients in the continuation group had a first-generation stent, as did 64% of the patients in the dual antiplatelet group of DES-LATE.⁴⁷ In the DAPT trial,³ 38% of the patients in the longer-duration arm had a first-generation stent, and in 26% of cases it was a paclitaxel-eluting stent.

Only clopidogrel was used as the second antiplatelet agent in DES-LATE, whereas prasugrel was used in 10% of patients in ARCTIC-Interruption and 35% in DAPT.

Yet none of these differences seem to explain the differences in outcome among the studies. ARCTIC-Interruption and DES-LATE did not show any benefit of continued dual antiplatelet therapy beyond 12 months. DAPT showed benefit of extended therapy with prasugrel or with clopidogrel, and with first-generation or second-generation drug-eluting stents. The most likely explanation for the different results was that DAPT was the only trial sufficiently powered to definitively assess the end points, including stent thrombosis.

A balance between ischemic efficacy and bleeding risk is the major consideration with any antithrombotic and antiplatelet therapy. In the three largest trials we discussed (the vascular disease subgroups of CHARISMA,³⁸ PEGASUS,³⁹ and DAPT³), comparison of the prespecified efficacy and safety end points of each trial suggests that dual antiplatelet therapy has a net benefit, particularly given the irreversible nature of ischemic end points.

In CHARISMA,³⁸ 60 cardiovascular deaths, myocardial infarctions, or strokes were prevented per year per 10,000 patients treated, at the cost of 28 excess moderate bleeding events.

In PEGASUS,³⁹ 42 cardiovascular deaths, myocardial infarctions, or strokes were prevented, at the cost of 79 excess bleeding events requiring transfusion.

In DAPT (a selected population who had tolerated dual antiplatelet therapy for 1 year), 106 deaths, myocardial infarctions, or stroke events were prevented, at the cost of 47 excess moderate bleeding events^.3

Indirect comparisons between trials are problematic, given different end point definitions, populations, and background therapies. But their results suggest that less-intensive inhibition with clopidogrel as the second antiplatelet long-term (as in CHARISMA) may provide the best balance of benefit vs risk.

BALANCING RISK AND BENEFIT

The evidence is unequivocal that dual antiplatelet therapy suppresses coronary ischemic complications resulting from thrombosis at sites of spontaneous plaque rupture following acute coronary syndromes or mechanical plaque disruption and foreign body implantation associated with percutaneous coronary intervention.

Three large-scale trials (DAPT,³ PEGASUS,³⁹ and the secondary prevention subgroup of CHARISMA³⁸) showed that the protective effect of dual antiplatelet therapy continues with prolonged therapy in patients who have experienced an acute coronary syndrome event or have received a drug-eluting stent. That benefit seems to be due to the action of these therapies on the culprit vessel (the one that caused the acute coronary syndrome or the site of stenting), as well as nonculprit arteries, emphasizing that dual antiplatelet therapy protects against atherosclerosis progression and future plaque rupture events.

For the durations studied in the longest trials thus far, 30 months (DAPT³) and 36 months (PEGASUS³⁹), event curves continue to diverge, indicating that the advantage of dual antiplatelet therapy may persist for an indefinite period of time. Thus, indefinite therapy with dual antiplatelet agents can be supported, particularly in patients with advanced coronary artery disease or those who have had multiple coronary events.

We believe that the balance of evidence suggests that smaller studies that failed to show a benefit of longer-term therapy were underpowered to do so.

The ischemic protection is associated with the adverse effect of increased bleeding risk. Unfortunately, there has been little success in guiding dual antiplatelet therapy based on ischemic vs bleeding risk, in part because the same factors that predict risk of ischemic complications seem to predict increased susceptibility to bleeding. Nevertheless, indirect comparisons between studies suggest that for longer-term therapy clopidogrel may be superior to ticagrelor or prasugrel: the absolute excess bleeding risk with dual antiplatelet therapy vs aspirin in the CHARISMA secondary prevention subgroup was less than that in PEGASUS, with similar absolute reductions in ischemic events. So while the TRITON-TIMI 38²² and PLATO²³ trials support the superiority of prasugrel or ticagrelor over clopidogrel for the first year after acute coronary syndrome, subsequent years of therapy may best be provided with clopidogrel.

Some patients may have identifiable factors that place them at very high risk of bleeding—need for surgical procedures, need for anticoagulation, or occurrence of bleeding complications or excessive “nuisance bleeding.” In those patients, the data suggest that dual antiplatelet therapy could be discontinued after 6 months, or perhaps even 3 months in the highest bleeding risk circumstances after second-generation drug-eluting stent placement.

WOEST⁴⁹ was an open-label randomized controlled trial that studied the safety of antiplatelet regimens in patients on anticoagulation requiring percutaneous coronary interventions. Patients were randomized to double therapy with anticoagulant and clopidogrel vs triple therapy with additional aspirin following percutaneous coronary intervention. The primary end point was bleeding events within 1 year. Clopidogrel without aspirin was associated with significantly fewer bleeding events compared with triple therapy, with no increase in adverse ischemic events. The strategy tested in the WOEST trial seems reasonable in the specific group of patients who require ongoing anticoagulant therapy after drug-eluting stent placement, recognizing that the trial was somewhat underpowered to make definitive conclusions, particularly in patients at high risk for stent thrombosis.

Based on the results of PEGASUS and the CHARISMA subgroup with established ischemic burden, in which dual antiplatelet therapy was started after an interruption following the index coronary event, it is also reasonable to restart long-term dual antiplatelet therapy in patients who require interruption for short-term indications such as a surgical procedure.            

Percutaneous coronary intervention for acute coronary syndromes has evolved, and so, hand in hand, has antiplatelet therapy. With the advent of clopidogrel and newer agents, several studies demonstrated the benefits of dual antiplatelet therapy in preventing major vascular ischemic complications. The findings culminated in a guideline recommendation for at least 12 months of dual antiplatelet therapy after placement of a drug-eluting stent, when feasible—a class I recommendation (treatment should be given), level of evidence B (limited populations evaluated).^1,2 But extending dual antiplatelet therapy beyond 12 months had no strong favorable evidence until the recent Dual Antiplatelet Therapy (DAPT) study³ shed light on this topic.

Here, we review the evidence thus far on the optimal duration of dual antiplatelet therapy in the secondary prevention of coronary artery disease.

PLATELETS IN ACUTE CORONARY SYNDROMES AND STENT THROMBOSIS

Acute coronary syndromes begin with fissuring or ulceration of a vulnerable atherosclerotic plaque, followed by thrombosis and occlusion, mediated by platelet adhesion, activation, and aggregation (Figure 1). Transient occlusion results in unstable angina or non-ST-elevation myocardial infarction, while total occlusion usually results in ST-elevation myocardial infarction.

Platelet aggregation is prominent among the mechanisms leading to stent thrombosis and vaso-occlusive ischemic complications after percutaneous coronary intervention. Thus, antiplatelet agents play a vital role in both primary and secondary prevention of cardiovascular events.^4–6

Adhesion, activation, and aggregation

Adhesion. Disruption of the vascular endothelium as a result of vulnerable plaque fissuring or ulceration exposes subendothelial thrombogenic collagen and von Willebrand factor to blood. Collagen engages platelets through their glycoprotein (GP) Ia, IIa, and VI receptors, and von Willebrand factor binds platelets through the GP Ib-IX-V receptor.

Activation. Once platelets adhere to the subendothelium, they undergo a conformational change and become activated. Simultaneous release of various autocrine and paracrine mediators including adenosine diphosphate, serotonin, epinephrine, thromboxane, and various ligand-receptor interactions all contribute to the activation cascade.  Adenosine diphosphate binds to the platelet receptor P2Y₁, leading to an increase in intracellular calcium, and it binds to P2Y₁₂, leading to a decrease in cyclic adenosine monophosphate, both of which cause GP IIb/IIIa receptor activation. Thromboxane A₂ released by platelets by cyclo-oxygenase 1 binds to alpha or beta variant receptors and contributes to GP IIb/IIIa activation through elevation of intracellular calcium levels.

Aggregation and thrombosis. Exposure of tissue factor to plasma following plaque rupture activates the coagulation cascade via the extrinsic pathway, which generates thrombin, a powerful platelet activator that causes thrombus formation via fibrin. Thrombin binds to protease-activated receptors PAR-1 and PAR-4 on platelets, causing an increase in intracellular calcium and a decrease in cyclic adenosine monophosphate with subsequent GP IIb/IIIa activation. GP IIb/IIIa facilitates platelet aggregation by binding to fibrinogen and forming a stable platelet thrombus.

In the early stages of thrombus formation, platelets predominate (“white” thrombi); further organization with fibrin results in older “red” thrombi. The stages of thrombi vary in non-ST-elevation and ST-elevation myocardial infarction and are prognostic markers of death.^4–8

PERCUTANEOUS INTERVENTION, RESTENOSIS, AND STENT THROMBOSIS

Percutaneous coronary intervention, the preferred means of revascularization for many patients, is performed emergently in patients with ST-elevation myocardial infarction, urgently in those with acute coronary syndromes without ST elevation, and electively in those with stable ischemic symptoms.

Percutaneous revascularization techniques have evolved from balloon angioplasty to bare-metal stents to drug-eluting stents, but each of these procedures has been associated with a periprocedural and postprocedural risk of thrombosis.

Balloon angioplasty was associated with vascular intimal injury, inciting elastic vascular recoil and smooth muscle cell proliferation leading to restenosis.

Bare-metal stents reduced the restenosis rate by eliminating vascular recoil, although restenosis still occurred within the stent because of neointimal proliferation of vascular smooth muscle cells. This was an important limitation, as both acute and subacute stent thrombosis were refractory to aggressive anticoagulation regimens that were associated with major bleeding complications and longer hospital length of stay. Stenting became mainstream practice only after the ISAR⁹ and STARS¹⁰ trials showed that dual antiplatelet therapy controlled stent thrombosis.

Drug-eluting stents coated with anti-proliferative and anti-inflammatory polymers markedly reduced in-stent restenosis rates by suppressing the initial vascular smooth-muscle proliferative response. However, they were still associated with late and very late stent thrombosis with incomplete endothelialization, even up to 40 months after implantation. Proposed mechanisms include incomplete stent apposition and inflammatory hypersensitivity reactions to the polymer coating. Incomplete stent apposition associated with low-velocity blood flow at the junction of the stent strut and vessel wall, together with delayed endothelialization, promotes platelet adhesion and aggregation, followed by thrombus formation.¹¹

Second-generation drug-eluting stents have thinner struts and more biocompatible polymers and are thought to favor more complete re-endothelialization, reducing the rates of stent thrombosis.^8,12,13

Predictors of early stent thrombosis

The Dutch Stent Thrombosis Registry and other studies looked at risk factors for stent thrombosis.^14,15

Procedure-related factors included:

• Stent undersizing
• Residual uncovered dissections after angioplasty
• Longer stents
• Low flow after angioplasty (< 3 on the 0–3 Thrombolysis in Myocardial Infarction [TIMI] scale).

Lesion-related factors included:

• Intermediate coronary artery disease both proximal and distal to the culprit lesions
• Bifurcation lesions.

Patient-related factors included:

• Low left ventricular ejection fraction
• Diabetes mellitus
• Peripheral arterial disease
Premature discontinuation of clopidogrel.

ANTIPLATELET AGENTS: MECHANISM OF ACTION

Various pathways play synergistic roles in platelet activation and aggregation and thrombus formation, and different antiplatelet agents inhibit these specific pathways, thus complementing each other and having additive effects (Figure 2, Table 1).^5,16–21

Aspirin inhibits cyclo-oxygenase 1

Cyclo-oxygenase 1, found in platelets, endothelial cells, and other cells, catalyzes the conversion of arachidonic acid to thromboxane A₂. Aspirin irreversibly inhibits cyclo-oxygenase 1 by acetylating its serine residue, preventing formation of thromboxane A₂ and preventing platelet activation and aggregation.

P2Y₁₂ ADP receptor antagonists

Clopidogrel and prasugrel are thienopyridine agents that irreversibly inhibit the P2Y₁₂ receptor, thereby preventing binding of adenosine diphosphate and the subsequent platelet activation-aggregation cascade. They are both prodrugs and require conversion by cytochrome P450 enzymes to active metabolites. Prasugrel is 10 times more potent than clopidogrel due to more efficient formation of its active metabolite, and it achieves a comparable effect on platelet inhibition 30 minutes faster than the peak effect of clopidogrel at 6 hours. The overall peak inhibitory effect of prasugrel is twice that of clopidogrel.²²

Ticagrelor, a cyclopentyl-triazolo-pyrimidine, directly and reversibly inhibits the P2Y₁₂ ADP receptor. Unlike clopidogrel and prasugrel, it does not need to be converted to an active metabolite, and it noncompetitively inhibits P2Y₁₂ at a site different from the adenosine diphosphate binding site.²³ Like prasugrel, ticagrelor inhibits platelet function more rapidly and more completely than clopidogrel.

Cangrelor, an intravenously administered analogue of adenosine triphosphate, reversibly inhibits the P2Y₁₂ receptor. It has undergone phase 3 trials but is not yet approved for clinical use.²⁴

WHY DUAL ANTIPLATELET THERAPY?

Aspirin is good, clopidogrel is better

Aspirin has a well-validated role in both primary and secondary prevention of coronary and noncoronary atherosclerotic vascular disease.

The CAPRIE trial found clopidogrel monotherapy to be superior to aspirin monotherapy in patients with established atherosclerotic vascular disease.²⁵

After stenting, short-term dual therapy is better than short-term warfarin

Thrombotic complications in the early postprocedural period were a major limitation of stenting, and existing anticoagulation regimens were ineffective in preventing them.^26,27

The ISAR trial studied the benefit of combined antiplatelet vs anticoagulant therapy after stent placement. Patients randomized to receive combined aspirin plus ticlopidine (an early P2Y₁₂ inhibitor) had significantly lower rates of primary cardiac, hemorrhagic, and vascular events at 30 days.⁹ Two other trials confirmed this finding.^28,29

STARS¹⁰ also confirmed the benefit of aspirin and ticlopidine after stenting. Patients were randomly assigned to aspirin alone, aspirin plus warfarin, or aspirin plus ticlopidine after stent placement. The rate of stent thrombosis at 30 days was significantly lower in the dual antiplatelet group than in the other two groups. The dual antiplatelet group had a higher rate of bleeding than the aspirin-alone group, but the rate was similar to that of the aspirin-plus-warfarin group.

Long-term dual antiplatelet therapy is beneficial in several situations

ISAR and STARS were landmark trials that showed stent thrombosis could be reduced by dual antiplatelet therapy for a 30-day period. However, the long-term role of dual antiplatelet therapy was still unknown.

The CURE trial^30–32 randomized patients presenting with acute coronary syndromes without ST elevation to receive clopidogrel plus aspirin or placebo plus aspirin for 3 to 12 months. The rate of the primary end point (cardiac death, nonfatal myocardial infarction, or stroke) was significantly lower in the clopidogrel-plus-aspirin group. A similar benefit of dual antiplatelet therapy was seen in the subgroup of patients who underwent percutaneous coronary intervention. Both pretreatment with clopidogrel plus aspirin for a median of 10 days prior to percutaneous intervention and continuing it for a mean of 9 months reduced major adverse cardiovascular events.

The CREDO trial²⁰ found that the combination of clopidogrel and aspirin significantly reduced the incidence of death, myocardial infarction, or stroke at 1 year after percutaneous coronary intervention. A subgroup of patients in this trial who had a longer pretreatment interval with a loading clopidogrel dose showed a benefit at 28 days, which was not as evident with a shorter loading dose interval.

The CLARITY-TIMI 28 trial^33,34 showed the advantage of adding clopidogrel to aspirin in patients receiving fibrinolytic therapy for ST-elevation myocardial infarction. Adding clopidogrel both improved the patency of the infarct-related artery and reduced ischemic complications. In patients who subsequently underwent percutaneous coronary intervention and stenting, clopidogrel pretreatment was associated with a significant decrease in ischemic complications before and after the procedure. There was no significant increase in bleeding complications in either group.

COMMIT/CCS 2³⁵ also showed the benefit of dual antiplatelet therapy in patients with ST-elevation myocardial infarction. Clopidogrel added to aspirin during the short-term in-hospital or postdischarge treatment period significantly reduced a composite end point of reinfarction, death, or stroke as well as death from any cause.

The CHARISMA trial^36–38 aimed to determine if patients who were more stable (ie, no recent acute coronary syndrome event or percutaneous coronary intervention) would benefit. Overall, CHARISMA showed no benefit of adding clopidogrel to aspirin compared with aspirin alone in a broad population of patients with established vascular disease (secondary prevention) or risk factors for vascular disease (primary prevention).

But importantly, though no benefit was seen in the primary prevention group, the large subgroup of patients with established atherosclerotic vascular disease (12,153 of the 15,603 patients in the trial) did benefit from dual antiplatelet therapy.^36,37 This subgroup showed an overall reduction in absolute risk of 1.5% (relative risk 0.88, P = .046) over a median follow-up of 27.6 months. This benefit was even more apparent in the 9,478 patients with prior myocardial infarction, stroke, or peripheral artery disease, for whom the relative risk reduction was 17.1% (P = .01) and the reduction in absolute risk 1.5%.³⁸

These results are comparable to the 2% absolute risk reduction in the CURE trial for similar end points over 9 months. In both studies, there was no significant increase in the risk of major bleeding or intracranial bleeding in the clopidogrel-plus-aspirin groups, although minor bleeding was increased by dual antiplatelet therapy.

The rate of severe bleeding, which was the primary safety end point in CHARISMA, was not significantly different in the clopidogrel-plus-aspirin group compared with the placebo-plus-aspirin group (relative risk 1.25, 95% CI 0.97–1.61, P = .09).

Thus, although the CHARISMA findings were negative overall, the positive finding observed in the predominant subgroup of patients with established vascular disease can therefore be considered supportive of the results of the subsequent trials discussed below.

The PEGASUS-TIMI 54 trial³⁹ studied the benefit of adding ticagrelor (60 or 90 mg) to low-dose aspirin in patients with stable coronary artery disease who had had a myocardial infarction 1 to 3 years earlier.

Confirming the results of the CHARISMA subgroup analysis, the incidence of the ischemic primary efficacy end point (a composite of cardiovascular death, myocardial infarction, and stroke) was significantly lower in both groups receiving ticagrelor plus aspirin compared with those receiving placebo plus aspirin. The Kaplan-Meier rate at 3 years for the ticagrelor 90 mg-plus-aspirin group was 7.85% vs 9.04% for the placebo-plus-aspirin group (hazard ratio 0.85, 95% confidence interval [CI] 0.75–0.96, P = .008). The rate for the ticagrelor 60 mg-plus-aspirin group was 7.77% vs 9.04% for the placebo-plus-aspirin group (hazard ratio 0.84, 95% CI 0.74–0.95, P = .004).

The rates of all TIMI major and minor bleeding, as well as bleeding requiring transfusion or discontinuation of the study drug, were significantly higher in both ticagrelor dosing groups than in the placebo group (P < .01 for both groups vs placebo). The rates of fatal bleeding and nonfatal intracranial hemorrhage were not significantly higher. Although there was an overall reduction in ischemic end points with the addition of ticagrelor, there was also a significantly higher incidence of bleeding in this group.

Comment. Thus, with or without percutaneous coronary intervention in acute coronary syndrome as well as in stable coronary artery disease, dual antiplatelet therapy was shown to improve outcomes and decrease ischemic complications compared with aspirin alone. It provided benefit in the setting of acute coronary syndrome (in the CURE trial) and percutaneous coronary intervention (in the CREDO trial) for up to 1 year.

Major questions remained to be addressed:

• Do the results of CREDO, which was performed before the current interventional era and the use of drug-eluting stents, reflect outcomes after current interventional practice?
• Could shorter periods of dual antiplatelet therapy be sufficient, especially with newer stents with less risk of late thrombosis?
• Does the benefit of dual antiplatelet therapy extend beyond the 1-year time period tested in those trials to date?

RECOMMENDATIONS FOR DOSING

The American College of Cardiology Foundation/American Heart Association guidelines for dosing of antiplatelet agents for non-ST-elevation myocardial infarction are summarized in Table 2, and those for ST-elevation myocardial infarction are summarized in Table 3.^1,2

WOULD SHORTER THERAPY AFTER STENTING WORK AS WELL?

The American College of Cardiology Foundation/American Heart Association currently recommend dual antiplatelet therapy for at least 12 months after drug-eluting stent placement, with shorter courses appropriate for patients who develop excessive bleeding complications or who are at high risk of bleeding.

Four trials (Table 4) evaluated whether shorter durations of dual antiplatelet therapy would suffice: SECURITY,⁴⁰ EXCELLENT,⁴¹ OPTIMIZE,⁴² and RESET.⁴³ All of them showed that short-duration therapy was not inferior to standard-duration therapy.⁴⁴ These studies were comparable in that:

• Patients were randomized at the time of percutaneous coronary intervention or within 24 hours of it.
• Most patients received a second-generation drug-eluting stent, with the following exceptions: in EXCELLENT,⁴¹ one-fourth of patients received a Cypher first-generation drug-eluting stent, and in RESET,⁴³ approximately one-fourth of the patients received a sirolimus-eluting stent in the standard-duration group for short lesions. Those patients with longer lesions in the RESET standard-duration group received an evero­limus drug-eluting stent.
• The second antiplatelet added to aspirin in all studies was clopidogrel, with the exception of the SECURITY trial, in which fewer than 2% of patients received ticagrelor or prasugrel.⁴⁰
• All the trials except RESET excluded patients who had had a myocardial infarction within 72 hours, and thus most patients studied had a lower risk profile.
• All of the trials sought to study noninferiority of short- vs standard-duration dual antiplatelet therapy, defined as the occurrence of a primary end point at 1 year (a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, target vessel failure or revascularization, or bleeding).

Their low-risk patient populations and infrequent end points rendered these studies underpowered to make definitive conclusions about the relative efficacy of 6-months vs 12-months of dual antiplatelet therapy.

WOULD LONGER THERAPY BE BETTER?

The PRODIGY trial⁴⁵ assessed durations of dual antiplatelet therapy both shorter and longer than the conventional 1 year, randomizing patients undergoing placement of a bare-metal stent, first-generation drug-eluting stent, or second-generation drug-eluting stent to receive aspirin and clopidogrel for either 6 months or 24 months. The study showed no significant difference in primary outcomes in the short- or long-duration groups.

Other trials that compared the standard 12 months of dual antiplatelet therapy with extended duration beyond 12 months were DAPT,³ ARCTIC-Interruption,⁴⁶ and DES-LATE.⁴⁷ The trials were comparable in that:

• All patients were randomized after completing 12 months of dual antiplatelet therapy following drug-eluting stent placement.
• All patients who were included had been free of major cardiac ischemic events or bleeding during the 12 months following stent placement.
• The primary aim of all three studies was to compare primary end points in groups receiving aspirin alone vs extended dual antiplatelet therapy. The primary end point was a composite of death due to a cardiovascular cause, nonfatal myocardial infarction, stroke, or stent thrombosis.
• The principal safety end point was bleeding.

Although the two earlier studies (ARCTIC-Interruption and DES-LATE) did not show any benefit of extended dual antiplatelet therapy compared with the standard 12-month duration, the recent DAPT study did.

The DAPT study

The DAPT study³ was an international, multicenter, placebo-controlled, double-blind randomized trial designed to examine the benefit of dual antiplatelet therapy beyond 1 year in a patient population large enough to provide definitive assessment of benefit and risk.

A total of 9,961 patients who received drug-eluting stents were randomized after 12 months of dual antiplatelet therapy to receive either a thienopyridine (clopidogrel or prasugrel) plus aspirin or placebo plus aspirin. They were followed for an additional 18 months. The coprimary efficacy end points were stent thrombosis and a composite of death, myocardial infarction, or stroke, while the primary safety end point was moderate or severe bleeding. The patients were also observed from months 30 to 33 on aspirin alone after stopping the thienopyridine.

Results. Longer therapy substantially reduced the risks of stent thrombosis (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.17–0.48) and the composite ischemic end point (HR 0.71, 95% CI 0.59–0.85). Follow-up during the 3-month thienopyridine discontinuation phase starting at 30 months revealed convergence of the ischemic event-rate curves in the two groups, which suggested that continuing dual antiplatelet therapy beyond 30 months might have been beneficial. Myocardial infarction unrelated to stent thrombosis accounted for 55% of the treatment benefit of dual antiplatelet therapy.

The risk of bleeding was higher in the thienopyridine group during the treatment period (2.5% vs 1.6%, P = .001). There was also a higher rate of noncardiovascular mortality in the thienopyridine group, although this difference may have been due to chance.^3,48

Why were the results different?

All three trials included first- and second-generation drug-eluting stents, with different proportions in different trials. In ARCTIC-Interruption,⁴⁶ 43% of the patients in the continuation group had a first-generation stent, as did 64% of the patients in the dual antiplatelet group of DES-LATE.⁴⁷ In the DAPT trial,³ 38% of the patients in the longer-duration arm had a first-generation stent, and in 26% of cases it was a paclitaxel-eluting stent.

Only clopidogrel was used as the second antiplatelet agent in DES-LATE, whereas prasugrel was used in 10% of patients in ARCTIC-Interruption and 35% in DAPT.

Yet none of these differences seem to explain the differences in outcome among the studies. ARCTIC-Interruption and DES-LATE did not show any benefit of continued dual antiplatelet therapy beyond 12 months. DAPT showed benefit of extended therapy with prasugrel or with clopidogrel, and with first-generation or second-generation drug-eluting stents. The most likely explanation for the different results was that DAPT was the only trial sufficiently powered to definitively assess the end points, including stent thrombosis.

A balance between ischemic efficacy and bleeding risk is the major consideration with any antithrombotic and antiplatelet therapy. In the three largest trials we discussed (the vascular disease subgroups of CHARISMA,³⁸ PEGASUS,³⁹ and DAPT³), comparison of the prespecified efficacy and safety end points of each trial suggests that dual antiplatelet therapy has a net benefit, particularly given the irreversible nature of ischemic end points.

In CHARISMA,³⁸ 60 cardiovascular deaths, myocardial infarctions, or strokes were prevented per year per 10,000 patients treated, at the cost of 28 excess moderate bleeding events.

In PEGASUS,³⁹ 42 cardiovascular deaths, myocardial infarctions, or strokes were prevented, at the cost of 79 excess bleeding events requiring transfusion.

In DAPT (a selected population who had tolerated dual antiplatelet therapy for 1 year), 106 deaths, myocardial infarctions, or stroke events were prevented, at the cost of 47 excess moderate bleeding events^.3

Indirect comparisons between trials are problematic, given different end point definitions, populations, and background therapies. But their results suggest that less-intensive inhibition with clopidogrel as the second antiplatelet long-term (as in CHARISMA) may provide the best balance of benefit vs risk.

BALANCING RISK AND BENEFIT

The evidence is unequivocal that dual antiplatelet therapy suppresses coronary ischemic complications resulting from thrombosis at sites of spontaneous plaque rupture following acute coronary syndromes or mechanical plaque disruption and foreign body implantation associated with percutaneous coronary intervention.

Three large-scale trials (DAPT,³ PEGASUS,³⁹ and the secondary prevention subgroup of CHARISMA³⁸) showed that the protective effect of dual antiplatelet therapy continues with prolonged therapy in patients who have experienced an acute coronary syndrome event or have received a drug-eluting stent. That benefit seems to be due to the action of these therapies on the culprit vessel (the one that caused the acute coronary syndrome or the site of stenting), as well as nonculprit arteries, emphasizing that dual antiplatelet therapy protects against atherosclerosis progression and future plaque rupture events.

For the durations studied in the longest trials thus far, 30 months (DAPT³) and 36 months (PEGASUS³⁹), event curves continue to diverge, indicating that the advantage of dual antiplatelet therapy may persist for an indefinite period of time. Thus, indefinite therapy with dual antiplatelet agents can be supported, particularly in patients with advanced coronary artery disease or those who have had multiple coronary events.

We believe that the balance of evidence suggests that smaller studies that failed to show a benefit of longer-term therapy were underpowered to do so.

The ischemic protection is associated with the adverse effect of increased bleeding risk. Unfortunately, there has been little success in guiding dual antiplatelet therapy based on ischemic vs bleeding risk, in part because the same factors that predict risk of ischemic complications seem to predict increased susceptibility to bleeding. Nevertheless, indirect comparisons between studies suggest that for longer-term therapy clopidogrel may be superior to ticagrelor or prasugrel: the absolute excess bleeding risk with dual antiplatelet therapy vs aspirin in the CHARISMA secondary prevention subgroup was less than that in PEGASUS, with similar absolute reductions in ischemic events. So while the TRITON-TIMI 38²² and PLATO²³ trials support the superiority of prasugrel or ticagrelor over clopidogrel for the first year after acute coronary syndrome, subsequent years of therapy may best be provided with clopidogrel.

Some patients may have identifiable factors that place them at very high risk of bleeding—need for surgical procedures, need for anticoagulation, or occurrence of bleeding complications or excessive “nuisance bleeding.” In those patients, the data suggest that dual antiplatelet therapy could be discontinued after 6 months, or perhaps even 3 months in the highest bleeding risk circumstances after second-generation drug-eluting stent placement.

WOEST⁴⁹ was an open-label randomized controlled trial that studied the safety of antiplatelet regimens in patients on anticoagulation requiring percutaneous coronary interventions. Patients were randomized to double therapy with anticoagulant and clopidogrel vs triple therapy with additional aspirin following percutaneous coronary intervention. The primary end point was bleeding events within 1 year. Clopidogrel without aspirin was associated with significantly fewer bleeding events compared with triple therapy, with no increase in adverse ischemic events. The strategy tested in the WOEST trial seems reasonable in the specific group of patients who require ongoing anticoagulant therapy after drug-eluting stent placement, recognizing that the trial was somewhat underpowered to make definitive conclusions, particularly in patients at high risk for stent thrombosis.

Based on the results of PEGASUS and the CHARISMA subgroup with established ischemic burden, in which dual antiplatelet therapy was started after an interruption following the index coronary event, it is also reasonable to restart long-term dual antiplatelet therapy in patients who require interruption for short-term indications such as a surgical procedure.            

Despite the historic association of gout with royalty and “rich eating,” gout disproportionately affects those of lower socioeconomic status.¹ Risk factors for gout, including obesity, chronic kidney disease, diabetes, and hypertension, are more common in African Americans, resulting in a higher prevalence of the disease. In addition, African Americans are less likely to receive the aggressive treatment for gout advocated by professional societies, such as anti-inflammatory medications during flares and prophylactic urate-lowering therapy.

This article reviews the epidemiology of gout and its pathophysiology, risk factors, and optimal management, focusing on African Americans and strategies to reduce healthcare disparities in this patient population.

GOUT IS COMMON AND SERIOUS

Gout is the most common inflammatory arthritis in the United States today, affecting 4% of the adult US population.² It is a chronic disease associated with high levels of uric acid, usually manifesting as intermittent attacks of painful monoarthritis, although multiple joints may be involved.

Despite a popular misconception that gout is merely an episodic nuisance, it is a serious disease that can significantly affect physical function and quality of life.³ A 2013 systematic review found that quality of life was significantly reduced in patients with gout, particularly those with polyarticular gout, tophi, comorbidities, and radiographic damage.⁴

Economic costs include decreased worker productivity and increased absences from work.^5,6 From 2001 to 2005, an estimated 2 million visits were made to primary care providers due to gout.⁷ Because gout frequently coexists with diabetes, hypertension, coronary artery disease, and kidney disease, it is often overlooked during routine clinic visits.³

HIGH URIC ACID HAS MANY EFFECTS

Uric acid, a product of purine metabolism, is the key mediator of gouty arthritis. Accumulation of uric acid in joints and other tissues leads to an exuberant inflammatory response manifesting as a gouty attack. When uncontrolled, uric acid may crystallize in joints and other structures, leading to tophi formation, which can cause chronic deforming and erosive arthritis, known as chronic tophaceous gout.⁸

Although gout is considered to be a musculoskeletal disorder, recent evidence indicates that hyperuricemia plays an important role in the development of renal disease and contributes to cardiovascular morbidity and death.⁹ Several studies have found that reducing uric acid levels lowers cardiovascular mortality rates and retards the progression of chronic kidney disease.¹⁰

MEN AND CERTAIN RACIAL GROUPS MOST AFFECTED

Large-scale epidemiologic surveys have established that prevalence varies widely among population groups. Premenopausal women are less likely to be affected than men, presumably due to the effect of female hormones on renal tubular excretion of uric acid.¹¹

Certain Asian populations (Filipinos, Taiwanese, Micronesians, the Maoris of New Zealand, Hmong Chinese immigrants in Minnesota) and African Americans have a high prevalence, while people from several sub-Saharan African countries have a very low prevalence. These differences are likely due to a variety of reasons, including genetic predisposition; diet (Table 1); risk factors such as obesity, diabetes, and hypertension; less access to healthcare resources; and inappropriate treatment.^12,13

AFRICAN AMERICANS ARE A DIVERSE GROUP

“African Americans” are a highly heterogeneous group making up about 13% of the US population. Most scholars now consider racial identity largely a product of socioeconomic and political circumstances rather than a scientific concept.¹⁴ The US Census Bureau defines African Americans (or “blacks”) as those having origins in the black racial groups of Africa,¹⁵  but even this is problematic, since it combines people as diverse as descendants of 17th, 18th, and 19th century enslaved Africans with recent first-generation African immigrants, as well as with Caribbean- and Latino-Americans of African heritage.

In addition, many African Americans trace their ancestry to other racial and ethnic groups, especially European and Native American. A study of nine European DNA markers among 10 African American populations in the United States and one population of Jamaicans of African descent found a range of frequencies from 7% among Jamaicans to 23% among African Americans living in New Orleans.¹⁶

Although such diversity argues against generalizing healthcare needs for the entire African American community, some evidence indicates that genetic markers for gene-disease associations may be consistent across traditional racial boundaries.¹⁷

GENETIC FACTORS CANNOT EXPLAIN GOUT DISPARITIES

Several small studies have found evidence of genetic factors mediating the risk for hyperuricemia and gout. Twin studies indicate that hyperuricemia is highly heritable,¹⁸ although they do not show a concordance in the heritability of gout, suggesting that environmental factors also have an important role in developing clinical manifestations of the disease.¹²

Genome-wide association studies have identified 28 separate loci influencing uric acid levels, including genes for uric acid transporters (eg, SLC2A9 and ABCG2), and metabolic pathway regulators (eg, PDZK1, SCL22A12, and PRPSAP1), but the distribution among African Americans is largely unknown.¹⁹ One important exception is SLC2A9, a renal tubular transporter of uric acid: variants of SLC2A9 were found exclusively in African Americans, but the clinical significance of this association is unclear.²⁰

Several epidemiologic studies have looked at gout in African Americans.

In the Coronary Artery Risk Development in Young Adults study,²¹ young African Americans had lower levels of uric acid than whites after adjusting for body mass index (BMI), glomerular filtration rate (GFR), diet, and medications. But after up to 20 years of follow-up, the risk of hyperuricemia was 2.3 times higher in African American women than in white women (95% confidence interval [CI] 1.34–3.99). Such differences were not found between African American and white men.

The National Health and Nutritional Examination Survey (NHANES) found that African American adolescents had lower uric acid levels than white adolescents after taking into account sugar intake, GFR, BMI, and onset of puberty.²²

The Multiple Risk Factor Intervention Trial²³ also found that among those with high cardiovascular risk, the incidence of hyperuricemia and gout was lower in African Americans than in whites.

COMORBID DISEASES MAY EXPLAIN DISPARITIES

Despite some evidence that African Americans have genetic factors that are protective against gout, they have a much greater frequency of acquired risk factors for gout, including obesity, physical inactivity, hypertension, diabetes mellitus, renal failure, high intake of seafood, elevated blood lead levels, and use of antihypertensive medications (Table 2).

Hochberg et al²⁴ examined the incidence of gout in 352 African American and 571 white physicians and found higher rates in African Americans (9% vs 5%). The authors suggested different rates of hypertension as an explanation, although the use of antihypertensive medications such as diuretics that promote hyperuricemia confounds the strength of this conclusion.

AFRICAN AMERICANS NEED STANDARD TREATMENT . . .

Unlike for heart failure, in which subgroup analyses of large prospective studies have found different efficacies of medications in African Americans than in whites, no such data exist for gout. Although there is a higher risk of allopurinol hypersensitivity in ethnic groups that express the HLA-B*5801 polymorphism (eg, Han Chinese, Korean, Thai, Japanese, Portuguese), African Americans are not known to be at greater risk.²⁵ There are also no special precautions for using febuxostat or probenecid in African Americans.

Absent any compelling reason, gout management should be the same regardless of ethnicity.²⁶ Patients should be counseled on primary prevention measures such as dietary and behavioral modification and, if necessary, started on aggressive urate-lowering therapy.²⁷

. . . BUT ARE LESS LIKELY TO HAVE GOUT APPROPRIATELY TREATED

African Americans with gout are less likely to receive urate-lowering therapy.²⁸ According to the 2002 National Ambulatory Medical Care Survey in the United States, African Americans with gout are far less likely to receive allopurinol than whites (42% vs 80%; odds ratio [OR] 0.18; 95% CI 0.04–0.78).²³ Even when therapy is prescribed, rates of nonadherence are greater in African Americans than in whites (OR 1.86, 95% CI 1.52–2.27), though the authors do not speculate why this is so.²⁹ No studies have compared rates of prescribing febuxostat to African Americans vs whites.

African Americans are also less likely to receive ongoing routine care for their gout. A 2007 study³⁰ of 663 veterans found that physicians were 1.41 times less likely to adhere to three selected quality indicators when dealing with nonwhite than white patients (95% CI 0.52–3.84). The three quality indicators studied were:

• Lowering of daily allopurinol dose to below 300 mg/day in the presence of renal insufficiency (no longer considered a quality measure)
• Monitoring of serum urate level at least once during the first 6 months of continued use of a xanthine oxidase inhibitor, such as allopurinol
• Monitoring of complete blood cell count and creatinine kinase at least every 6 months in patients with renal impairment receiving long-term prophylactic oral colchicine (> 0.5 mg/day for at least 6 months).

The finding was independent of age, comorbidity index, healthcare access, and utilization characteristics (eg, number of inpatient and outpatient visits, type of physician, most frequently seen physician).

LIFESTYLE MODIFICATION

Dietary modification is a useful initial step toward reducing uric acid levels (Table 1).²⁷ The following measures are recommended:

Reduce alcohol intake. Alcoholic beverages, particularly beer, are strongly linked to hyperuricemia, according to a 2013 meta-analysis.³¹ Although alcohol consumption is lower in African Americans than in whites, mortality rates from cirrhosis and other alcohol-related diseases are 10% higher, suggesting metabolic differences that render African Americans more susceptible to the negative health effects of alcohol.³²

Avoid sugary drinks. Sweetened beverages, especially those rich in fructose, are also implicated in hyperuricemia and gout. NHANES found an increase in serum uric acid of 0.33 mg/dL (95% CI, 0.11–0.73) in those consuming one to three sugar-sweetened drinks per day compared with nonconsumers, adjusting for total energy intake, age, sex, medications, hypertension, and GFR.³³ A prospective study also found a relative risk of 1.85 for those who drink two or more sugar-sweetened beverages per day compared with those who drink fewer than one per month (95% CI 1.08–3.16).³⁴

Unfortunately, African Americans consume a disproportionate amount of sugar from all sources: 17% of African Americans are considered heavy consumers vs 9% of whites.³⁵

Limit foods rich in purines. Red meat, seafood, and some vegetables, including asparagus, spinach, peas, cauliflower, and mushrooms, are associated with increased serum uric acid levels. NHANES found that greater meat and seafood consumption was associated with increased uric acid levels. Choi et al³⁶ found that the risk of gout increased by 21% with each additional daily serving of meat; the relative risk of developing gout was 1.41 (95% CI 1.07–1.86) in the fifth quintile of meat intake compared with the first quintile, and 1.51 (95% CI 1.17–1.95) in the fifth quintile of seafood consumption.

Despite these associations with high-purine food consumption and gout, many purine-rich foods may not contribute to hyperuricemia, and therefore a low-purine diet may not be protective. Interestingly, purine-rich vegetable protein intake is not associated with increased gout risk.³⁷

Increase dairy consumption. Dairy in the diet is associated with a lower incidence of gout, with a decrease of 0.21 mg/dL (95% CI –0.37 to –0.04) in serum uric acid levels between the highest and lowest quintiles of dairy consumption.³⁸ A randomized controlled trial found a 10% reduction in serum uric acid levels with milk consumption.³⁹

Enjoy coffee. Coffee intake has been inversely correlated with gout. Daily intake of 4 to 5 cups of coffee is associated with a relative risk of 0.60 (95% CI 0.41–0.87) vs no coffee.⁴⁰

Vitamin C and cherry juice^41,42 have also been linked to lower gout risk, but the data are less robust.

Control weight. Primary care providers should advise patients to increase physical activity and maintain a healthy weight.

In a prospective study, Choi et al⁴³ found that, in men, the risk of gout increased with the BMI. Compared with men with BMIs in the range of 21 to 22.9 kg/m², the relative risks were:

• 1.95 (95% CI 1.44–2.65) at BMI 25 to 29.9 kg/m²
• 2.33 (95% CI 1.62–3.36) at BMI 30 to 34.9 kg/m²
• 2.97 (95% CI 1.73–5.10) at BMI > 35 kg/m².

In addition, those who gained more than 13.6 kg since age 21 had a relative risk of 1.99 (95% CI 1.49–2.66) of developing gout compared with those whose weight remained within 1.8 kg.  

For those who cannot achieve weight loss through conservative measures, bariatric surgery has shown promise. In a prospective study of 60 obese patients (BMI > 35 kg/m²) with gout and type 2 diabetes mellitus, uric acid steadily declined during the first year after bariatric surgery.⁴⁴

TREATMENT OF ACUTE ATTACKS

Gout can be effectively managed in most patients. Behavioral and pharmacologic interventions are cheap and effective and have been shown to halt further damage to joints as well as retard the progression of renal disease and reduce cardiovascular morbidity.

During acute attacks, anti-inflammatory medications, principally glucocorticoids, nonsteroidal anti-inflammatory drugs, and colchicine, should be given promptly to reduce the intensity and duration of flares.

Although traditional teaching has been that urate-lowering therapy should not be initiated during an acute gout attack because it could prolong the duration of the attack, guidelines now permit it, based on studies showing that therapy does not prolong attacks.^45,46

AGGRESSIVE URATE-LOWERING THERAPY FOR PROPHYLAXIS

Long-term treatment of gout is aimed at reducing uric acid levels by mitigating modifiable risk factors and through urate-lowering therapy.⁴⁶ For many patients, conservative management with dietary and other behavioral changes is not sufficient to prevent further attacks of gout, necessitating urate-lowering therapy. Comorbid diseases such as obesity, hypertension, chronic kidney disease, and diabetes should also be addressed because they promote hyperuricemia and gouty attacks.⁴⁷

A number of organizations have issued gout management guidelines over the past decade, including the American College of Rheumatology (ACR) in 2012, the European League Against Rheumatism (2006, updated in 2014), and the British Society of Rheumatology (2007). All recommend urate-lowering therapy to prevent gout flares.

The American and European guidelines recommend a target uric acid level below 6 mg/dL, and the British guidelines recommend a target below 5 mg/dL.⁴⁸ For patients with palpable and visible tophi, the ACR guidelines state that lowering to below 5 mg/dL may be needed.⁴⁶

First-line agents for urate-lowering therapy are xanthine oxidase inhibitors, which include allopurinol (costing $0.48 per generic 100-mg tablet or $0.92 per 300-mg tablet), and febuxostat ($5.38 per 40-mg or 80-mg tablet). For patients with contraindications or intolerances to allopurinol or febuxostat, probenecid ($1.15 per 500-mg tablet), which functions as a uricosuric agent (ie, increases urinary excretion of uric acid), may be used.

Losartan ($1.68 per 25-mg tablet) and fenofibrate ($1.91 per 48-mg tablet) are also often used to reduce uric acid levels, but they have only modest effects and are not approved for this indication in the United States.⁴⁹

MANAGE CHRONIC CASES WITH CONTINUED THERAPY

ACR guidelines strongly emphasize continuing prophylaxis in case of ongoing gout activity (ie, detection of tophi on examination, recent gout attacks, or chronic gouty arthritis) (Table 3). The following durations have been proposed for prophylaxis:

• 6 months after an attack
• 6 months after achieving target uric acid level in patients with evidence of tophi
• 3 months after achieving target uric acid level in patients with resolved tophi. 

Two randomized controlled trials support the use of the anti-inflammatory agent colchicine ($4.30 per tablet) for prophylaxis when initiating urate-lowering therapy.^50,51

Monitor uric acid levels, renal function, adverse effects

The initial dosage of urate-lowering agents depends on the presence of kidney disease (Table 3).

Allopurinol is typically started at 50 mg to 100 mg oral daily, and titrated upward in increments of 100 mg depending on uric acid levels. According to the ACR guidelines, uric acid levels should be measured every 2 to 5 weeks.⁴⁶ The Febuxostat vs Allopurinol Streamline Trial found that 97% of patients reached target uric acid levels within two titrations.⁵²

Especially during the first months of therapy, physicians should be vigilant for adverse effects of allopurinol, including hypersensitivity reaction (rash, fever, Stevens-Johnson syndrome), hepatotoxicity, and myelotoxicity (bone marrow suppression), and for effects of febuxostat, such as rash, diarrhea, elevations in aminotransferase levels, and upper respiratory tract infections.⁵³ Although the maximum acceptable dose of allopurinol is 800 mg even in chronic kidney disease, regularly monitoring for hypersensitivity reactions and other adverse effects is needed if doses are above 300 mg per day.⁴⁶

Routine follow-up is essential

Adherence to therapy should be assessed at every visit. Patients should be counseled that gout is a chronic disease and that they should continue on urate-lowering therapy even if they are not having acute attacks. Adverse effects of medications should be monitored and addressed, although for allopurinol and febuxostat these are rare beyond the first few months of initiation and titration. If worsening of gout or uric acid levels occurs, therapy should be augmented and contributors to hyperuricemia reviewed. In refractory cases, rheumatology consultation may be needed; medications such as pegloticase ($16,800/mL) may be deemed necessary for severe tophaceous gout or for patients who need more rapid reduction of urates.⁴⁹

STRATEGIES TO ADDRESS DISPARITIES

Creative approaches are needed to engage African American communities to reduce the burden of gout. No trials have been published evaluating methods for reducing health disparities with gout, but strategies for other chronic conditions may be applicable.

Incorporate guidelines better. Although setting and disseminating guidelines should ensure that care is standardized, studies have found that primary care physicians and rheumatologists frequently do not implement them.^3,54 Reasons cited for poor adherence to gout guidelines include their relatively recent release, poor patient adherence, lack of measurement tools, and inadequate education of primary care physicians. Incorporating the guidelines as “best practice advisories” into electronic medical record systems has been proposed to improve their implementation.⁴⁶

Use a team approach. Some quality improvement projects have used pharmacists and nurses to help implement gout guidelines. In two studies, empowering nurses and pharmacists to better educate patients and implement standardized protocols for titrating urate-lowering medications led to sustained improvements in maintaining serum uric acid levels less than 6 mg/dL.^55–57

Multidisciplinary involvement by nutritionists, physicians, and community health workers have been found to help improve glycemic control in African Americans.⁵⁸ Similar efforts can be undertaken to improve control of uric acid levels through dietary modification and improved compliance.

Address patient concerns. Substantial gaps exist in knowledge about gout between providers and the general population, although large studies specifically focusing on African Americans are lacking.⁵⁹ Qualitative studies suggest that patient experience of gout may vary depending on race, with African Americans more likely than whites to rank the following concerns regarding gout as high: dietary restrictions, emotional burden, severe pain, the need for canes or crutches during flares, and gout bringing their day to a halt.⁶⁰ Another study among African Americans with gout found concerns about the effectiveness of urate-lowering therapy, side effects of medications, polypharmacy, pill size, cost, refill issues, and forgetting to take medications regularly.⁶¹

Despite the historic association of gout with royalty and “rich eating,” gout disproportionately affects those of lower socioeconomic status.¹ Risk factors for gout, including obesity, chronic kidney disease, diabetes, and hypertension, are more common in African Americans, resulting in a higher prevalence of the disease. In addition, African Americans are less likely to receive the aggressive treatment for gout advocated by professional societies, such as anti-inflammatory medications during flares and prophylactic urate-lowering therapy.

This article reviews the epidemiology of gout and its pathophysiology, risk factors, and optimal management, focusing on African Americans and strategies to reduce healthcare disparities in this patient population.

GOUT IS COMMON AND SERIOUS

Gout is the most common inflammatory arthritis in the United States today, affecting 4% of the adult US population.² It is a chronic disease associated with high levels of uric acid, usually manifesting as intermittent attacks of painful monoarthritis, although multiple joints may be involved.

Despite a popular misconception that gout is merely an episodic nuisance, it is a serious disease that can significantly affect physical function and quality of life.³ A 2013 systematic review found that quality of life was significantly reduced in patients with gout, particularly those with polyarticular gout, tophi, comorbidities, and radiographic damage.⁴

Economic costs include decreased worker productivity and increased absences from work.^5,6 From 2001 to 2005, an estimated 2 million visits were made to primary care providers due to gout.⁷ Because gout frequently coexists with diabetes, hypertension, coronary artery disease, and kidney disease, it is often overlooked during routine clinic visits.³

HIGH URIC ACID HAS MANY EFFECTS

Uric acid, a product of purine metabolism, is the key mediator of gouty arthritis. Accumulation of uric acid in joints and other tissues leads to an exuberant inflammatory response manifesting as a gouty attack. When uncontrolled, uric acid may crystallize in joints and other structures, leading to tophi formation, which can cause chronic deforming and erosive arthritis, known as chronic tophaceous gout.⁸

Although gout is considered to be a musculoskeletal disorder, recent evidence indicates that hyperuricemia plays an important role in the development of renal disease and contributes to cardiovascular morbidity and death.⁹ Several studies have found that reducing uric acid levels lowers cardiovascular mortality rates and retards the progression of chronic kidney disease.¹⁰

MEN AND CERTAIN RACIAL GROUPS MOST AFFECTED

Large-scale epidemiologic surveys have established that prevalence varies widely among population groups. Premenopausal women are less likely to be affected than men, presumably due to the effect of female hormones on renal tubular excretion of uric acid.¹¹

Certain Asian populations (Filipinos, Taiwanese, Micronesians, the Maoris of New Zealand, Hmong Chinese immigrants in Minnesota) and African Americans have a high prevalence, while people from several sub-Saharan African countries have a very low prevalence. These differences are likely due to a variety of reasons, including genetic predisposition; diet (Table 1); risk factors such as obesity, diabetes, and hypertension; less access to healthcare resources; and inappropriate treatment.^12,13

AFRICAN AMERICANS ARE A DIVERSE GROUP

“African Americans” are a highly heterogeneous group making up about 13% of the US population. Most scholars now consider racial identity largely a product of socioeconomic and political circumstances rather than a scientific concept.¹⁴ The US Census Bureau defines African Americans (or “blacks”) as those having origins in the black racial groups of Africa,¹⁵  but even this is problematic, since it combines people as diverse as descendants of 17th, 18th, and 19th century enslaved Africans with recent first-generation African immigrants, as well as with Caribbean- and Latino-Americans of African heritage.

In addition, many African Americans trace their ancestry to other racial and ethnic groups, especially European and Native American. A study of nine European DNA markers among 10 African American populations in the United States and one population of Jamaicans of African descent found a range of frequencies from 7% among Jamaicans to 23% among African Americans living in New Orleans.¹⁶

Although such diversity argues against generalizing healthcare needs for the entire African American community, some evidence indicates that genetic markers for gene-disease associations may be consistent across traditional racial boundaries.¹⁷

GENETIC FACTORS CANNOT EXPLAIN GOUT DISPARITIES

Several small studies have found evidence of genetic factors mediating the risk for hyperuricemia and gout. Twin studies indicate that hyperuricemia is highly heritable,¹⁸ although they do not show a concordance in the heritability of gout, suggesting that environmental factors also have an important role in developing clinical manifestations of the disease.¹²

Genome-wide association studies have identified 28 separate loci influencing uric acid levels, including genes for uric acid transporters (eg, SLC2A9 and ABCG2), and metabolic pathway regulators (eg, PDZK1, SCL22A12, and PRPSAP1), but the distribution among African Americans is largely unknown.¹⁹ One important exception is SLC2A9, a renal tubular transporter of uric acid: variants of SLC2A9 were found exclusively in African Americans, but the clinical significance of this association is unclear.²⁰

Several epidemiologic studies have looked at gout in African Americans.

In the Coronary Artery Risk Development in Young Adults study,²¹ young African Americans had lower levels of uric acid than whites after adjusting for body mass index (BMI), glomerular filtration rate (GFR), diet, and medications. But after up to 20 years of follow-up, the risk of hyperuricemia was 2.3 times higher in African American women than in white women (95% confidence interval [CI] 1.34–3.99). Such differences were not found between African American and white men.

The National Health and Nutritional Examination Survey (NHANES) found that African American adolescents had lower uric acid levels than white adolescents after taking into account sugar intake, GFR, BMI, and onset of puberty.²²

The Multiple Risk Factor Intervention Trial²³ also found that among those with high cardiovascular risk, the incidence of hyperuricemia and gout was lower in African Americans than in whites.

COMORBID DISEASES MAY EXPLAIN DISPARITIES

Despite some evidence that African Americans have genetic factors that are protective against gout, they have a much greater frequency of acquired risk factors for gout, including obesity, physical inactivity, hypertension, diabetes mellitus, renal failure, high intake of seafood, elevated blood lead levels, and use of antihypertensive medications (Table 2).

Hochberg et al²⁴ examined the incidence of gout in 352 African American and 571 white physicians and found higher rates in African Americans (9% vs 5%). The authors suggested different rates of hypertension as an explanation, although the use of antihypertensive medications such as diuretics that promote hyperuricemia confounds the strength of this conclusion.

AFRICAN AMERICANS NEED STANDARD TREATMENT . . .

Unlike for heart failure, in which subgroup analyses of large prospective studies have found different efficacies of medications in African Americans than in whites, no such data exist for gout. Although there is a higher risk of allopurinol hypersensitivity in ethnic groups that express the HLA-B*5801 polymorphism (eg, Han Chinese, Korean, Thai, Japanese, Portuguese), African Americans are not known to be at greater risk.²⁵ There are also no special precautions for using febuxostat or probenecid in African Americans.

Absent any compelling reason, gout management should be the same regardless of ethnicity.²⁶ Patients should be counseled on primary prevention measures such as dietary and behavioral modification and, if necessary, started on aggressive urate-lowering therapy.²⁷

. . . BUT ARE LESS LIKELY TO HAVE GOUT APPROPRIATELY TREATED

African Americans with gout are less likely to receive urate-lowering therapy.²⁸ According to the 2002 National Ambulatory Medical Care Survey in the United States, African Americans with gout are far less likely to receive allopurinol than whites (42% vs 80%; odds ratio [OR] 0.18; 95% CI 0.04–0.78).²³ Even when therapy is prescribed, rates of nonadherence are greater in African Americans than in whites (OR 1.86, 95% CI 1.52–2.27), though the authors do not speculate why this is so.²⁹ No studies have compared rates of prescribing febuxostat to African Americans vs whites.

African Americans are also less likely to receive ongoing routine care for their gout. A 2007 study³⁰ of 663 veterans found that physicians were 1.41 times less likely to adhere to three selected quality indicators when dealing with nonwhite than white patients (95% CI 0.52–3.84). The three quality indicators studied were:

• Lowering of daily allopurinol dose to below 300 mg/day in the presence of renal insufficiency (no longer considered a quality measure)
• Monitoring of serum urate level at least once during the first 6 months of continued use of a xanthine oxidase inhibitor, such as allopurinol
• Monitoring of complete blood cell count and creatinine kinase at least every 6 months in patients with renal impairment receiving long-term prophylactic oral colchicine (> 0.5 mg/day for at least 6 months).

The finding was independent of age, comorbidity index, healthcare access, and utilization characteristics (eg, number of inpatient and outpatient visits, type of physician, most frequently seen physician).

LIFESTYLE MODIFICATION

Dietary modification is a useful initial step toward reducing uric acid levels (Table 1).²⁷ The following measures are recommended:

Reduce alcohol intake. Alcoholic beverages, particularly beer, are strongly linked to hyperuricemia, according to a 2013 meta-analysis.³¹ Although alcohol consumption is lower in African Americans than in whites, mortality rates from cirrhosis and other alcohol-related diseases are 10% higher, suggesting metabolic differences that render African Americans more susceptible to the negative health effects of alcohol.³²

Avoid sugary drinks. Sweetened beverages, especially those rich in fructose, are also implicated in hyperuricemia and gout. NHANES found an increase in serum uric acid of 0.33 mg/dL (95% CI, 0.11–0.73) in those consuming one to three sugar-sweetened drinks per day compared with nonconsumers, adjusting for total energy intake, age, sex, medications, hypertension, and GFR.³³ A prospective study also found a relative risk of 1.85 for those who drink two or more sugar-sweetened beverages per day compared with those who drink fewer than one per month (95% CI 1.08–3.16).³⁴

Unfortunately, African Americans consume a disproportionate amount of sugar from all sources: 17% of African Americans are considered heavy consumers vs 9% of whites.³⁵

Limit foods rich in purines. Red meat, seafood, and some vegetables, including asparagus, spinach, peas, cauliflower, and mushrooms, are associated with increased serum uric acid levels. NHANES found that greater meat and seafood consumption was associated with increased uric acid levels. Choi et al³⁶ found that the risk of gout increased by 21% with each additional daily serving of meat; the relative risk of developing gout was 1.41 (95% CI 1.07–1.86) in the fifth quintile of meat intake compared with the first quintile, and 1.51 (95% CI 1.17–1.95) in the fifth quintile of seafood consumption.

Despite these associations with high-purine food consumption and gout, many purine-rich foods may not contribute to hyperuricemia, and therefore a low-purine diet may not be protective. Interestingly, purine-rich vegetable protein intake is not associated with increased gout risk.³⁷

Increase dairy consumption. Dairy in the diet is associated with a lower incidence of gout, with a decrease of 0.21 mg/dL (95% CI –0.37 to –0.04) in serum uric acid levels between the highest and lowest quintiles of dairy consumption.³⁸ A randomized controlled trial found a 10% reduction in serum uric acid levels with milk consumption.³⁹

Enjoy coffee. Coffee intake has been inversely correlated with gout. Daily intake of 4 to 5 cups of coffee is associated with a relative risk of 0.60 (95% CI 0.41–0.87) vs no coffee.⁴⁰

Vitamin C and cherry juice^41,42 have also been linked to lower gout risk, but the data are less robust.

Control weight. Primary care providers should advise patients to increase physical activity and maintain a healthy weight.

In a prospective study, Choi et al⁴³ found that, in men, the risk of gout increased with the BMI. Compared with men with BMIs in the range of 21 to 22.9 kg/m², the relative risks were:

• 1.95 (95% CI 1.44–2.65) at BMI 25 to 29.9 kg/m²
• 2.33 (95% CI 1.62–3.36) at BMI 30 to 34.9 kg/m²
• 2.97 (95% CI 1.73–5.10) at BMI > 35 kg/m².

In addition, those who gained more than 13.6 kg since age 21 had a relative risk of 1.99 (95% CI 1.49–2.66) of developing gout compared with those whose weight remained within 1.8 kg.  

For those who cannot achieve weight loss through conservative measures, bariatric surgery has shown promise. In a prospective study of 60 obese patients (BMI > 35 kg/m²) with gout and type 2 diabetes mellitus, uric acid steadily declined during the first year after bariatric surgery.⁴⁴

TREATMENT OF ACUTE ATTACKS

Gout can be effectively managed in most patients. Behavioral and pharmacologic interventions are cheap and effective and have been shown to halt further damage to joints as well as retard the progression of renal disease and reduce cardiovascular morbidity.

During acute attacks, anti-inflammatory medications, principally glucocorticoids, nonsteroidal anti-inflammatory drugs, and colchicine, should be given promptly to reduce the intensity and duration of flares.

Although traditional teaching has been that urate-lowering therapy should not be initiated during an acute gout attack because it could prolong the duration of the attack, guidelines now permit it, based on studies showing that therapy does not prolong attacks.^45,46

AGGRESSIVE URATE-LOWERING THERAPY FOR PROPHYLAXIS

Long-term treatment of gout is aimed at reducing uric acid levels by mitigating modifiable risk factors and through urate-lowering therapy.⁴⁶ For many patients, conservative management with dietary and other behavioral changes is not sufficient to prevent further attacks of gout, necessitating urate-lowering therapy. Comorbid diseases such as obesity, hypertension, chronic kidney disease, and diabetes should also be addressed because they promote hyperuricemia and gouty attacks.⁴⁷

A number of organizations have issued gout management guidelines over the past decade, including the American College of Rheumatology (ACR) in 2012, the European League Against Rheumatism (2006, updated in 2014), and the British Society of Rheumatology (2007). All recommend urate-lowering therapy to prevent gout flares.

The American and European guidelines recommend a target uric acid level below 6 mg/dL, and the British guidelines recommend a target below 5 mg/dL.⁴⁸ For patients with palpable and visible tophi, the ACR guidelines state that lowering to below 5 mg/dL may be needed.⁴⁶

First-line agents for urate-lowering therapy are xanthine oxidase inhibitors, which include allopurinol (costing $0.48 per generic 100-mg tablet or $0.92 per 300-mg tablet), and febuxostat ($5.38 per 40-mg or 80-mg tablet). For patients with contraindications or intolerances to allopurinol or febuxostat, probenecid ($1.15 per 500-mg tablet), which functions as a uricosuric agent (ie, increases urinary excretion of uric acid), may be used.

Losartan ($1.68 per 25-mg tablet) and fenofibrate ($1.91 per 48-mg tablet) are also often used to reduce uric acid levels, but they have only modest effects and are not approved for this indication in the United States.⁴⁹

MANAGE CHRONIC CASES WITH CONTINUED THERAPY

ACR guidelines strongly emphasize continuing prophylaxis in case of ongoing gout activity (ie, detection of tophi on examination, recent gout attacks, or chronic gouty arthritis) (Table 3). The following durations have been proposed for prophylaxis:

• 6 months after an attack
• 6 months after achieving target uric acid level in patients with evidence of tophi
• 3 months after achieving target uric acid level in patients with resolved tophi. 

Two randomized controlled trials support the use of the anti-inflammatory agent colchicine ($4.30 per tablet) for prophylaxis when initiating urate-lowering therapy.^50,51

Monitor uric acid levels, renal function, adverse effects

The initial dosage of urate-lowering agents depends on the presence of kidney disease (Table 3).

Allopurinol is typically started at 50 mg to 100 mg oral daily, and titrated upward in increments of 100 mg depending on uric acid levels. According to the ACR guidelines, uric acid levels should be measured every 2 to 5 weeks.⁴⁶ The Febuxostat vs Allopurinol Streamline Trial found that 97% of patients reached target uric acid levels within two titrations.⁵²

Especially during the first months of therapy, physicians should be vigilant for adverse effects of allopurinol, including hypersensitivity reaction (rash, fever, Stevens-Johnson syndrome), hepatotoxicity, and myelotoxicity (bone marrow suppression), and for effects of febuxostat, such as rash, diarrhea, elevations in aminotransferase levels, and upper respiratory tract infections.⁵³ Although the maximum acceptable dose of allopurinol is 800 mg even in chronic kidney disease, regularly monitoring for hypersensitivity reactions and other adverse effects is needed if doses are above 300 mg per day.⁴⁶

Routine follow-up is essential

Adherence to therapy should be assessed at every visit. Patients should be counseled that gout is a chronic disease and that they should continue on urate-lowering therapy even if they are not having acute attacks. Adverse effects of medications should be monitored and addressed, although for allopurinol and febuxostat these are rare beyond the first few months of initiation and titration. If worsening of gout or uric acid levels occurs, therapy should be augmented and contributors to hyperuricemia reviewed. In refractory cases, rheumatology consultation may be needed; medications such as pegloticase ($16,800/mL) may be deemed necessary for severe tophaceous gout or for patients who need more rapid reduction of urates.⁴⁹

STRATEGIES TO ADDRESS DISPARITIES

Creative approaches are needed to engage African American communities to reduce the burden of gout. No trials have been published evaluating methods for reducing health disparities with gout, but strategies for other chronic conditions may be applicable.

Incorporate guidelines better. Although setting and disseminating guidelines should ensure that care is standardized, studies have found that primary care physicians and rheumatologists frequently do not implement them.^3,54 Reasons cited for poor adherence to gout guidelines include their relatively recent release, poor patient adherence, lack of measurement tools, and inadequate education of primary care physicians. Incorporating the guidelines as “best practice advisories” into electronic medical record systems has been proposed to improve their implementation.⁴⁶

Use a team approach. Some quality improvement projects have used pharmacists and nurses to help implement gout guidelines. In two studies, empowering nurses and pharmacists to better educate patients and implement standardized protocols for titrating urate-lowering medications led to sustained improvements in maintaining serum uric acid levels less than 6 mg/dL.^55–57

Multidisciplinary involvement by nutritionists, physicians, and community health workers have been found to help improve glycemic control in African Americans.⁵⁸ Similar efforts can be undertaken to improve control of uric acid levels through dietary modification and improved compliance.

Address patient concerns. Substantial gaps exist in knowledge about gout between providers and the general population, although large studies specifically focusing on African Americans are lacking.⁵⁹ Qualitative studies suggest that patient experience of gout may vary depending on race, with African Americans more likely than whites to rank the following concerns regarding gout as high: dietary restrictions, emotional burden, severe pain, the need for canes or crutches during flares, and gout bringing their day to a halt.⁶⁰ Another study among African Americans with gout found concerns about the effectiveness of urate-lowering therapy, side effects of medications, polypharmacy, pill size, cost, refill issues, and forgetting to take medications regularly.⁶¹

Despite the historic association of gout with royalty and “rich eating,” gout disproportionately affects those of lower socioeconomic status.¹ Risk factors for gout, including obesity, chronic kidney disease, diabetes, and hypertension, are more common in African Americans, resulting in a higher prevalence of the disease. In addition, African Americans are less likely to receive the aggressive treatment for gout advocated by professional societies, such as anti-inflammatory medications during flares and prophylactic urate-lowering therapy.

This article reviews the epidemiology of gout and its pathophysiology, risk factors, and optimal management, focusing on African Americans and strategies to reduce healthcare disparities in this patient population.

GOUT IS COMMON AND SERIOUS

Gout is the most common inflammatory arthritis in the United States today, affecting 4% of the adult US population.² It is a chronic disease associated with high levels of uric acid, usually manifesting as intermittent attacks of painful monoarthritis, although multiple joints may be involved.

Despite a popular misconception that gout is merely an episodic nuisance, it is a serious disease that can significantly affect physical function and quality of life.³ A 2013 systematic review found that quality of life was significantly reduced in patients with gout, particularly those with polyarticular gout, tophi, comorbidities, and radiographic damage.⁴

Economic costs include decreased worker productivity and increased absences from work.^5,6 From 2001 to 2005, an estimated 2 million visits were made to primary care providers due to gout.⁷ Because gout frequently coexists with diabetes, hypertension, coronary artery disease, and kidney disease, it is often overlooked during routine clinic visits.³

HIGH URIC ACID HAS MANY EFFECTS

Uric acid, a product of purine metabolism, is the key mediator of gouty arthritis. Accumulation of uric acid in joints and other tissues leads to an exuberant inflammatory response manifesting as a gouty attack. When uncontrolled, uric acid may crystallize in joints and other structures, leading to tophi formation, which can cause chronic deforming and erosive arthritis, known as chronic tophaceous gout.⁸

Although gout is considered to be a musculoskeletal disorder, recent evidence indicates that hyperuricemia plays an important role in the development of renal disease and contributes to cardiovascular morbidity and death.⁹ Several studies have found that reducing uric acid levels lowers cardiovascular mortality rates and retards the progression of chronic kidney disease.¹⁰

MEN AND CERTAIN RACIAL GROUPS MOST AFFECTED

Large-scale epidemiologic surveys have established that prevalence varies widely among population groups. Premenopausal women are less likely to be affected than men, presumably due to the effect of female hormones on renal tubular excretion of uric acid.¹¹

Certain Asian populations (Filipinos, Taiwanese, Micronesians, the Maoris of New Zealand, Hmong Chinese immigrants in Minnesota) and African Americans have a high prevalence, while people from several sub-Saharan African countries have a very low prevalence. These differences are likely due to a variety of reasons, including genetic predisposition; diet (Table 1); risk factors such as obesity, diabetes, and hypertension; less access to healthcare resources; and inappropriate treatment.^12,13

AFRICAN AMERICANS ARE A DIVERSE GROUP

“African Americans” are a highly heterogeneous group making up about 13% of the US population. Most scholars now consider racial identity largely a product of socioeconomic and political circumstances rather than a scientific concept.¹⁴ The US Census Bureau defines African Americans (or “blacks”) as those having origins in the black racial groups of Africa,¹⁵  but even this is problematic, since it combines people as diverse as descendants of 17th, 18th, and 19th century enslaved Africans with recent first-generation African immigrants, as well as with Caribbean- and Latino-Americans of African heritage.

In addition, many African Americans trace their ancestry to other racial and ethnic groups, especially European and Native American. A study of nine European DNA markers among 10 African American populations in the United States and one population of Jamaicans of African descent found a range of frequencies from 7% among Jamaicans to 23% among African Americans living in New Orleans.¹⁶

Although such diversity argues against generalizing healthcare needs for the entire African American community, some evidence indicates that genetic markers for gene-disease associations may be consistent across traditional racial boundaries.¹⁷

GENETIC FACTORS CANNOT EXPLAIN GOUT DISPARITIES

Several small studies have found evidence of genetic factors mediating the risk for hyperuricemia and gout. Twin studies indicate that hyperuricemia is highly heritable,¹⁸ although they do not show a concordance in the heritability of gout, suggesting that environmental factors also have an important role in developing clinical manifestations of the disease.¹²

Genome-wide association studies have identified 28 separate loci influencing uric acid levels, including genes for uric acid transporters (eg, SLC2A9 and ABCG2), and metabolic pathway regulators (eg, PDZK1, SCL22A12, and PRPSAP1), but the distribution among African Americans is largely unknown.¹⁹ One important exception is SLC2A9, a renal tubular transporter of uric acid: variants of SLC2A9 were found exclusively in African Americans, but the clinical significance of this association is unclear.²⁰

Several epidemiologic studies have looked at gout in African Americans.

In the Coronary Artery Risk Development in Young Adults study,²¹ young African Americans had lower levels of uric acid than whites after adjusting for body mass index (BMI), glomerular filtration rate (GFR), diet, and medications. But after up to 20 years of follow-up, the risk of hyperuricemia was 2.3 times higher in African American women than in white women (95% confidence interval [CI] 1.34–3.99). Such differences were not found between African American and white men.

The National Health and Nutritional Examination Survey (NHANES) found that African American adolescents had lower uric acid levels than white adolescents after taking into account sugar intake, GFR, BMI, and onset of puberty.²²

The Multiple Risk Factor Intervention Trial²³ also found that among those with high cardiovascular risk, the incidence of hyperuricemia and gout was lower in African Americans than in whites.

COMORBID DISEASES MAY EXPLAIN DISPARITIES

Despite some evidence that African Americans have genetic factors that are protective against gout, they have a much greater frequency of acquired risk factors for gout, including obesity, physical inactivity, hypertension, diabetes mellitus, renal failure, high intake of seafood, elevated blood lead levels, and use of antihypertensive medications (Table 2).

Hochberg et al²⁴ examined the incidence of gout in 352 African American and 571 white physicians and found higher rates in African Americans (9% vs 5%). The authors suggested different rates of hypertension as an explanation, although the use of antihypertensive medications such as diuretics that promote hyperuricemia confounds the strength of this conclusion.

AFRICAN AMERICANS NEED STANDARD TREATMENT . . .

Unlike for heart failure, in which subgroup analyses of large prospective studies have found different efficacies of medications in African Americans than in whites, no such data exist for gout. Although there is a higher risk of allopurinol hypersensitivity in ethnic groups that express the HLA-B*5801 polymorphism (eg, Han Chinese, Korean, Thai, Japanese, Portuguese), African Americans are not known to be at greater risk.²⁵ There are also no special precautions for using febuxostat or probenecid in African Americans.

Absent any compelling reason, gout management should be the same regardless of ethnicity.²⁶ Patients should be counseled on primary prevention measures such as dietary and behavioral modification and, if necessary, started on aggressive urate-lowering therapy.²⁷

. . . BUT ARE LESS LIKELY TO HAVE GOUT APPROPRIATELY TREATED

African Americans with gout are less likely to receive urate-lowering therapy.²⁸ According to the 2002 National Ambulatory Medical Care Survey in the United States, African Americans with gout are far less likely to receive allopurinol than whites (42% vs 80%; odds ratio [OR] 0.18; 95% CI 0.04–0.78).²³ Even when therapy is prescribed, rates of nonadherence are greater in African Americans than in whites (OR 1.86, 95% CI 1.52–2.27), though the authors do not speculate why this is so.²⁹ No studies have compared rates of prescribing febuxostat to African Americans vs whites.

African Americans are also less likely to receive ongoing routine care for their gout. A 2007 study³⁰ of 663 veterans found that physicians were 1.41 times less likely to adhere to three selected quality indicators when dealing with nonwhite than white patients (95% CI 0.52–3.84). The three quality indicators studied were:

• Lowering of daily allopurinol dose to below 300 mg/day in the presence of renal insufficiency (no longer considered a quality measure)
• Monitoring of serum urate level at least once during the first 6 months of continued use of a xanthine oxidase inhibitor, such as allopurinol
• Monitoring of complete blood cell count and creatinine kinase at least every 6 months in patients with renal impairment receiving long-term prophylactic oral colchicine (> 0.5 mg/day for at least 6 months).

The finding was independent of age, comorbidity index, healthcare access, and utilization characteristics (eg, number of inpatient and outpatient visits, type of physician, most frequently seen physician).

LIFESTYLE MODIFICATION

Dietary modification is a useful initial step toward reducing uric acid levels (Table 1).²⁷ The following measures are recommended:

Reduce alcohol intake. Alcoholic beverages, particularly beer, are strongly linked to hyperuricemia, according to a 2013 meta-analysis.³¹ Although alcohol consumption is lower in African Americans than in whites, mortality rates from cirrhosis and other alcohol-related diseases are 10% higher, suggesting metabolic differences that render African Americans more susceptible to the negative health effects of alcohol.³²

Avoid sugary drinks. Sweetened beverages, especially those rich in fructose, are also implicated in hyperuricemia and gout. NHANES found an increase in serum uric acid of 0.33 mg/dL (95% CI, 0.11–0.73) in those consuming one to three sugar-sweetened drinks per day compared with nonconsumers, adjusting for total energy intake, age, sex, medications, hypertension, and GFR.³³ A prospective study also found a relative risk of 1.85 for those who drink two or more sugar-sweetened beverages per day compared with those who drink fewer than one per month (95% CI 1.08–3.16).³⁴

Unfortunately, African Americans consume a disproportionate amount of sugar from all sources: 17% of African Americans are considered heavy consumers vs 9% of whites.³⁵

Limit foods rich in purines. Red meat, seafood, and some vegetables, including asparagus, spinach, peas, cauliflower, and mushrooms, are associated with increased serum uric acid levels. NHANES found that greater meat and seafood consumption was associated with increased uric acid levels. Choi et al³⁶ found that the risk of gout increased by 21% with each additional daily serving of meat; the relative risk of developing gout was 1.41 (95% CI 1.07–1.86) in the fifth quintile of meat intake compared with the first quintile, and 1.51 (95% CI 1.17–1.95) in the fifth quintile of seafood consumption.

Despite these associations with high-purine food consumption and gout, many purine-rich foods may not contribute to hyperuricemia, and therefore a low-purine diet may not be protective. Interestingly, purine-rich vegetable protein intake is not associated with increased gout risk.³⁷

Increase dairy consumption. Dairy in the diet is associated with a lower incidence of gout, with a decrease of 0.21 mg/dL (95% CI –0.37 to –0.04) in serum uric acid levels between the highest and lowest quintiles of dairy consumption.³⁸ A randomized controlled trial found a 10% reduction in serum uric acid levels with milk consumption.³⁹

Enjoy coffee. Coffee intake has been inversely correlated with gout. Daily intake of 4 to 5 cups of coffee is associated with a relative risk of 0.60 (95% CI 0.41–0.87) vs no coffee.⁴⁰

Vitamin C and cherry juice^41,42 have also been linked to lower gout risk, but the data are less robust.

Control weight. Primary care providers should advise patients to increase physical activity and maintain a healthy weight.

In a prospective study, Choi et al⁴³ found that, in men, the risk of gout increased with the BMI. Compared with men with BMIs in the range of 21 to 22.9 kg/m², the relative risks were:

• 1.95 (95% CI 1.44–2.65) at BMI 25 to 29.9 kg/m²
• 2.33 (95% CI 1.62–3.36) at BMI 30 to 34.9 kg/m²
• 2.97 (95% CI 1.73–5.10) at BMI > 35 kg/m².

In addition, those who gained more than 13.6 kg since age 21 had a relative risk of 1.99 (95% CI 1.49–2.66) of developing gout compared with those whose weight remained within 1.8 kg.  

For those who cannot achieve weight loss through conservative measures, bariatric surgery has shown promise. In a prospective study of 60 obese patients (BMI > 35 kg/m²) with gout and type 2 diabetes mellitus, uric acid steadily declined during the first year after bariatric surgery.⁴⁴

TREATMENT OF ACUTE ATTACKS

Gout can be effectively managed in most patients. Behavioral and pharmacologic interventions are cheap and effective and have been shown to halt further damage to joints as well as retard the progression of renal disease and reduce cardiovascular morbidity.

During acute attacks, anti-inflammatory medications, principally glucocorticoids, nonsteroidal anti-inflammatory drugs, and colchicine, should be given promptly to reduce the intensity and duration of flares.

Although traditional teaching has been that urate-lowering therapy should not be initiated during an acute gout attack because it could prolong the duration of the attack, guidelines now permit it, based on studies showing that therapy does not prolong attacks.^45,46

AGGRESSIVE URATE-LOWERING THERAPY FOR PROPHYLAXIS

Long-term treatment of gout is aimed at reducing uric acid levels by mitigating modifiable risk factors and through urate-lowering therapy.⁴⁶ For many patients, conservative management with dietary and other behavioral changes is not sufficient to prevent further attacks of gout, necessitating urate-lowering therapy. Comorbid diseases such as obesity, hypertension, chronic kidney disease, and diabetes should also be addressed because they promote hyperuricemia and gouty attacks.⁴⁷

A number of organizations have issued gout management guidelines over the past decade, including the American College of Rheumatology (ACR) in 2012, the European League Against Rheumatism (2006, updated in 2014), and the British Society of Rheumatology (2007). All recommend urate-lowering therapy to prevent gout flares.

The American and European guidelines recommend a target uric acid level below 6 mg/dL, and the British guidelines recommend a target below 5 mg/dL.⁴⁸ For patients with palpable and visible tophi, the ACR guidelines state that lowering to below 5 mg/dL may be needed.⁴⁶

First-line agents for urate-lowering therapy are xanthine oxidase inhibitors, which include allopurinol (costing $0.48 per generic 100-mg tablet or $0.92 per 300-mg tablet), and febuxostat ($5.38 per 40-mg or 80-mg tablet). For patients with contraindications or intolerances to allopurinol or febuxostat, probenecid ($1.15 per 500-mg tablet), which functions as a uricosuric agent (ie, increases urinary excretion of uric acid), may be used.

Losartan ($1.68 per 25-mg tablet) and fenofibrate ($1.91 per 48-mg tablet) are also often used to reduce uric acid levels, but they have only modest effects and are not approved for this indication in the United States.⁴⁹

MANAGE CHRONIC CASES WITH CONTINUED THERAPY

ACR guidelines strongly emphasize continuing prophylaxis in case of ongoing gout activity (ie, detection of tophi on examination, recent gout attacks, or chronic gouty arthritis) (Table 3). The following durations have been proposed for prophylaxis:

• 6 months after an attack
• 6 months after achieving target uric acid level in patients with evidence of tophi
• 3 months after achieving target uric acid level in patients with resolved tophi. 

Two randomized controlled trials support the use of the anti-inflammatory agent colchicine ($4.30 per tablet) for prophylaxis when initiating urate-lowering therapy.^50,51

Monitor uric acid levels, renal function, adverse effects

The initial dosage of urate-lowering agents depends on the presence of kidney disease (Table 3).

Allopurinol is typically started at 50 mg to 100 mg oral daily, and titrated upward in increments of 100 mg depending on uric acid levels. According to the ACR guidelines, uric acid levels should be measured every 2 to 5 weeks.⁴⁶ The Febuxostat vs Allopurinol Streamline Trial found that 97% of patients reached target uric acid levels within two titrations.⁵²

Especially during the first months of therapy, physicians should be vigilant for adverse effects of allopurinol, including hypersensitivity reaction (rash, fever, Stevens-Johnson syndrome), hepatotoxicity, and myelotoxicity (bone marrow suppression), and for effects of febuxostat, such as rash, diarrhea, elevations in aminotransferase levels, and upper respiratory tract infections.⁵³ Although the maximum acceptable dose of allopurinol is 800 mg even in chronic kidney disease, regularly monitoring for hypersensitivity reactions and other adverse effects is needed if doses are above 300 mg per day.⁴⁶

Routine follow-up is essential

Adherence to therapy should be assessed at every visit. Patients should be counseled that gout is a chronic disease and that they should continue on urate-lowering therapy even if they are not having acute attacks. Adverse effects of medications should be monitored and addressed, although for allopurinol and febuxostat these are rare beyond the first few months of initiation and titration. If worsening of gout or uric acid levels occurs, therapy should be augmented and contributors to hyperuricemia reviewed. In refractory cases, rheumatology consultation may be needed; medications such as pegloticase ($16,800/mL) may be deemed necessary for severe tophaceous gout or for patients who need more rapid reduction of urates.⁴⁹

STRATEGIES TO ADDRESS DISPARITIES

Creative approaches are needed to engage African American communities to reduce the burden of gout. No trials have been published evaluating methods for reducing health disparities with gout, but strategies for other chronic conditions may be applicable.

Incorporate guidelines better. Although setting and disseminating guidelines should ensure that care is standardized, studies have found that primary care physicians and rheumatologists frequently do not implement them.^3,54 Reasons cited for poor adherence to gout guidelines include their relatively recent release, poor patient adherence, lack of measurement tools, and inadequate education of primary care physicians. Incorporating the guidelines as “best practice advisories” into electronic medical record systems has been proposed to improve their implementation.⁴⁶

Use a team approach. Some quality improvement projects have used pharmacists and nurses to help implement gout guidelines. In two studies, empowering nurses and pharmacists to better educate patients and implement standardized protocols for titrating urate-lowering medications led to sustained improvements in maintaining serum uric acid levels less than 6 mg/dL.^55–57

Multidisciplinary involvement by nutritionists, physicians, and community health workers have been found to help improve glycemic control in African Americans.⁵⁸ Similar efforts can be undertaken to improve control of uric acid levels through dietary modification and improved compliance.

Address patient concerns. Substantial gaps exist in knowledge about gout between providers and the general population, although large studies specifically focusing on African Americans are lacking.⁵⁹ Qualitative studies suggest that patient experience of gout may vary depending on race, with African Americans more likely than whites to rank the following concerns regarding gout as high: dietary restrictions, emotional burden, severe pain, the need for canes or crutches during flares, and gout bringing their day to a halt.⁶⁰ Another study among African Americans with gout found concerns about the effectiveness of urate-lowering therapy, side effects of medications, polypharmacy, pill size, cost, refill issues, and forgetting to take medications regularly.⁶¹

The role of diet in controlling symptoms of irritable bowel syndrome (IBS) has gained much traction over the years,¹ but until recently, diet therapy for IBS has been hindered by a lack of quality evidence, in part because of the challenges of conducting dietary clinical trials.

See related editorial

Several clinical trials have now been done that support a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) for managing IBS. Although restrictive and difficult to follow, the low-FODMAP diet is gaining popularity.

This article provides an overview of dietary interventions used to manage IBS, focusing on the low-FODMAP diet. We discuss mechanisms of malabsorption of FODMAPs and the role of FODMAPS in symptom induction; highlight clinical trials that provide evidence of benefits of the diet for IBS; and discuss the steps to implement it. We also address the nutritional adequacy of the diet and its potential effects on the gut microbiome.

IBS IS A COMMON FUNCTIONAL DISORDER

IBS is one of the most commonly diagnosed gastrointestinal disorders, and it has a significant impact on quality of life.² It is a functional disorder characterized by chronic abdominal pain and altered bowel habits in the absence of a structural or organic cause.

The Rome IV diagnostic criteria define IBS by the following: 

• Recurrent abdominal pain or discomfort at least 1 day a week in the last 3 months, associated with two or more of the following:
• Symptoms improved by defecation
• Onset associated with a change in frequency of stool
• Onset associated with a change in form or appearance of stool.

IBS mainly arises during young adulthood but can be diagnosed at any age.³

The pathophysiology of IBS involves mechanisms such as bowel distention, altered bowel motility, visceral hypersensitivity, and disruption of mucosal permeability.⁴ Several therapeutic modalities targeting these mechanisms have been implemented in IBS management, including antispasmodics, laxatives, antidepressants, antibiotics, and behavioral therapy. Diet is only one line of treatment and is most effective when part of a multipronged approach.

TRADITIONAL DIETARY MANAGEMENT

Diet is important in inducing the symptoms of IBS—and in controlling them. Patients identify eating as a common precipitator of symptoms, but the complex diet-symptom interaction is not fully understood and varies widely among patients. Traditional dietary advice for IBS includes adhering to a regular meal pattern, avoiding large meals, and reducing intake of fat, insoluble fibers, caffeine, spicy and gas-producing foods, and carbonated beverages.^5,6

Increase soluble fiber

Fiber and fiber supplements, particularly soluble fibers such as psyllium, calcium polycarbophil, and ispaghula husk are often recommended. A meta-analysis⁷ found that soluble fiber but not insoluble fiber (eg, wheat bran) is associated with an improvement in IBS symptoms (relative risk [RR] 0.84, 95% confidence interval [CI] 0.73–0.94). By improving stool consistency and accelerating transit, soluble fiber is especially useful in constipation-predominant IBS while posing a low risk for adverse outcomes.⁷ Fiber should be started at a low dose and gradually increased over several weeks to as much as 20 to 30 g/day.

Avoid wheat

Only about 4% of patients with IBS also have celiac disease, but estimating the prevalence of nonceliac gluten sensitivity is confounded by overlapping symptoms. There is some evidence implicating gluten in IBS: celiac disease and IBS overlap in their symptoms, and symptoms are often precipitated by gluten-containing foods in patients with IBS.⁸ The pathogenesis of gluten-induced (or wheat-induced) symptoms in IBS is unclear, and studies have had conflicting results as to the benefits of gluten restriction in IBS.⁹

In a study of patients with IBS whose symptoms improved when they started a gluten-free and low-FODMAP diet, symptoms did not return when gluten was reintroduced, suggesting that it is the fructan (a FODMAP) component of wheat rather than gluten that contributes to symptoms in IBS.¹⁰

Probiotics

Probiotics are increasingly being recommended as dietary supplements for people with IBS, as awareness increases of  the importance of the gut microbiota. In addition to their effects on the gut microbiota, probiotics in IBS have been shown to have anti-inflammatory effects, to alter gut motility, to modulate visceral hypersensitivity, and to restore epithelial integrity.

In a meta-analysis, Ford et al¹¹ found that probiotics improved global IBS symptoms more than placebo (RR 0.79, 95% CI 0.70–0.89) and also reduced abdominal pain, bloating, and flatulence scores.

Which species and strains are most beneficial and the optimal dosing and duration of treatment are still unclear. Data from studies of prebiotics (nutrients that encourage the growth of probiotic bacteria) and synbiotics (combinations of prebiotics and probiotics) are limited and insufficient to draw conclusions.

FODMAPS ARE SHORT-CHAIN CARBOHYDRATES

The term FODMAPs was initially coined by researchers at Monash University in Australia to describe  a collection of poorly absorbed short-chain fermentable carbohydrates that are natural components of many foods:

• Oligosaccharides, including fructans (which include inulins) and galacto-oligosaccharides
• Disaccharides, including lactose and sucrose
• Monosaccharides, including fructose
• Polyols, including sorbitol and mannitol.¹²

Intake of FODMAPs, especially fructose, has increased in Western diets over the past several decades from increased consumption of fruits and concentrated fruit juices, as well as from the widespread use of high-fructose corn syrup in processed foods and beverages.¹³

FODMAPs ARE POORLY ABSORBED

Different FODMAPs can be poorly absorbed for different reasons (Table 1). The poor absorption is related either to reduced or absent digestive enzymes (ie, hydrolases) or to slow transport across the intestinal mucosa. Excess FODMAPs in the distal small intestine and proximal colon exert osmotic pressure, drawing more water into the lumen. FODMAPs are also rapidly fermented by colonic bacteria, producing gas, bowel distention, and altered motility, all of which induce IBS symptoms.¹⁴

Fructans are fructose polymers that are not absorbed in human intestines. They have no intestinal hydrolases and no mechanisms for direct transport across the epithelium. However, a negligible amount may be absorbed after being degraded by microbes in the gut.¹⁵ Most dietary fructans are obtained from wheat and onion, which are actually low in fructans but tend to be consumed in large quantities.¹⁶

Galacto-oligosaccharides are available for colonic fermentation after ingestion due to lack of a human alpha-galactosidase. Common sources of galacto-oligosaccharides include legumes, nuts, seeds, some grains, dairy products, human milk, and some commercially produced forms added to infant formula.^17,18

Lactose is poorly absorbed in people with lactase deficiency. It is mainly present in dairy products but is also added to commercial foods, including breads, cakes, and some diet products.¹⁹

Fructose is the most abundant FODMAP in the Western diet. It is either present as a free sugar or generated from the digestive breakdown of sucrose. In the intestine, it is absorbed via a direct low-capacity glucose transporter (GLUT)-5 and through GLUT-2, which is more efficient but requires the coexistence of glucose. Because of this requirement, fructose is more likely to be malabsorbed when present in excess of glucose, as in people with diminished sucrase activity. The main sources of fructose in the Western diet are fruits and fruit products, honey, and foods with added high-fructose sweeteners.¹³

Polyols such as sorbitol and mannitol are absorbed by slow passive diffusion because they have no active intestinal transport system. They are found in fruits and vegetables. Sugar-free chewing gum is a particularly rich source of sorbitol.²⁰

QUANTIFYING FODMAP CONTENT

As interest in the low-FODMAP diet grew, studies were conducted to quantify FODMAPs in foods. One study used high-performance liquid chromatography to analyze FODMAP content in foods,²¹ and another evaluated fructan levels in a variety of fruits and vegetables using enzymatic hydrolysis.²² The Monash University low-FODMAP diet smartphone application provides patients and healthcare providers easy access to updated and detailed food analyses.²³

Table 2 lists foods high in FODMAPs along with low-FODMAP alternatives. Total FODMAP intake is important, as the effects are additive.²⁴ Readers and patients can be directed to the following websites for more information on the low-FODMAP diet: www.med.monash.edu/cecs/gastro/fodmap or www.ibsfree.net/what-is-fodmap-diet.

LOW-FODMAP DIET REDUCES SYMPTOMS

The low-FODMAP diet was inspired by the results of several studies that evaluated the role of dietary carbohydrates in inducing IBS symptoms and found improvement with their restriction.^25,26

One study found that 74% of patients with IBS had less bloating, nausea, abdominal pain, and diarrhea when they restricted their intake of fructose and fructans.²⁷

A prospective trial randomized 41 patients with IBS to 4 weeks of either a low-FODMAP diet or their habitual diet.²⁸ The low-FODMAP diet resulted in greater improvement in overall IBS symptoms (P < .05) and stool frequency (P = .008). This study was limited by different habitual diets between patients and by lack of standardization of the low-FODMAP diet.

Halmos et al,²⁹ in a randomized crossover trial, compared gastrointestinal symptoms in IBS patients over 3 weeks on a low-FODMAP diet vs a moderate-FODMAP (ie, regular) diet, as well as in healthy controls. Food was provided by the study and was matched for all nutrients. Up to 70% of the IBS patients had significantly lower overall symptom scores while on a low-FODMAP diet vs IBS patients on a regular diet (P < .001); bloating, abdominal pain, and flatulence were reduced. Symptoms were minimal and unaffected by either diet in the healthy controls.

A double-blind trial³⁰ randomly assigned 25 patients with IBS who initially responded to a low-FODMAP diet to be challenged by a graduated dose of fructose alone, fructans alone, a combination of both, or glucose. The severity of overall and individual symptoms was markedly more reduced with glucose consumption than with the other carbohydrates: 70% of patients receiving fructose, 77% of those receiving fructans, and 79% of those receiving a mixture of both reported that their symptoms were not adequately controlled, compared with 14% of patients receiving glucose (P ≤ .002).³⁰

Murray et al³¹ evaluated the gastrointestinal tract after a carbohydrate challenge consisting of 0.5 L of water containing 40 g of glucose, fructose, or inulin or a combination of 40 g of glucose and 40 g of fructose in 16 healthy volunteers. Magnetic resonance imaging was performed hourly for 5 hours to assess the volume of gastric contents, small-bowel water content, and colonic gas. Breath hydrogen was also measured, and symptoms were recorded after each imaging session.

Fructose significantly increased small-bowel water content compared with glucose (mean difference 28 L/min, P < .001), but combined glucose and fructose lessened the effect. Inulin had no significant effect on small-bowel water content (mean difference with glucose 2 L/min, P > .7) but led to the greatest production of colonic gas compared with glucose alone (mean difference 15 L/min, P < .05) and combined glucose and fructose (mean difference 12 L/min, P < .05). Inulin also produced the most breath hydrogen: 81% of participants had a rise after drinking inulin compared with 50% after drinking fructose. Glucose did not affect breath hydrogen concentrations, and combined glucose and fructose significantly reduced the concentration measured vs fructose alone. In patients who reported “gas” symptoms, a correlation was observed between the volume of gas in the colon and gas symptoms (r = 0.59, P < .0001).³¹

The authors concluded³¹ that long-chain carbohydrates such as inulin have a greater effect on colonic gas production and little effect on small-bowel water content, whereas small-chain FODMAPs such as fructose are likely to cause luminal distention in both the small and large intestines. The study also showed that combining equal amounts of glucose and fructose reduces malabsorption of fructose in the small bowel and reduces the effect of fructose on small-bowel water content and breath hydrogen concentration.³¹

PROBIOTICS HELP

A Danish study³² randomized 123 patients with IBS to one of three treatments: a low-FODMAP diet, a normal diet with probiotics containing the strain Lactobacillus rhamnosus GG (two capsules daily), or no special intervention. Symptoms were recorded weekly. IBS severity scores at week 6 were lower in patients on either the low-FODMAP diet or probiotics compared with the control group (P < .01). Subgroup analysis determined that patients with primarily diarrheal symptoms were more likely to have improved quality of life with the low-FODMAP diet.

A LOW-FODMAP DIET MAY ALSO HELP IN INFLAMMATORY BOWEL DISEASE

The low-FODMAP diet has also been studied in patients with inflammatory bowel disease with functional gut symptoms. In a retrospective pilot study,³³ overall symptoms improved in about half of such patients on a low-FODMAP diet. A controlled dietary intervention trial is needed to confirm these findings and define the role of the low-FODMAP approach for patients with inflammatory bowel disease.

Marsh et al³⁴ performed a meta-analysis of six randomized clinical trials and 16 nonrandomized interventions of a low-FODMAP diet on improving functional gastrointestinal symptoms in patients with either IBS or inflammatory bowel disease. They found significant improvements in:

• IBS Symptoms Severity Scores in the randomized trials (odds ratio [OR] 0.44, 95% CI 0.25–0.76)
• IBS Symptoms Severity Scores in the nonrandomized interventions (OR 0.03, 95% CI 0.01–0.2) 
• IBS Quality of Life scores in the randomized trials (OR 1.84, 95% CI 1.12–3.03)
• IBS Quality of Life scores in the nonrandomized interventions (OR 3.18, 95% CI 1.6–6.31)
• Overall symptom severity in the randomized trials (OR 1.81, 95% CI 1.11–2.95).

DIETARY COUNSELING IS RECOMMENDED

Adherence is a major factor in the success of the low-FODMAP diet in IBS management and is strongly correlated with improved symptoms.³⁵ Patients should be counseled on the role of food in inducing their symptoms. Haphazard dietary advice can be detrimental to outcomes, as many diets restrict food groups, impairing the consumption of essential nutrients.³⁶ The involvement of a knowledgeable dietitian is helpful, as physicians may lack sufficient training in dietary skills and knowledge of food composition.

Access to and cost of dietary counseling can be prohibitive for some patients. Group consultation, which can decrease costs to each patient, has been found to be as effective as one-on-one sessions when administering the low-FODMAP diet in functional bowel disorders.³⁷

ELIMINATION, THEN REINTRODUCTION

Before embarking on the low-FODMAP diet, the patient’s interest in making dietary changes should be explored, a dietary history taken, and unusual food choices or dietary behaviors assessed. The patient’s ability to adopt a restricted diet should also be gauged.

The diet should be implemented in two phases. The initial phase involves strict elimination of foods high in FODMAPs, usually over 6 to 8 weeks.³⁸ Symptom control should be assessed: failure to control symptoms requires assessment of adherence.

If symptoms are successfully controlled, then the second phase should begin with the aim of following a less-restricted version of the diet as tolerated. Foods should gradually be phased back in and symptoms monitored. This approach minimizes unnecessary dietary restriction and ensures that a maximum variety in the diet is achieved while maintaining adequate symptom control.³⁹

LOW-FODMAP DIET ALTERS THE GUT MICROBIOTA

Multiple putative benefits of certain bacterial species for colonic health have been reported, including the production of short-chain fatty acids. Colonic luminal concentrations of short-chain fatty acids may be important to gut health, given their role in intestinal secretion, absorption, motility, and epithelial cell structure. Because short-chain fatty acids are products of bacterial fermentation, a change in the delivery of fermentable substrates to the colon would be expected to alter the concentrations and output of fecal short-chain fatty acids.¹⁸

Several studies evaluated the effect of the low-FODMAP diet on intestinal microbiota, finding a change in the bacterial profile in the stool of patients who adopt this diet. Staudacher et al²⁸ found a marked reduction in luminal bifidobacteria concentration after 4 weeks of a low-FODMAP diet in patients with IBS.

A single-blind randomized crossover trial⁴⁰ investigated the effects of a low-FODMAP diet vs a carefully matched typical Australian diet in 27 patients with IBS and 6 healthy controls. Marked differences in absolute and relative bacterial abundance and diversity were found between the diets, but not in short-chain fatty acids or gut transit time. Compared with fecal microbiota on the typical diet, low FODMAP intake was associated with reduced absolute abundance of bacteria, and the typical FODMAP diet had evidence of stimulation of the growth of bacterial groups with putative health benefits.

The authors concluded⁴⁰ that the functional significance and health implications of such changes are reasons for caution when reducing FODMAP intake in the long term and recommended liberalizing FODMAP restriction to the level of adequate symptom control in IBS patients. The study also recommended that people without symptoms not go on the low-FODMAP diet.⁴⁰

Molecular approaches to characterize the gut microbiota are also being explored in an effort to identify its association with diet.

The sustainability of changes in gut microbiota and the potential long-term impact on health of following a low-FODMAP diet require further evaluation. In the meantime, patients following this diet should have FODMAP foods reintroduced based on tolerance and should consider taking probiotic supplements.⁴¹

DIETARY ADEQUACY OF THE LOW-FODMAP DIET

Continual dietary counseling should minimize nutritional inadequacies and ensure that FODMAPS are restricted only enough to control symptoms. Because no single food group is completely eliminated in this diet, patients are unlikely to experience inadequate nutrition.

Ledochowski et al²⁶ found that in the initial, strict phase of the diet, total intake of carbohydrates (eg, starches, sugars) was reduced but intake of total energy, protein, fat, and nonstarch polysaccharides was not affected. Calcium intake was reduced in those following a low-FODMAP diet for 4 weeks.

The diet can also reduce total fiber intake and subsequently worsen constipation-predominant IBS. For those patients, lightly fermented high-fiber alternatives like oat and rice bran can be used.

ACCUMULATING EVIDENCE

The low-FODMAP diet is accumulating quality evidence for its effectiveness in controlling the functional gastrointestinal symptoms in patients with IBS. It can be difficult to adhere to over the long term due to its restrictiveness, and it is important to gradually liberalize the diet while tailoring it to the individual patient and monitoring symptoms. Further clinical trials are needed to evaluate this diet in different IBS subtypes and other gastrointestinal disorders, while defining its nutritional adequacy and effects on the intestinal microbiota profile.

The role of diet in controlling symptoms of irritable bowel syndrome (IBS) has gained much traction over the years,¹ but until recently, diet therapy for IBS has been hindered by a lack of quality evidence, in part because of the challenges of conducting dietary clinical trials.

See related editorial

Several clinical trials have now been done that support a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) for managing IBS. Although restrictive and difficult to follow, the low-FODMAP diet is gaining popularity.

This article provides an overview of dietary interventions used to manage IBS, focusing on the low-FODMAP diet. We discuss mechanisms of malabsorption of FODMAPs and the role of FODMAPS in symptom induction; highlight clinical trials that provide evidence of benefits of the diet for IBS; and discuss the steps to implement it. We also address the nutritional adequacy of the diet and its potential effects on the gut microbiome.

IBS IS A COMMON FUNCTIONAL DISORDER

IBS is one of the most commonly diagnosed gastrointestinal disorders, and it has a significant impact on quality of life.² It is a functional disorder characterized by chronic abdominal pain and altered bowel habits in the absence of a structural or organic cause.

The Rome IV diagnostic criteria define IBS by the following: 

• Recurrent abdominal pain or discomfort at least 1 day a week in the last 3 months, associated with two or more of the following:
• Symptoms improved by defecation
• Onset associated with a change in frequency of stool
• Onset associated with a change in form or appearance of stool.

IBS mainly arises during young adulthood but can be diagnosed at any age.³

The pathophysiology of IBS involves mechanisms such as bowel distention, altered bowel motility, visceral hypersensitivity, and disruption of mucosal permeability.⁴ Several therapeutic modalities targeting these mechanisms have been implemented in IBS management, including antispasmodics, laxatives, antidepressants, antibiotics, and behavioral therapy. Diet is only one line of treatment and is most effective when part of a multipronged approach.

TRADITIONAL DIETARY MANAGEMENT

Diet is important in inducing the symptoms of IBS—and in controlling them. Patients identify eating as a common precipitator of symptoms, but the complex diet-symptom interaction is not fully understood and varies widely among patients. Traditional dietary advice for IBS includes adhering to a regular meal pattern, avoiding large meals, and reducing intake of fat, insoluble fibers, caffeine, spicy and gas-producing foods, and carbonated beverages.^5,6

Increase soluble fiber

Fiber and fiber supplements, particularly soluble fibers such as psyllium, calcium polycarbophil, and ispaghula husk are often recommended. A meta-analysis⁷ found that soluble fiber but not insoluble fiber (eg, wheat bran) is associated with an improvement in IBS symptoms (relative risk [RR] 0.84, 95% confidence interval [CI] 0.73–0.94). By improving stool consistency and accelerating transit, soluble fiber is especially useful in constipation-predominant IBS while posing a low risk for adverse outcomes.⁷ Fiber should be started at a low dose and gradually increased over several weeks to as much as 20 to 30 g/day.

Avoid wheat

Only about 4% of patients with IBS also have celiac disease, but estimating the prevalence of nonceliac gluten sensitivity is confounded by overlapping symptoms. There is some evidence implicating gluten in IBS: celiac disease and IBS overlap in their symptoms, and symptoms are often precipitated by gluten-containing foods in patients with IBS.⁸ The pathogenesis of gluten-induced (or wheat-induced) symptoms in IBS is unclear, and studies have had conflicting results as to the benefits of gluten restriction in IBS.⁹

In a study of patients with IBS whose symptoms improved when they started a gluten-free and low-FODMAP diet, symptoms did not return when gluten was reintroduced, suggesting that it is the fructan (a FODMAP) component of wheat rather than gluten that contributes to symptoms in IBS.¹⁰

Probiotics

Probiotics are increasingly being recommended as dietary supplements for people with IBS, as awareness increases of  the importance of the gut microbiota. In addition to their effects on the gut microbiota, probiotics in IBS have been shown to have anti-inflammatory effects, to alter gut motility, to modulate visceral hypersensitivity, and to restore epithelial integrity.

In a meta-analysis, Ford et al¹¹ found that probiotics improved global IBS symptoms more than placebo (RR 0.79, 95% CI 0.70–0.89) and also reduced abdominal pain, bloating, and flatulence scores.

Which species and strains are most beneficial and the optimal dosing and duration of treatment are still unclear. Data from studies of prebiotics (nutrients that encourage the growth of probiotic bacteria) and synbiotics (combinations of prebiotics and probiotics) are limited and insufficient to draw conclusions.

FODMAPS ARE SHORT-CHAIN CARBOHYDRATES

The term FODMAPs was initially coined by researchers at Monash University in Australia to describe  a collection of poorly absorbed short-chain fermentable carbohydrates that are natural components of many foods:

• Oligosaccharides, including fructans (which include inulins) and galacto-oligosaccharides
• Disaccharides, including lactose and sucrose
• Monosaccharides, including fructose
• Polyols, including sorbitol and mannitol.¹²

Intake of FODMAPs, especially fructose, has increased in Western diets over the past several decades from increased consumption of fruits and concentrated fruit juices, as well as from the widespread use of high-fructose corn syrup in processed foods and beverages.¹³

FODMAPs ARE POORLY ABSORBED

Different FODMAPs can be poorly absorbed for different reasons (Table 1). The poor absorption is related either to reduced or absent digestive enzymes (ie, hydrolases) or to slow transport across the intestinal mucosa. Excess FODMAPs in the distal small intestine and proximal colon exert osmotic pressure, drawing more water into the lumen. FODMAPs are also rapidly fermented by colonic bacteria, producing gas, bowel distention, and altered motility, all of which induce IBS symptoms.¹⁴

Fructans are fructose polymers that are not absorbed in human intestines. They have no intestinal hydrolases and no mechanisms for direct transport across the epithelium. However, a negligible amount may be absorbed after being degraded by microbes in the gut.¹⁵ Most dietary fructans are obtained from wheat and onion, which are actually low in fructans but tend to be consumed in large quantities.¹⁶

Galacto-oligosaccharides are available for colonic fermentation after ingestion due to lack of a human alpha-galactosidase. Common sources of galacto-oligosaccharides include legumes, nuts, seeds, some grains, dairy products, human milk, and some commercially produced forms added to infant formula.^17,18

Lactose is poorly absorbed in people with lactase deficiency. It is mainly present in dairy products but is also added to commercial foods, including breads, cakes, and some diet products.¹⁹

Fructose is the most abundant FODMAP in the Western diet. It is either present as a free sugar or generated from the digestive breakdown of sucrose. In the intestine, it is absorbed via a direct low-capacity glucose transporter (GLUT)-5 and through GLUT-2, which is more efficient but requires the coexistence of glucose. Because of this requirement, fructose is more likely to be malabsorbed when present in excess of glucose, as in people with diminished sucrase activity. The main sources of fructose in the Western diet are fruits and fruit products, honey, and foods with added high-fructose sweeteners.¹³

Polyols such as sorbitol and mannitol are absorbed by slow passive diffusion because they have no active intestinal transport system. They are found in fruits and vegetables. Sugar-free chewing gum is a particularly rich source of sorbitol.²⁰

QUANTIFYING FODMAP CONTENT

As interest in the low-FODMAP diet grew, studies were conducted to quantify FODMAPs in foods. One study used high-performance liquid chromatography to analyze FODMAP content in foods,²¹ and another evaluated fructan levels in a variety of fruits and vegetables using enzymatic hydrolysis.²² The Monash University low-FODMAP diet smartphone application provides patients and healthcare providers easy access to updated and detailed food analyses.²³

Table 2 lists foods high in FODMAPs along with low-FODMAP alternatives. Total FODMAP intake is important, as the effects are additive.²⁴ Readers and patients can be directed to the following websites for more information on the low-FODMAP diet: www.med.monash.edu/cecs/gastro/fodmap or www.ibsfree.net/what-is-fodmap-diet.

LOW-FODMAP DIET REDUCES SYMPTOMS

The low-FODMAP diet was inspired by the results of several studies that evaluated the role of dietary carbohydrates in inducing IBS symptoms and found improvement with their restriction.^25,26

One study found that 74% of patients with IBS had less bloating, nausea, abdominal pain, and diarrhea when they restricted their intake of fructose and fructans.²⁷

A prospective trial randomized 41 patients with IBS to 4 weeks of either a low-FODMAP diet or their habitual diet.²⁸ The low-FODMAP diet resulted in greater improvement in overall IBS symptoms (P < .05) and stool frequency (P = .008). This study was limited by different habitual diets between patients and by lack of standardization of the low-FODMAP diet.

Halmos et al,²⁹ in a randomized crossover trial, compared gastrointestinal symptoms in IBS patients over 3 weeks on a low-FODMAP diet vs a moderate-FODMAP (ie, regular) diet, as well as in healthy controls. Food was provided by the study and was matched for all nutrients. Up to 70% of the IBS patients had significantly lower overall symptom scores while on a low-FODMAP diet vs IBS patients on a regular diet (P < .001); bloating, abdominal pain, and flatulence were reduced. Symptoms were minimal and unaffected by either diet in the healthy controls.

A double-blind trial³⁰ randomly assigned 25 patients with IBS who initially responded to a low-FODMAP diet to be challenged by a graduated dose of fructose alone, fructans alone, a combination of both, or glucose. The severity of overall and individual symptoms was markedly more reduced with glucose consumption than with the other carbohydrates: 70% of patients receiving fructose, 77% of those receiving fructans, and 79% of those receiving a mixture of both reported that their symptoms were not adequately controlled, compared with 14% of patients receiving glucose (P ≤ .002).³⁰

Murray et al³¹ evaluated the gastrointestinal tract after a carbohydrate challenge consisting of 0.5 L of water containing 40 g of glucose, fructose, or inulin or a combination of 40 g of glucose and 40 g of fructose in 16 healthy volunteers. Magnetic resonance imaging was performed hourly for 5 hours to assess the volume of gastric contents, small-bowel water content, and colonic gas. Breath hydrogen was also measured, and symptoms were recorded after each imaging session.

Fructose significantly increased small-bowel water content compared with glucose (mean difference 28 L/min, P < .001), but combined glucose and fructose lessened the effect. Inulin had no significant effect on small-bowel water content (mean difference with glucose 2 L/min, P > .7) but led to the greatest production of colonic gas compared with glucose alone (mean difference 15 L/min, P < .05) and combined glucose and fructose (mean difference 12 L/min, P < .05). Inulin also produced the most breath hydrogen: 81% of participants had a rise after drinking inulin compared with 50% after drinking fructose. Glucose did not affect breath hydrogen concentrations, and combined glucose and fructose significantly reduced the concentration measured vs fructose alone. In patients who reported “gas” symptoms, a correlation was observed between the volume of gas in the colon and gas symptoms (r = 0.59, P < .0001).³¹

The authors concluded³¹ that long-chain carbohydrates such as inulin have a greater effect on colonic gas production and little effect on small-bowel water content, whereas small-chain FODMAPs such as fructose are likely to cause luminal distention in both the small and large intestines. The study also showed that combining equal amounts of glucose and fructose reduces malabsorption of fructose in the small bowel and reduces the effect of fructose on small-bowel water content and breath hydrogen concentration.³¹

PROBIOTICS HELP

A Danish study³² randomized 123 patients with IBS to one of three treatments: a low-FODMAP diet, a normal diet with probiotics containing the strain Lactobacillus rhamnosus GG (two capsules daily), or no special intervention. Symptoms were recorded weekly. IBS severity scores at week 6 were lower in patients on either the low-FODMAP diet or probiotics compared with the control group (P < .01). Subgroup analysis determined that patients with primarily diarrheal symptoms were more likely to have improved quality of life with the low-FODMAP diet.

A LOW-FODMAP DIET MAY ALSO HELP IN INFLAMMATORY BOWEL DISEASE

The low-FODMAP diet has also been studied in patients with inflammatory bowel disease with functional gut symptoms. In a retrospective pilot study,³³ overall symptoms improved in about half of such patients on a low-FODMAP diet. A controlled dietary intervention trial is needed to confirm these findings and define the role of the low-FODMAP approach for patients with inflammatory bowel disease.

Marsh et al³⁴ performed a meta-analysis of six randomized clinical trials and 16 nonrandomized interventions of a low-FODMAP diet on improving functional gastrointestinal symptoms in patients with either IBS or inflammatory bowel disease. They found significant improvements in:

• IBS Symptoms Severity Scores in the randomized trials (odds ratio [OR] 0.44, 95% CI 0.25–0.76)
• IBS Symptoms Severity Scores in the nonrandomized interventions (OR 0.03, 95% CI 0.01–0.2) 
• IBS Quality of Life scores in the randomized trials (OR 1.84, 95% CI 1.12–3.03)
• IBS Quality of Life scores in the nonrandomized interventions (OR 3.18, 95% CI 1.6–6.31)
• Overall symptom severity in the randomized trials (OR 1.81, 95% CI 1.11–2.95).

DIETARY COUNSELING IS RECOMMENDED

Adherence is a major factor in the success of the low-FODMAP diet in IBS management and is strongly correlated with improved symptoms.³⁵ Patients should be counseled on the role of food in inducing their symptoms. Haphazard dietary advice can be detrimental to outcomes, as many diets restrict food groups, impairing the consumption of essential nutrients.³⁶ The involvement of a knowledgeable dietitian is helpful, as physicians may lack sufficient training in dietary skills and knowledge of food composition.

Access to and cost of dietary counseling can be prohibitive for some patients. Group consultation, which can decrease costs to each patient, has been found to be as effective as one-on-one sessions when administering the low-FODMAP diet in functional bowel disorders.³⁷

ELIMINATION, THEN REINTRODUCTION

Before embarking on the low-FODMAP diet, the patient’s interest in making dietary changes should be explored, a dietary history taken, and unusual food choices or dietary behaviors assessed. The patient’s ability to adopt a restricted diet should also be gauged.

The diet should be implemented in two phases. The initial phase involves strict elimination of foods high in FODMAPs, usually over 6 to 8 weeks.³⁸ Symptom control should be assessed: failure to control symptoms requires assessment of adherence.

If symptoms are successfully controlled, then the second phase should begin with the aim of following a less-restricted version of the diet as tolerated. Foods should gradually be phased back in and symptoms monitored. This approach minimizes unnecessary dietary restriction and ensures that a maximum variety in the diet is achieved while maintaining adequate symptom control.³⁹

LOW-FODMAP DIET ALTERS THE GUT MICROBIOTA

Multiple putative benefits of certain bacterial species for colonic health have been reported, including the production of short-chain fatty acids. Colonic luminal concentrations of short-chain fatty acids may be important to gut health, given their role in intestinal secretion, absorption, motility, and epithelial cell structure. Because short-chain fatty acids are products of bacterial fermentation, a change in the delivery of fermentable substrates to the colon would be expected to alter the concentrations and output of fecal short-chain fatty acids.¹⁸

Several studies evaluated the effect of the low-FODMAP diet on intestinal microbiota, finding a change in the bacterial profile in the stool of patients who adopt this diet. Staudacher et al²⁸ found a marked reduction in luminal bifidobacteria concentration after 4 weeks of a low-FODMAP diet in patients with IBS.

A single-blind randomized crossover trial⁴⁰ investigated the effects of a low-FODMAP diet vs a carefully matched typical Australian diet in 27 patients with IBS and 6 healthy controls. Marked differences in absolute and relative bacterial abundance and diversity were found between the diets, but not in short-chain fatty acids or gut transit time. Compared with fecal microbiota on the typical diet, low FODMAP intake was associated with reduced absolute abundance of bacteria, and the typical FODMAP diet had evidence of stimulation of the growth of bacterial groups with putative health benefits.

The authors concluded⁴⁰ that the functional significance and health implications of such changes are reasons for caution when reducing FODMAP intake in the long term and recommended liberalizing FODMAP restriction to the level of adequate symptom control in IBS patients. The study also recommended that people without symptoms not go on the low-FODMAP diet.⁴⁰

Molecular approaches to characterize the gut microbiota are also being explored in an effort to identify its association with diet.

The sustainability of changes in gut microbiota and the potential long-term impact on health of following a low-FODMAP diet require further evaluation. In the meantime, patients following this diet should have FODMAP foods reintroduced based on tolerance and should consider taking probiotic supplements.⁴¹

DIETARY ADEQUACY OF THE LOW-FODMAP DIET

Continual dietary counseling should minimize nutritional inadequacies and ensure that FODMAPS are restricted only enough to control symptoms. Because no single food group is completely eliminated in this diet, patients are unlikely to experience inadequate nutrition.

Ledochowski et al²⁶ found that in the initial, strict phase of the diet, total intake of carbohydrates (eg, starches, sugars) was reduced but intake of total energy, protein, fat, and nonstarch polysaccharides was not affected. Calcium intake was reduced in those following a low-FODMAP diet for 4 weeks.

The diet can also reduce total fiber intake and subsequently worsen constipation-predominant IBS. For those patients, lightly fermented high-fiber alternatives like oat and rice bran can be used.

ACCUMULATING EVIDENCE

The low-FODMAP diet is accumulating quality evidence for its effectiveness in controlling the functional gastrointestinal symptoms in patients with IBS. It can be difficult to adhere to over the long term due to its restrictiveness, and it is important to gradually liberalize the diet while tailoring it to the individual patient and monitoring symptoms. Further clinical trials are needed to evaluate this diet in different IBS subtypes and other gastrointestinal disorders, while defining its nutritional adequacy and effects on the intestinal microbiota profile.

The role of diet in controlling symptoms of irritable bowel syndrome (IBS) has gained much traction over the years,¹ but until recently, diet therapy for IBS has been hindered by a lack of quality evidence, in part because of the challenges of conducting dietary clinical trials.

See related editorial

Several clinical trials have now been done that support a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) for managing IBS. Although restrictive and difficult to follow, the low-FODMAP diet is gaining popularity.

This article provides an overview of dietary interventions used to manage IBS, focusing on the low-FODMAP diet. We discuss mechanisms of malabsorption of FODMAPs and the role of FODMAPS in symptom induction; highlight clinical trials that provide evidence of benefits of the diet for IBS; and discuss the steps to implement it. We also address the nutritional adequacy of the diet and its potential effects on the gut microbiome.

IBS IS A COMMON FUNCTIONAL DISORDER

IBS is one of the most commonly diagnosed gastrointestinal disorders, and it has a significant impact on quality of life.² It is a functional disorder characterized by chronic abdominal pain and altered bowel habits in the absence of a structural or organic cause.

The Rome IV diagnostic criteria define IBS by the following: 

• Recurrent abdominal pain or discomfort at least 1 day a week in the last 3 months, associated with two or more of the following:
• Symptoms improved by defecation
• Onset associated with a change in frequency of stool
• Onset associated with a change in form or appearance of stool.

IBS mainly arises during young adulthood but can be diagnosed at any age.³

The pathophysiology of IBS involves mechanisms such as bowel distention, altered bowel motility, visceral hypersensitivity, and disruption of mucosal permeability.⁴ Several therapeutic modalities targeting these mechanisms have been implemented in IBS management, including antispasmodics, laxatives, antidepressants, antibiotics, and behavioral therapy. Diet is only one line of treatment and is most effective when part of a multipronged approach.

TRADITIONAL DIETARY MANAGEMENT

Diet is important in inducing the symptoms of IBS—and in controlling them. Patients identify eating as a common precipitator of symptoms, but the complex diet-symptom interaction is not fully understood and varies widely among patients. Traditional dietary advice for IBS includes adhering to a regular meal pattern, avoiding large meals, and reducing intake of fat, insoluble fibers, caffeine, spicy and gas-producing foods, and carbonated beverages.^5,6

Increase soluble fiber

Fiber and fiber supplements, particularly soluble fibers such as psyllium, calcium polycarbophil, and ispaghula husk are often recommended. A meta-analysis⁷ found that soluble fiber but not insoluble fiber (eg, wheat bran) is associated with an improvement in IBS symptoms (relative risk [RR] 0.84, 95% confidence interval [CI] 0.73–0.94). By improving stool consistency and accelerating transit, soluble fiber is especially useful in constipation-predominant IBS while posing a low risk for adverse outcomes.⁷ Fiber should be started at a low dose and gradually increased over several weeks to as much as 20 to 30 g/day.

Avoid wheat

Only about 4% of patients with IBS also have celiac disease, but estimating the prevalence of nonceliac gluten sensitivity is confounded by overlapping symptoms. There is some evidence implicating gluten in IBS: celiac disease and IBS overlap in their symptoms, and symptoms are often precipitated by gluten-containing foods in patients with IBS.⁸ The pathogenesis of gluten-induced (or wheat-induced) symptoms in IBS is unclear, and studies have had conflicting results as to the benefits of gluten restriction in IBS.⁹

In a study of patients with IBS whose symptoms improved when they started a gluten-free and low-FODMAP diet, symptoms did not return when gluten was reintroduced, suggesting that it is the fructan (a FODMAP) component of wheat rather than gluten that contributes to symptoms in IBS.¹⁰

Probiotics

Probiotics are increasingly being recommended as dietary supplements for people with IBS, as awareness increases of  the importance of the gut microbiota. In addition to their effects on the gut microbiota, probiotics in IBS have been shown to have anti-inflammatory effects, to alter gut motility, to modulate visceral hypersensitivity, and to restore epithelial integrity.

In a meta-analysis, Ford et al¹¹ found that probiotics improved global IBS symptoms more than placebo (RR 0.79, 95% CI 0.70–0.89) and also reduced abdominal pain, bloating, and flatulence scores.

Which species and strains are most beneficial and the optimal dosing and duration of treatment are still unclear. Data from studies of prebiotics (nutrients that encourage the growth of probiotic bacteria) and synbiotics (combinations of prebiotics and probiotics) are limited and insufficient to draw conclusions.

FODMAPS ARE SHORT-CHAIN CARBOHYDRATES

The term FODMAPs was initially coined by researchers at Monash University in Australia to describe  a collection of poorly absorbed short-chain fermentable carbohydrates that are natural components of many foods:

• Oligosaccharides, including fructans (which include inulins) and galacto-oligosaccharides
• Disaccharides, including lactose and sucrose
• Monosaccharides, including fructose
• Polyols, including sorbitol and mannitol.¹²

Intake of FODMAPs, especially fructose, has increased in Western diets over the past several decades from increased consumption of fruits and concentrated fruit juices, as well as from the widespread use of high-fructose corn syrup in processed foods and beverages.¹³

FODMAPs ARE POORLY ABSORBED

Different FODMAPs can be poorly absorbed for different reasons (Table 1). The poor absorption is related either to reduced or absent digestive enzymes (ie, hydrolases) or to slow transport across the intestinal mucosa. Excess FODMAPs in the distal small intestine and proximal colon exert osmotic pressure, drawing more water into the lumen. FODMAPs are also rapidly fermented by colonic bacteria, producing gas, bowel distention, and altered motility, all of which induce IBS symptoms.¹⁴

Fructans are fructose polymers that are not absorbed in human intestines. They have no intestinal hydrolases and no mechanisms for direct transport across the epithelium. However, a negligible amount may be absorbed after being degraded by microbes in the gut.¹⁵ Most dietary fructans are obtained from wheat and onion, which are actually low in fructans but tend to be consumed in large quantities.¹⁶

Galacto-oligosaccharides are available for colonic fermentation after ingestion due to lack of a human alpha-galactosidase. Common sources of galacto-oligosaccharides include legumes, nuts, seeds, some grains, dairy products, human milk, and some commercially produced forms added to infant formula.^17,18

Lactose is poorly absorbed in people with lactase deficiency. It is mainly present in dairy products but is also added to commercial foods, including breads, cakes, and some diet products.¹⁹

Fructose is the most abundant FODMAP in the Western diet. It is either present as a free sugar or generated from the digestive breakdown of sucrose. In the intestine, it is absorbed via a direct low-capacity glucose transporter (GLUT)-5 and through GLUT-2, which is more efficient but requires the coexistence of glucose. Because of this requirement, fructose is more likely to be malabsorbed when present in excess of glucose, as in people with diminished sucrase activity. The main sources of fructose in the Western diet are fruits and fruit products, honey, and foods with added high-fructose sweeteners.¹³

Polyols such as sorbitol and mannitol are absorbed by slow passive diffusion because they have no active intestinal transport system. They are found in fruits and vegetables. Sugar-free chewing gum is a particularly rich source of sorbitol.²⁰

QUANTIFYING FODMAP CONTENT

As interest in the low-FODMAP diet grew, studies were conducted to quantify FODMAPs in foods. One study used high-performance liquid chromatography to analyze FODMAP content in foods,²¹ and another evaluated fructan levels in a variety of fruits and vegetables using enzymatic hydrolysis.²² The Monash University low-FODMAP diet smartphone application provides patients and healthcare providers easy access to updated and detailed food analyses.²³

Table 2 lists foods high in FODMAPs along with low-FODMAP alternatives. Total FODMAP intake is important, as the effects are additive.²⁴ Readers and patients can be directed to the following websites for more information on the low-FODMAP diet: www.med.monash.edu/cecs/gastro/fodmap or www.ibsfree.net/what-is-fodmap-diet.

LOW-FODMAP DIET REDUCES SYMPTOMS

The low-FODMAP diet was inspired by the results of several studies that evaluated the role of dietary carbohydrates in inducing IBS symptoms and found improvement with their restriction.^25,26

One study found that 74% of patients with IBS had less bloating, nausea, abdominal pain, and diarrhea when they restricted their intake of fructose and fructans.²⁷

A prospective trial randomized 41 patients with IBS to 4 weeks of either a low-FODMAP diet or their habitual diet.²⁸ The low-FODMAP diet resulted in greater improvement in overall IBS symptoms (P < .05) and stool frequency (P = .008). This study was limited by different habitual diets between patients and by lack of standardization of the low-FODMAP diet.

Halmos et al,²⁹ in a randomized crossover trial, compared gastrointestinal symptoms in IBS patients over 3 weeks on a low-FODMAP diet vs a moderate-FODMAP (ie, regular) diet, as well as in healthy controls. Food was provided by the study and was matched for all nutrients. Up to 70% of the IBS patients had significantly lower overall symptom scores while on a low-FODMAP diet vs IBS patients on a regular diet (P < .001); bloating, abdominal pain, and flatulence were reduced. Symptoms were minimal and unaffected by either diet in the healthy controls.

A double-blind trial³⁰ randomly assigned 25 patients with IBS who initially responded to a low-FODMAP diet to be challenged by a graduated dose of fructose alone, fructans alone, a combination of both, or glucose. The severity of overall and individual symptoms was markedly more reduced with glucose consumption than with the other carbohydrates: 70% of patients receiving fructose, 77% of those receiving fructans, and 79% of those receiving a mixture of both reported that their symptoms were not adequately controlled, compared with 14% of patients receiving glucose (P ≤ .002).³⁰

Murray et al³¹ evaluated the gastrointestinal tract after a carbohydrate challenge consisting of 0.5 L of water containing 40 g of glucose, fructose, or inulin or a combination of 40 g of glucose and 40 g of fructose in 16 healthy volunteers. Magnetic resonance imaging was performed hourly for 5 hours to assess the volume of gastric contents, small-bowel water content, and colonic gas. Breath hydrogen was also measured, and symptoms were recorded after each imaging session.

Fructose significantly increased small-bowel water content compared with glucose (mean difference 28 L/min, P < .001), but combined glucose and fructose lessened the effect. Inulin had no significant effect on small-bowel water content (mean difference with glucose 2 L/min, P > .7) but led to the greatest production of colonic gas compared with glucose alone (mean difference 15 L/min, P < .05) and combined glucose and fructose (mean difference 12 L/min, P < .05). Inulin also produced the most breath hydrogen: 81% of participants had a rise after drinking inulin compared with 50% after drinking fructose. Glucose did not affect breath hydrogen concentrations, and combined glucose and fructose significantly reduced the concentration measured vs fructose alone. In patients who reported “gas” symptoms, a correlation was observed between the volume of gas in the colon and gas symptoms (r = 0.59, P < .0001).³¹

The authors concluded³¹ that long-chain carbohydrates such as inulin have a greater effect on colonic gas production and little effect on small-bowel water content, whereas small-chain FODMAPs such as fructose are likely to cause luminal distention in both the small and large intestines. The study also showed that combining equal amounts of glucose and fructose reduces malabsorption of fructose in the small bowel and reduces the effect of fructose on small-bowel water content and breath hydrogen concentration.³¹

PROBIOTICS HELP

A Danish study³² randomized 123 patients with IBS to one of three treatments: a low-FODMAP diet, a normal diet with probiotics containing the strain Lactobacillus rhamnosus GG (two capsules daily), or no special intervention. Symptoms were recorded weekly. IBS severity scores at week 6 were lower in patients on either the low-FODMAP diet or probiotics compared with the control group (P < .01). Subgroup analysis determined that patients with primarily diarrheal symptoms were more likely to have improved quality of life with the low-FODMAP diet.

A LOW-FODMAP DIET MAY ALSO HELP IN INFLAMMATORY BOWEL DISEASE

The low-FODMAP diet has also been studied in patients with inflammatory bowel disease with functional gut symptoms. In a retrospective pilot study,³³ overall symptoms improved in about half of such patients on a low-FODMAP diet. A controlled dietary intervention trial is needed to confirm these findings and define the role of the low-FODMAP approach for patients with inflammatory bowel disease.

Marsh et al³⁴ performed a meta-analysis of six randomized clinical trials and 16 nonrandomized interventions of a low-FODMAP diet on improving functional gastrointestinal symptoms in patients with either IBS or inflammatory bowel disease. They found significant improvements in:

• IBS Symptoms Severity Scores in the randomized trials (odds ratio [OR] 0.44, 95% CI 0.25–0.76)
• IBS Symptoms Severity Scores in the nonrandomized interventions (OR 0.03, 95% CI 0.01–0.2) 
• IBS Quality of Life scores in the randomized trials (OR 1.84, 95% CI 1.12–3.03)
• IBS Quality of Life scores in the nonrandomized interventions (OR 3.18, 95% CI 1.6–6.31)
• Overall symptom severity in the randomized trials (OR 1.81, 95% CI 1.11–2.95).

DIETARY COUNSELING IS RECOMMENDED

Adherence is a major factor in the success of the low-FODMAP diet in IBS management and is strongly correlated with improved symptoms.³⁵ Patients should be counseled on the role of food in inducing their symptoms. Haphazard dietary advice can be detrimental to outcomes, as many diets restrict food groups, impairing the consumption of essential nutrients.³⁶ The involvement of a knowledgeable dietitian is helpful, as physicians may lack sufficient training in dietary skills and knowledge of food composition.

Access to and cost of dietary counseling can be prohibitive for some patients. Group consultation, which can decrease costs to each patient, has been found to be as effective as one-on-one sessions when administering the low-FODMAP diet in functional bowel disorders.³⁷

ELIMINATION, THEN REINTRODUCTION

Before embarking on the low-FODMAP diet, the patient’s interest in making dietary changes should be explored, a dietary history taken, and unusual food choices or dietary behaviors assessed. The patient’s ability to adopt a restricted diet should also be gauged.

The diet should be implemented in two phases. The initial phase involves strict elimination of foods high in FODMAPs, usually over 6 to 8 weeks.³⁸ Symptom control should be assessed: failure to control symptoms requires assessment of adherence.

If symptoms are successfully controlled, then the second phase should begin with the aim of following a less-restricted version of the diet as tolerated. Foods should gradually be phased back in and symptoms monitored. This approach minimizes unnecessary dietary restriction and ensures that a maximum variety in the diet is achieved while maintaining adequate symptom control.³⁹

LOW-FODMAP DIET ALTERS THE GUT MICROBIOTA

Multiple putative benefits of certain bacterial species for colonic health have been reported, including the production of short-chain fatty acids. Colonic luminal concentrations of short-chain fatty acids may be important to gut health, given their role in intestinal secretion, absorption, motility, and epithelial cell structure. Because short-chain fatty acids are products of bacterial fermentation, a change in the delivery of fermentable substrates to the colon would be expected to alter the concentrations and output of fecal short-chain fatty acids.¹⁸

Several studies evaluated the effect of the low-FODMAP diet on intestinal microbiota, finding a change in the bacterial profile in the stool of patients who adopt this diet. Staudacher et al²⁸ found a marked reduction in luminal bifidobacteria concentration after 4 weeks of a low-FODMAP diet in patients with IBS.

A single-blind randomized crossover trial⁴⁰ investigated the effects of a low-FODMAP diet vs a carefully matched typical Australian diet in 27 patients with IBS and 6 healthy controls. Marked differences in absolute and relative bacterial abundance and diversity were found between the diets, but not in short-chain fatty acids or gut transit time. Compared with fecal microbiota on the typical diet, low FODMAP intake was associated with reduced absolute abundance of bacteria, and the typical FODMAP diet had evidence of stimulation of the growth of bacterial groups with putative health benefits.

The authors concluded⁴⁰ that the functional significance and health implications of such changes are reasons for caution when reducing FODMAP intake in the long term and recommended liberalizing FODMAP restriction to the level of adequate symptom control in IBS patients. The study also recommended that people without symptoms not go on the low-FODMAP diet.⁴⁰

Molecular approaches to characterize the gut microbiota are also being explored in an effort to identify its association with diet.

The sustainability of changes in gut microbiota and the potential long-term impact on health of following a low-FODMAP diet require further evaluation. In the meantime, patients following this diet should have FODMAP foods reintroduced based on tolerance and should consider taking probiotic supplements.⁴¹

DIETARY ADEQUACY OF THE LOW-FODMAP DIET

Continual dietary counseling should minimize nutritional inadequacies and ensure that FODMAPS are restricted only enough to control symptoms. Because no single food group is completely eliminated in this diet, patients are unlikely to experience inadequate nutrition.

Ledochowski et al²⁶ found that in the initial, strict phase of the diet, total intake of carbohydrates (eg, starches, sugars) was reduced but intake of total energy, protein, fat, and nonstarch polysaccharides was not affected. Calcium intake was reduced in those following a low-FODMAP diet for 4 weeks.

The diet can also reduce total fiber intake and subsequently worsen constipation-predominant IBS. For those patients, lightly fermented high-fiber alternatives like oat and rice bran can be used.

ACCUMULATING EVIDENCE

The low-FODMAP diet is accumulating quality evidence for its effectiveness in controlling the functional gastrointestinal symptoms in patients with IBS. It can be difficult to adhere to over the long term due to its restrictiveness, and it is important to gradually liberalize the diet while tailoring it to the individual patient and monitoring symptoms. Further clinical trials are needed to evaluate this diet in different IBS subtypes and other gastrointestinal disorders, while defining its nutritional adequacy and effects on the intestinal microbiota profile.

Diet plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and is an effective tool in managing this disorder. This includes a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs).

See related article

These indigestible and poorly absorbed short-chain carbohydrates trigger IBS symptoms and are thought to exert their effects by increasing osmotic pressure in the lumen of the intestine and by providing a substrate for bacterial fermentation with consequent gas production.¹ The gas causes abdominal distention, and the change in pressure in the lumen of the large intestine affects the release of serotonin, causing abdominal pain and discomfort.

THE MECHANISMS ARE COMPLICATED

Recent studies have shown that the mechanisms by which FODMAPs exert their effects are more complicated than originally thought.¹

All segments of the gastrointestinal tract contain endocrine cells scattered between the mucosal epithelial cells facing the intestinal lumen.^1,2 There are at least 10 types of endocrine cell, and they regulate gastrointestinal motility, secretion, absorption, visceral sensitivity, local immune defense, cell proliferation, and appetite.^2–4 Abnormal densities of gastrointestinal endocrine cells have been reported in patients with IBS, which may explain the dysmotility, visceral hypersensitivity, and abnormal intestinal secretion seen in these patients.⁵

But other factors such as diet, intestinal microbiota, genetics, and low-grade inflammation also play pivotal roles in the pathophysiology of IBS by exerting effects on gastrointestinal endocrine cells. The abnormalities in the gastrointestinal endocrine cells in IBS are thought to be brought about by aberrant differentiation of stem cells into endocrine cells (Figure 1).⁶

A diet low in FODMAPs appears to induce changes in the intestinal microbiota and gastrointestinal endocrine cells and to reduce IBS symptoms.⁶

GLUTEN IS IMPLICATED

Another dietary factor in IBS is gluten. Symptoms of IBS and celiac disease overlap: most studies have found that fewer than 5% of patients with celiac disease are misdiagnosed as having IBS based on the symptom criteria for IBS, but some studies report a rate as high as 32%.⁷ In addition, 38% of patients with celiac disease who consume a gluten-free diet fulfill the symptom-based Rome criteria for IBS.⁷

The contribution of gluten to IBS does not end with the coexistence of IBS and celiac disease, but also includes the newly debated diagnosis of nonceliac gluten sensitivity, characterized by gastrointestinal symptoms (abdominal pain, diarrhea, constipation, nausea, and vomiting) and other symptoms (headache, musculoskeletal pain, “brain fog,” fatigue, and depression) that are similar to those of IBS. Symptoms are triggered by the ingestion of wheat products, are improved after wheat products are removed from the diet, and relapse after a wheat challenge.⁷

Nonceliac gluten sensitivity is often perceivable by patients, resulting in self-diagnosis and self-treatment.⁴ However, it is not clear whether it is gluten or the fructans and galactans in wheat that are responsible for triggering their symptoms.⁷

DIETARY GUIDANCE IS NEEDED

A low-FODMAP diet with small amounts of insoluble dietary fiber improves symptoms and quality of life in patients with IBS, but dietary guidance is critical and should be personalized because patients differ in how they tolerate foods rich in FODMAPs, probably owing to differing intestinal microbiota among individuals.^3,8 Intake of probiotics increases tolerance of FODMAP-rich foods and should also be recommended.^3,8,9 Because of the rigorous restrictions of the low-FODMAP diet, patients who receive personalized guidance are more inclined to adhere to the diet and to avoid vitamin and mineral deficiencies.⁹

Diet plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and is an effective tool in managing this disorder. This includes a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs).

See related article

These indigestible and poorly absorbed short-chain carbohydrates trigger IBS symptoms and are thought to exert their effects by increasing osmotic pressure in the lumen of the intestine and by providing a substrate for bacterial fermentation with consequent gas production.¹ The gas causes abdominal distention, and the change in pressure in the lumen of the large intestine affects the release of serotonin, causing abdominal pain and discomfort.

THE MECHANISMS ARE COMPLICATED

Recent studies have shown that the mechanisms by which FODMAPs exert their effects are more complicated than originally thought.¹

All segments of the gastrointestinal tract contain endocrine cells scattered between the mucosal epithelial cells facing the intestinal lumen.^1,2 There are at least 10 types of endocrine cell, and they regulate gastrointestinal motility, secretion, absorption, visceral sensitivity, local immune defense, cell proliferation, and appetite.^2–4 Abnormal densities of gastrointestinal endocrine cells have been reported in patients with IBS, which may explain the dysmotility, visceral hypersensitivity, and abnormal intestinal secretion seen in these patients.⁵

But other factors such as diet, intestinal microbiota, genetics, and low-grade inflammation also play pivotal roles in the pathophysiology of IBS by exerting effects on gastrointestinal endocrine cells. The abnormalities in the gastrointestinal endocrine cells in IBS are thought to be brought about by aberrant differentiation of stem cells into endocrine cells (Figure 1).⁶

A diet low in FODMAPs appears to induce changes in the intestinal microbiota and gastrointestinal endocrine cells and to reduce IBS symptoms.⁶

GLUTEN IS IMPLICATED

Another dietary factor in IBS is gluten. Symptoms of IBS and celiac disease overlap: most studies have found that fewer than 5% of patients with celiac disease are misdiagnosed as having IBS based on the symptom criteria for IBS, but some studies report a rate as high as 32%.⁷ In addition, 38% of patients with celiac disease who consume a gluten-free diet fulfill the symptom-based Rome criteria for IBS.⁷

The contribution of gluten to IBS does not end with the coexistence of IBS and celiac disease, but also includes the newly debated diagnosis of nonceliac gluten sensitivity, characterized by gastrointestinal symptoms (abdominal pain, diarrhea, constipation, nausea, and vomiting) and other symptoms (headache, musculoskeletal pain, “brain fog,” fatigue, and depression) that are similar to those of IBS. Symptoms are triggered by the ingestion of wheat products, are improved after wheat products are removed from the diet, and relapse after a wheat challenge.⁷

Nonceliac gluten sensitivity is often perceivable by patients, resulting in self-diagnosis and self-treatment.⁴ However, it is not clear whether it is gluten or the fructans and galactans in wheat that are responsible for triggering their symptoms.⁷

DIETARY GUIDANCE IS NEEDED

A low-FODMAP diet with small amounts of insoluble dietary fiber improves symptoms and quality of life in patients with IBS, but dietary guidance is critical and should be personalized because patients differ in how they tolerate foods rich in FODMAPs, probably owing to differing intestinal microbiota among individuals.^3,8 Intake of probiotics increases tolerance of FODMAP-rich foods and should also be recommended.^3,8,9 Because of the rigorous restrictions of the low-FODMAP diet, patients who receive personalized guidance are more inclined to adhere to the diet and to avoid vitamin and mineral deficiencies.⁹

Diet plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and is an effective tool in managing this disorder. This includes a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs).

See related article

These indigestible and poorly absorbed short-chain carbohydrates trigger IBS symptoms and are thought to exert their effects by increasing osmotic pressure in the lumen of the intestine and by providing a substrate for bacterial fermentation with consequent gas production.¹ The gas causes abdominal distention, and the change in pressure in the lumen of the large intestine affects the release of serotonin, causing abdominal pain and discomfort.

THE MECHANISMS ARE COMPLICATED

Recent studies have shown that the mechanisms by which FODMAPs exert their effects are more complicated than originally thought.¹

All segments of the gastrointestinal tract contain endocrine cells scattered between the mucosal epithelial cells facing the intestinal lumen.^1,2 There are at least 10 types of endocrine cell, and they regulate gastrointestinal motility, secretion, absorption, visceral sensitivity, local immune defense, cell proliferation, and appetite.^2–4 Abnormal densities of gastrointestinal endocrine cells have been reported in patients with IBS, which may explain the dysmotility, visceral hypersensitivity, and abnormal intestinal secretion seen in these patients.⁵

But other factors such as diet, intestinal microbiota, genetics, and low-grade inflammation also play pivotal roles in the pathophysiology of IBS by exerting effects on gastrointestinal endocrine cells. The abnormalities in the gastrointestinal endocrine cells in IBS are thought to be brought about by aberrant differentiation of stem cells into endocrine cells (Figure 1).⁶

A diet low in FODMAPs appears to induce changes in the intestinal microbiota and gastrointestinal endocrine cells and to reduce IBS symptoms.⁶

GLUTEN IS IMPLICATED

Another dietary factor in IBS is gluten. Symptoms of IBS and celiac disease overlap: most studies have found that fewer than 5% of patients with celiac disease are misdiagnosed as having IBS based on the symptom criteria for IBS, but some studies report a rate as high as 32%.⁷ In addition, 38% of patients with celiac disease who consume a gluten-free diet fulfill the symptom-based Rome criteria for IBS.⁷

The contribution of gluten to IBS does not end with the coexistence of IBS and celiac disease, but also includes the newly debated diagnosis of nonceliac gluten sensitivity, characterized by gastrointestinal symptoms (abdominal pain, diarrhea, constipation, nausea, and vomiting) and other symptoms (headache, musculoskeletal pain, “brain fog,” fatigue, and depression) that are similar to those of IBS. Symptoms are triggered by the ingestion of wheat products, are improved after wheat products are removed from the diet, and relapse after a wheat challenge.⁷

Nonceliac gluten sensitivity is often perceivable by patients, resulting in self-diagnosis and self-treatment.⁴ However, it is not clear whether it is gluten or the fructans and galactans in wheat that are responsible for triggering their symptoms.⁷

DIETARY GUIDANCE IS NEEDED

A low-FODMAP diet with small amounts of insoluble dietary fiber improves symptoms and quality of life in patients with IBS, but dietary guidance is critical and should be personalized because patients differ in how they tolerate foods rich in FODMAPs, probably owing to differing intestinal microbiota among individuals.^3,8 Intake of probiotics increases tolerance of FODMAP-rich foods and should also be recommended.^3,8,9 Because of the rigorous restrictions of the low-FODMAP diet, patients who receive personalized guidance are more inclined to adhere to the diet and to avoid vitamin and mineral deficiencies.⁹

Labeling for prescription opioid pain or cough medicines and benzodiazepines will now carry the strongest available warning regarding serious side effects and death associated with their combined use, according to the Food and Drug Administration.

The new boxed warnings urge health care professionals to limit prescribing opioid pain medicines with benzodiazepines or other central nervous system depressants only to patients for whom alternative treatment options are inadequate, and to limit dosages and treatment duration to the minimum possible while achieving the desired clinical effect.

“First, the FDA is requiring companies to update their product labeling for ... benzodiazepines and opioids to include possible harms when they are used together. Second, we are requiring new or updated medication guides for these drugs reflecting those same warnings,” said Doug Throckmorton, MD, deputy director of the FDA’s Center for Drug Evaluation and Research, during a telebriefing.

Opioids will include a warning regarding prescribing with benzodiazepines and other central nervous system depressants, including alcohol. Benzodiazepines will include a warning regarding prescribing with opioids.

In addition, the FDA has issued a safety communication to “warn the public about the serious risk of taking these products together to help make doctors more cautious and patients better informed,” Dr. Throckmorton said.

The action comes amid ongoing efforts to address an epidemic of opioid addiction across the United States, and in response to a first-of-its-kind “citizen petition” calling for the boxed warnings.

A coalition of health officials from multiple cities, states, and U.S. territories initiated that petition in February, and thousands of concerned community members started an additional online petition. Those petitions were in response to both the increasing combined use of opioids and benzodiazepines and a concomitant increase in the risk of serious side effects and deaths associated with their combined use, according to Baltimore City Health Commissioner Leana Wen, MD.

As an emergency physician, Dr. Wen said that she has seen firsthand the alarming trends; one in three unintentional overdose deaths from prescribed opioids also involve benzodiazepines, she noted.

“In my state of Maryland in 2014, benzodiazepines were associated with 19% of prescription opioid deaths, and 59% of benzodiazepine-associated deaths involved prescription opioids. We also noted the growing biological evidence that combining these medications caused sleepiness and slowed breathing, increasing the likelihood of a fatal overdose,” she said.

Dr. Throckmorton further noted that emergency department visits and deaths involving patients prescribed both opioids and benzodiazepines have increased significantly over time. From 2004 to 2011, the rate of nonmedical use–related emergency department visits increased significantly each year, and overdose deaths involving both drug classes during that period nearly tripled on an annual basis.

“Communities have been seeing this trend for some time, but ultimately we needed data in order to act today,” FDA Commissioner Robert Califf, MD, said during the telebriefing.

The current action is just “one part of a larger effort to address this epidemic.

“We remain focused and deeply committed to contributing to the comprehensive effort to address the opioid epidemic,” Dr. Califf said. The FDA “will continue to monitor these products carefully and take additional actions as needed, and will share updates with the public as necessary as we work to address this public health crisis.”

Dr. Califf noted that the current action is part of the FDA’s Opioids Action Plan, which is “importantly not meant just to cover illicit or abusive use of opioids.”

“So, you’ll be hearing a lot more from us, because this is a national crisis that is not going away. We’re making progress on the prescribing, and we’re seeing a reduction in the use of opioids now,” he noted. “But we’re still seeing many overdoses.

“This is a continuum, and we’ll continue to try to do everything we can to address the epidemic,” Dr. Califf concluded.

[email protected]

Labeling for prescription opioid pain or cough medicines and benzodiazepines will now carry the strongest available warning regarding serious side effects and death associated with their combined use, according to the Food and Drug Administration.

The new boxed warnings urge health care professionals to limit prescribing opioid pain medicines with benzodiazepines or other central nervous system depressants only to patients for whom alternative treatment options are inadequate, and to limit dosages and treatment duration to the minimum possible while achieving the desired clinical effect.

“First, the FDA is requiring companies to update their product labeling for ... benzodiazepines and opioids to include possible harms when they are used together. Second, we are requiring new or updated medication guides for these drugs reflecting those same warnings,” said Doug Throckmorton, MD, deputy director of the FDA’s Center for Drug Evaluation and Research, during a telebriefing.

Opioids will include a warning regarding prescribing with benzodiazepines and other central nervous system depressants, including alcohol. Benzodiazepines will include a warning regarding prescribing with opioids.

In addition, the FDA has issued a safety communication to “warn the public about the serious risk of taking these products together to help make doctors more cautious and patients better informed,” Dr. Throckmorton said.

The action comes amid ongoing efforts to address an epidemic of opioid addiction across the United States, and in response to a first-of-its-kind “citizen petition” calling for the boxed warnings.

A coalition of health officials from multiple cities, states, and U.S. territories initiated that petition in February, and thousands of concerned community members started an additional online petition. Those petitions were in response to both the increasing combined use of opioids and benzodiazepines and a concomitant increase in the risk of serious side effects and deaths associated with their combined use, according to Baltimore City Health Commissioner Leana Wen, MD.

As an emergency physician, Dr. Wen said that she has seen firsthand the alarming trends; one in three unintentional overdose deaths from prescribed opioids also involve benzodiazepines, she noted.

“In my state of Maryland in 2014, benzodiazepines were associated with 19% of prescription opioid deaths, and 59% of benzodiazepine-associated deaths involved prescription opioids. We also noted the growing biological evidence that combining these medications caused sleepiness and slowed breathing, increasing the likelihood of a fatal overdose,” she said.

Dr. Throckmorton further noted that emergency department visits and deaths involving patients prescribed both opioids and benzodiazepines have increased significantly over time. From 2004 to 2011, the rate of nonmedical use–related emergency department visits increased significantly each year, and overdose deaths involving both drug classes during that period nearly tripled on an annual basis.

“Communities have been seeing this trend for some time, but ultimately we needed data in order to act today,” FDA Commissioner Robert Califf, MD, said during the telebriefing.

The current action is just “one part of a larger effort to address this epidemic.

“We remain focused and deeply committed to contributing to the comprehensive effort to address the opioid epidemic,” Dr. Califf said. The FDA “will continue to monitor these products carefully and take additional actions as needed, and will share updates with the public as necessary as we work to address this public health crisis.”

Dr. Califf noted that the current action is part of the FDA’s Opioids Action Plan, which is “importantly not meant just to cover illicit or abusive use of opioids.”

“So, you’ll be hearing a lot more from us, because this is a national crisis that is not going away. We’re making progress on the prescribing, and we’re seeing a reduction in the use of opioids now,” he noted. “But we’re still seeing many overdoses.

“This is a continuum, and we’ll continue to try to do everything we can to address the epidemic,” Dr. Califf concluded.

[email protected]

Labeling for prescription opioid pain or cough medicines and benzodiazepines will now carry the strongest available warning regarding serious side effects and death associated with their combined use, according to the Food and Drug Administration.

The new boxed warnings urge health care professionals to limit prescribing opioid pain medicines with benzodiazepines or other central nervous system depressants only to patients for whom alternative treatment options are inadequate, and to limit dosages and treatment duration to the minimum possible while achieving the desired clinical effect.

“First, the FDA is requiring companies to update their product labeling for ... benzodiazepines and opioids to include possible harms when they are used together. Second, we are requiring new or updated medication guides for these drugs reflecting those same warnings,” said Doug Throckmorton, MD, deputy director of the FDA’s Center for Drug Evaluation and Research, during a telebriefing.

Opioids will include a warning regarding prescribing with benzodiazepines and other central nervous system depressants, including alcohol. Benzodiazepines will include a warning regarding prescribing with opioids.

In addition, the FDA has issued a safety communication to “warn the public about the serious risk of taking these products together to help make doctors more cautious and patients better informed,” Dr. Throckmorton said.

The action comes amid ongoing efforts to address an epidemic of opioid addiction across the United States, and in response to a first-of-its-kind “citizen petition” calling for the boxed warnings.

A coalition of health officials from multiple cities, states, and U.S. territories initiated that petition in February, and thousands of concerned community members started an additional online petition. Those petitions were in response to both the increasing combined use of opioids and benzodiazepines and a concomitant increase in the risk of serious side effects and deaths associated with their combined use, according to Baltimore City Health Commissioner Leana Wen, MD.

As an emergency physician, Dr. Wen said that she has seen firsthand the alarming trends; one in three unintentional overdose deaths from prescribed opioids also involve benzodiazepines, she noted.

“In my state of Maryland in 2014, benzodiazepines were associated with 19% of prescription opioid deaths, and 59% of benzodiazepine-associated deaths involved prescription opioids. We also noted the growing biological evidence that combining these medications caused sleepiness and slowed breathing, increasing the likelihood of a fatal overdose,” she said.

Dr. Throckmorton further noted that emergency department visits and deaths involving patients prescribed both opioids and benzodiazepines have increased significantly over time. From 2004 to 2011, the rate of nonmedical use–related emergency department visits increased significantly each year, and overdose deaths involving both drug classes during that period nearly tripled on an annual basis.

“Communities have been seeing this trend for some time, but ultimately we needed data in order to act today,” FDA Commissioner Robert Califf, MD, said during the telebriefing.

The current action is just “one part of a larger effort to address this epidemic.

“We remain focused and deeply committed to contributing to the comprehensive effort to address the opioid epidemic,” Dr. Califf said. The FDA “will continue to monitor these products carefully and take additional actions as needed, and will share updates with the public as necessary as we work to address this public health crisis.”

Dr. Califf noted that the current action is part of the FDA’s Opioids Action Plan, which is “importantly not meant just to cover illicit or abusive use of opioids.”

“So, you’ll be hearing a lot more from us, because this is a national crisis that is not going away. We’re making progress on the prescribing, and we’re seeing a reduction in the use of opioids now,” he noted. “But we’re still seeing many overdoses.

“This is a continuum, and we’ll continue to try to do everything we can to address the epidemic,” Dr. Califf concluded.

[email protected]

NEWPORT BEACH, CALIF. – In the clinical opinion of Kelly M. Cordoro, MD, anyone who cares for patients with severe atopic dermatitis understands the sense of misery that can ensue.

“Atopic dermatitis patients don’t sleep well; they have poor school and work performance,” she said at the annual meeting of the Pacific Dermatologic Association. “They have absences. They’re unable to play; they can’t exercise. This leads to social disability; isolation from peers, and it goes on and on. The patients are miserable, the whole family is miserable, and we as physicians trying to sort out how to optimally treat them are miserable trying to figure out what the next best step is.”

The good news is, several drugs in the pipeline hold promise for atopic dermatitis patients, thanks largely to emerging data on its pathophysiology. In addition, mechanisms of itch, which are not yet fully understood, are also being unraveled. “It’s exciting to read the literature about the interaction of the skin, the immune system, and the nervous system,” said Dr. Cordoro, a pediatric dermatologist at the University of California, San Francisco. “Many of the mediators of itch are being identified. That has allowed for the development of targeted therapies against many of them.”

One of the promising treatments on the horizon for atopic dermatitis patients is phosphodiesterase-4 (PDE4) inhibitors. PDE-4 is a predominant cAMP-degrading enzyme in keratinocytes and inflammatory cells. “It’s really a candidate for not only atopic dermatitis but for psoriasis,” she said.

Oral PDE-4 inhibitors are already approved for psoriasis. Apremilast (Otezla) was approved by the Food and Drug Administration in 2014 for psoriasis and psoriatic arthritis, and a phase II trial of topical apremilast in adults with AD has been completed and the results are pending. “I look forward to seeing if this can help our patients,” Dr. Cordoro said.

Another promising agent for atopic dermatitis is 2% crisaborole topical ointment, a boron-based PDE-4 inhibitor developed by Anacor Pharmaceuticals. Dr. Cordoro described this compound as an anti-inflammatory agent that modifies inflammation by inhibiting the degradation of cAMP by PDE4, resulting in downstream modification of nuclear factor-kB and T-cell signaling pathways.

“Crisaborole has shown promising results from four clinical studies in patients 2 years of age and older, with notable improvements in all atopic dermatitis parameters,” she said (J Am Acad Dermatol. 2016 Sept;75[3]:494-503.e). The FDA review of crisaborole for the treatment of mild to moderate atopic dermatitis in children and adults is currently underway, and is expected to be completed by early January 2017.

An especially favorable drug in development for atopic dermatitis is dupilumab, a fully human monoclonal antibody that targets the interleukin (IL)–4 receptor, and inhibits IL-4 and IL-13 signaling. A published trial of its use in adults with moderate to severe atopic dermatitis showed rapid improvements in all atopic dermatitis clinical indices (N Engl J Med. 2014;371[2]:130-9). The most common side effects were headache and pharyngitis, and skin infections and flares were more common in the placebo group, compared with the treatment group.

Dupilumab “has the potential to shift the treatment landscape of atopic dermatitis, because it can actually change the molecular signature of dermatitic skin, reducing inflammatory and proliferative markers,” Dr. Cordoro said. There are ongoing trials in adult and pediatric populations and FDA approval is anticipated in early 2017.

Published reports also suggest a role for the IL-12/23 pathway inhibitor ustekinumab in severe refractory adult atopic dermatitis (Int J Dermatol. 2012;51[1]:115-6 and JAAD Case Reports 2015;1:25-6). Additional studies are ongoing.

Therapies for itch that have completed phase II trials include the anti-IL31R monoclonal antibody nemolizumab (CIM331); the neurokinin-1R antagonist VLY-686; and the neurokinin-1R antagonist aprepitant gel.

Dr. Cordoro disclosed that she is a consultant for Celgene Corporation, Valeant, and Anacor Pharmaceuticals.

[email protected]

NEWPORT BEACH, CALIF. – In the clinical opinion of Kelly M. Cordoro, MD, anyone who cares for patients with severe atopic dermatitis understands the sense of misery that can ensue.

“Atopic dermatitis patients don’t sleep well; they have poor school and work performance,” she said at the annual meeting of the Pacific Dermatologic Association. “They have absences. They’re unable to play; they can’t exercise. This leads to social disability; isolation from peers, and it goes on and on. The patients are miserable, the whole family is miserable, and we as physicians trying to sort out how to optimally treat them are miserable trying to figure out what the next best step is.”

The good news is, several drugs in the pipeline hold promise for atopic dermatitis patients, thanks largely to emerging data on its pathophysiology. In addition, mechanisms of itch, which are not yet fully understood, are also being unraveled. “It’s exciting to read the literature about the interaction of the skin, the immune system, and the nervous system,” said Dr. Cordoro, a pediatric dermatologist at the University of California, San Francisco. “Many of the mediators of itch are being identified. That has allowed for the development of targeted therapies against many of them.”

One of the promising treatments on the horizon for atopic dermatitis patients is phosphodiesterase-4 (PDE4) inhibitors. PDE-4 is a predominant cAMP-degrading enzyme in keratinocytes and inflammatory cells. “It’s really a candidate for not only atopic dermatitis but for psoriasis,” she said.

Oral PDE-4 inhibitors are already approved for psoriasis. Apremilast (Otezla) was approved by the Food and Drug Administration in 2014 for psoriasis and psoriatic arthritis, and a phase II trial of topical apremilast in adults with AD has been completed and the results are pending. “I look forward to seeing if this can help our patients,” Dr. Cordoro said.

Another promising agent for atopic dermatitis is 2% crisaborole topical ointment, a boron-based PDE-4 inhibitor developed by Anacor Pharmaceuticals. Dr. Cordoro described this compound as an anti-inflammatory agent that modifies inflammation by inhibiting the degradation of cAMP by PDE4, resulting in downstream modification of nuclear factor-kB and T-cell signaling pathways.

“Crisaborole has shown promising results from four clinical studies in patients 2 years of age and older, with notable improvements in all atopic dermatitis parameters,” she said (J Am Acad Dermatol. 2016 Sept;75[3]:494-503.e). The FDA review of crisaborole for the treatment of mild to moderate atopic dermatitis in children and adults is currently underway, and is expected to be completed by early January 2017.

An especially favorable drug in development for atopic dermatitis is dupilumab, a fully human monoclonal antibody that targets the interleukin (IL)–4 receptor, and inhibits IL-4 and IL-13 signaling. A published trial of its use in adults with moderate to severe atopic dermatitis showed rapid improvements in all atopic dermatitis clinical indices (N Engl J Med. 2014;371[2]:130-9). The most common side effects were headache and pharyngitis, and skin infections and flares were more common in the placebo group, compared with the treatment group.

Dupilumab “has the potential to shift the treatment landscape of atopic dermatitis, because it can actually change the molecular signature of dermatitic skin, reducing inflammatory and proliferative markers,” Dr. Cordoro said. There are ongoing trials in adult and pediatric populations and FDA approval is anticipated in early 2017.

Published reports also suggest a role for the IL-12/23 pathway inhibitor ustekinumab in severe refractory adult atopic dermatitis (Int J Dermatol. 2012;51[1]:115-6 and JAAD Case Reports 2015;1:25-6). Additional studies are ongoing.

Therapies for itch that have completed phase II trials include the anti-IL31R monoclonal antibody nemolizumab (CIM331); the neurokinin-1R antagonist VLY-686; and the neurokinin-1R antagonist aprepitant gel.

Dr. Cordoro disclosed that she is a consultant for Celgene Corporation, Valeant, and Anacor Pharmaceuticals.

[email protected]

NEWPORT BEACH, CALIF. – In the clinical opinion of Kelly M. Cordoro, MD, anyone who cares for patients with severe atopic dermatitis understands the sense of misery that can ensue.

“Atopic dermatitis patients don’t sleep well; they have poor school and work performance,” she said at the annual meeting of the Pacific Dermatologic Association. “They have absences. They’re unable to play; they can’t exercise. This leads to social disability; isolation from peers, and it goes on and on. The patients are miserable, the whole family is miserable, and we as physicians trying to sort out how to optimally treat them are miserable trying to figure out what the next best step is.”

The good news is, several drugs in the pipeline hold promise for atopic dermatitis patients, thanks largely to emerging data on its pathophysiology. In addition, mechanisms of itch, which are not yet fully understood, are also being unraveled. “It’s exciting to read the literature about the interaction of the skin, the immune system, and the nervous system,” said Dr. Cordoro, a pediatric dermatologist at the University of California, San Francisco. “Many of the mediators of itch are being identified. That has allowed for the development of targeted therapies against many of them.”

One of the promising treatments on the horizon for atopic dermatitis patients is phosphodiesterase-4 (PDE4) inhibitors. PDE-4 is a predominant cAMP-degrading enzyme in keratinocytes and inflammatory cells. “It’s really a candidate for not only atopic dermatitis but for psoriasis,” she said.

Oral PDE-4 inhibitors are already approved for psoriasis. Apremilast (Otezla) was approved by the Food and Drug Administration in 2014 for psoriasis and psoriatic arthritis, and a phase II trial of topical apremilast in adults with AD has been completed and the results are pending. “I look forward to seeing if this can help our patients,” Dr. Cordoro said.

Another promising agent for atopic dermatitis is 2% crisaborole topical ointment, a boron-based PDE-4 inhibitor developed by Anacor Pharmaceuticals. Dr. Cordoro described this compound as an anti-inflammatory agent that modifies inflammation by inhibiting the degradation of cAMP by PDE4, resulting in downstream modification of nuclear factor-kB and T-cell signaling pathways.

“Crisaborole has shown promising results from four clinical studies in patients 2 years of age and older, with notable improvements in all atopic dermatitis parameters,” she said (J Am Acad Dermatol. 2016 Sept;75[3]:494-503.e). The FDA review of crisaborole for the treatment of mild to moderate atopic dermatitis in children and adults is currently underway, and is expected to be completed by early January 2017.

An especially favorable drug in development for atopic dermatitis is dupilumab, a fully human monoclonal antibody that targets the interleukin (IL)–4 receptor, and inhibits IL-4 and IL-13 signaling. A published trial of its use in adults with moderate to severe atopic dermatitis showed rapid improvements in all atopic dermatitis clinical indices (N Engl J Med. 2014;371[2]:130-9). The most common side effects were headache and pharyngitis, and skin infections and flares were more common in the placebo group, compared with the treatment group.

Dupilumab “has the potential to shift the treatment landscape of atopic dermatitis, because it can actually change the molecular signature of dermatitic skin, reducing inflammatory and proliferative markers,” Dr. Cordoro said. There are ongoing trials in adult and pediatric populations and FDA approval is anticipated in early 2017.

Published reports also suggest a role for the IL-12/23 pathway inhibitor ustekinumab in severe refractory adult atopic dermatitis (Int J Dermatol. 2012;51[1]:115-6 and JAAD Case Reports 2015;1:25-6). Additional studies are ongoing.

Therapies for itch that have completed phase II trials include the anti-IL31R monoclonal antibody nemolizumab (CIM331); the neurokinin-1R antagonist VLY-686; and the neurokinin-1R antagonist aprepitant gel.

Dr. Cordoro disclosed that she is a consultant for Celgene Corporation, Valeant, and Anacor Pharmaceuticals.

[email protected]

Adding the long-acting beta-agonist salmeterol to fluticasone in a fixed-dose combination didn’t increase serious asthma-related events among children aged 4-11 years, according to a report published online Sept. 1 in the New England Journal of Medicine.

After long-acting beta-agonists were introduced as add-on therapy for uncontrolled asthma, two large studies involving adults linked the treatment to an increase in asthma-related death. Other studies found no such association.

The FDA mandated that all four manufacturers of those agents in the United States perform large postmarketing safety trials to establish the noninferiority of the approach. In response, GlaxoSmithKline, the only maker of a long-acting beta-agonist with a pediatric indication (salmeterol), performed this international randomized, double-blind, controlled trial at 567 medical centers in 32 countries, said David A. Stempel, MD, of Respiratory Clinical Development, GSK, Research Triangle Park, N.C., and his associates.

The trial involved 6,208 children aged 4-11 years who had controlled or uncontrolled asthma with a history of exacerbations during the preceding year. The participants were randomly assigned to receive 26 weeks of a lower fixed-dose combination of salmeterol plus fluticasone, a higher fixed-dose combination, a lower dose of fluticasone alone, or a higher dose of fluticasone alone, delivered twice daily via a disk device.

The primary safety endpoint was a composite of death, endotracheal intubation, and hospitalization. No deaths or intubations occurred.

A total of 27 patients taking combined therapy and 21 taking fluticasone alone required hospitalization for asthma (hazard ratio, 1.28). The number of severe asthma exacerbations was 14% lower when salmeterol was added to fluticasone, a nonsignificant difference.

The results demonstrate the noninferiority of the combined therapy, Dr. Stempel and his associates said (N Engl J Med. 2016 Sep 1;375[9]:840-9).

The percentage of children who withdrew from the study because of asthma exacerbations was identical in the two groups (1.1% of each), and the percentage who had a serious adverse event was nearly identical (1.8% vs 1.7%, respectively). The mean percentage of rescue therapy–free days also was similar (83.0% vs 81.9%), as was the mean percentage of days in which asthma was controlled (74.8% vs. 73.4%).

At the conclusion of the study, 88.1% of the fluticasone-plus-salmeterol group had controlled asthma, as did 88.5% of the fluticasone-only group. Meaningful differences between the two treatments could not be identified among various subgroups of patients – defined by age, sex, and race – because the overall number of adverse events was so low, the investigators added.

They cautioned that the trial excluded children who had a history of multiple asthma-related hospitalizations and intubations. Therefore, the findings may not be applicable to patients with very severe asthma, the researchers cautioned.

GlaxoSmithKline sponsored the trial in response to a Food and Drug Administration mandate for large postmarketing safety studies from the marketers of long-acting beta agonist–containing products sold in the United States. Dr. Stempel is an employee of GSK; his associates reported ties to numerous industry sources.

Adding the long-acting beta-agonist salmeterol to fluticasone in a fixed-dose combination didn’t increase serious asthma-related events among children aged 4-11 years, according to a report published online Sept. 1 in the New England Journal of Medicine.

After long-acting beta-agonists were introduced as add-on therapy for uncontrolled asthma, two large studies involving adults linked the treatment to an increase in asthma-related death. Other studies found no such association.

The FDA mandated that all four manufacturers of those agents in the United States perform large postmarketing safety trials to establish the noninferiority of the approach. In response, GlaxoSmithKline, the only maker of a long-acting beta-agonist with a pediatric indication (salmeterol), performed this international randomized, double-blind, controlled trial at 567 medical centers in 32 countries, said David A. Stempel, MD, of Respiratory Clinical Development, GSK, Research Triangle Park, N.C., and his associates.

The trial involved 6,208 children aged 4-11 years who had controlled or uncontrolled asthma with a history of exacerbations during the preceding year. The participants were randomly assigned to receive 26 weeks of a lower fixed-dose combination of salmeterol plus fluticasone, a higher fixed-dose combination, a lower dose of fluticasone alone, or a higher dose of fluticasone alone, delivered twice daily via a disk device.

The primary safety endpoint was a composite of death, endotracheal intubation, and hospitalization. No deaths or intubations occurred.

A total of 27 patients taking combined therapy and 21 taking fluticasone alone required hospitalization for asthma (hazard ratio, 1.28). The number of severe asthma exacerbations was 14% lower when salmeterol was added to fluticasone, a nonsignificant difference.

The results demonstrate the noninferiority of the combined therapy, Dr. Stempel and his associates said (N Engl J Med. 2016 Sep 1;375[9]:840-9).

The percentage of children who withdrew from the study because of asthma exacerbations was identical in the two groups (1.1% of each), and the percentage who had a serious adverse event was nearly identical (1.8% vs 1.7%, respectively). The mean percentage of rescue therapy–free days also was similar (83.0% vs 81.9%), as was the mean percentage of days in which asthma was controlled (74.8% vs. 73.4%).

At the conclusion of the study, 88.1% of the fluticasone-plus-salmeterol group had controlled asthma, as did 88.5% of the fluticasone-only group. Meaningful differences between the two treatments could not be identified among various subgroups of patients – defined by age, sex, and race – because the overall number of adverse events was so low, the investigators added.

They cautioned that the trial excluded children who had a history of multiple asthma-related hospitalizations and intubations. Therefore, the findings may not be applicable to patients with very severe asthma, the researchers cautioned.

GlaxoSmithKline sponsored the trial in response to a Food and Drug Administration mandate for large postmarketing safety studies from the marketers of long-acting beta agonist–containing products sold in the United States. Dr. Stempel is an employee of GSK; his associates reported ties to numerous industry sources.

Adding the long-acting beta-agonist salmeterol to fluticasone in a fixed-dose combination didn’t increase serious asthma-related events among children aged 4-11 years, according to a report published online Sept. 1 in the New England Journal of Medicine.

After long-acting beta-agonists were introduced as add-on therapy for uncontrolled asthma, two large studies involving adults linked the treatment to an increase in asthma-related death. Other studies found no such association.

The FDA mandated that all four manufacturers of those agents in the United States perform large postmarketing safety trials to establish the noninferiority of the approach. In response, GlaxoSmithKline, the only maker of a long-acting beta-agonist with a pediatric indication (salmeterol), performed this international randomized, double-blind, controlled trial at 567 medical centers in 32 countries, said David A. Stempel, MD, of Respiratory Clinical Development, GSK, Research Triangle Park, N.C., and his associates.

The trial involved 6,208 children aged 4-11 years who had controlled or uncontrolled asthma with a history of exacerbations during the preceding year. The participants were randomly assigned to receive 26 weeks of a lower fixed-dose combination of salmeterol plus fluticasone, a higher fixed-dose combination, a lower dose of fluticasone alone, or a higher dose of fluticasone alone, delivered twice daily via a disk device.

The primary safety endpoint was a composite of death, endotracheal intubation, and hospitalization. No deaths or intubations occurred.

A total of 27 patients taking combined therapy and 21 taking fluticasone alone required hospitalization for asthma (hazard ratio, 1.28). The number of severe asthma exacerbations was 14% lower when salmeterol was added to fluticasone, a nonsignificant difference.

The results demonstrate the noninferiority of the combined therapy, Dr. Stempel and his associates said (N Engl J Med. 2016 Sep 1;375[9]:840-9).

The percentage of children who withdrew from the study because of asthma exacerbations was identical in the two groups (1.1% of each), and the percentage who had a serious adverse event was nearly identical (1.8% vs 1.7%, respectively). The mean percentage of rescue therapy–free days also was similar (83.0% vs 81.9%), as was the mean percentage of days in which asthma was controlled (74.8% vs. 73.4%).

At the conclusion of the study, 88.1% of the fluticasone-plus-salmeterol group had controlled asthma, as did 88.5% of the fluticasone-only group. Meaningful differences between the two treatments could not be identified among various subgroups of patients – defined by age, sex, and race – because the overall number of adverse events was so low, the investigators added.

They cautioned that the trial excluded children who had a history of multiple asthma-related hospitalizations and intubations. Therefore, the findings may not be applicable to patients with very severe asthma, the researchers cautioned.

GlaxoSmithKline sponsored the trial in response to a Food and Drug Administration mandate for large postmarketing safety studies from the marketers of long-acting beta agonist–containing products sold in the United States. Dr. Stempel is an employee of GSK; his associates reported ties to numerous industry sources.

Adding formoterol to budesonide in a fixed-dose combination does not increase serous asthma-related events in adolescents and adults, according to a report published online Sept. 1 in the New England Journal of Medicine.

This finding from a multicenter randomized double-blind clinical trial involving 11,693 patients should allay safety concerns about adding long-acting beta-agonists to inhaled glucocorticoids in moderate to severe asthma. Previously, two large studies linked such additive therapy to increased asthma-related deaths and other serious outcomes, but other clinical trials and numerous meta-analyses found no such increase.

©MattZ90/thinkstockphotos.com

In 2009, the Food and Drug Administration mandated that the four manufacturers of long-acting beta-agonists available in the United States conduct postmarketing safety analyses of these agents. The current trial is AstraZeneca’s response to the mandate, said Stephen P. Peters, MD, PhD, of Wake Forest University, Winston-Salem N.C., and his associates.

They assessed patients aged 12 years and older who had taken daily asthma medication for at least 1 year before enrollment and had a history of at least one exacerbation during that year. These participants were enrolled at 534 medical centers in 25 countries during 2011-2015 and randomly assigned to receive either budesonide plus formoterol (5,846 patients) or budesonide alone (5,847 patients) through an inhaler twice daily for 26 weeks. The primary endpoint was a composite of asthma-related death, intubation, and hospitalization.

A total of 43 patients in the combined-therapy group had 49 serious asthma-related events, while 40 patients in the budesonide-only group had 45 such events. This is a nonsignificant difference and establishes the noninferiority of the combined treatment regarding this outcome, the investigators said (N Engl J Med. 2016 Sept 1. doi: 10.1056/NEJMoa1511190).

In addition, 539 (9.2%) of the patients in the combined-therapy group reported 637 asthma exacerbations, while 633 in the budesonide-only group had 762 exacerbations. Thus, the risk of having an asthma exacerbation was 16.5% lower with combined therapy (HR, 0.84).

Both study groups had a clinically relevant improvement in asthma control as measured by the ACQ-6, and the combined therapy yielded a significantly greater benefit. The percentage of patients who had a clinically relevant improvement in asthma control at the conclusion of treatment also favored budesonide plus formoterol (58.7% vs. 54.4%). And the combined-therapy group also had a greater mean number of symptom-free days, had fewer night-time awakenings, and used fewer doses of rescue medications, Dr. Peters and his associates said.

Given that asthma-related deaths are rare, none of the four individual manufacturer-sponsored postmarketing studies required by the FDA can be powered for a separate analysis of that endpoint. “Any between-group differences in asthma-related death will need to be evaluated in the context of pooled data from the four studies, once they are all completed,” the investigators added.

Dr. Peters and his associates reported ties to numerous industry sources.

Adding formoterol to budesonide in a fixed-dose combination does not increase serous asthma-related events in adolescents and adults, according to a report published online Sept. 1 in the New England Journal of Medicine.

This finding from a multicenter randomized double-blind clinical trial involving 11,693 patients should allay safety concerns about adding long-acting beta-agonists to inhaled glucocorticoids in moderate to severe asthma. Previously, two large studies linked such additive therapy to increased asthma-related deaths and other serious outcomes, but other clinical trials and numerous meta-analyses found no such increase.

©MattZ90/thinkstockphotos.com

In 2009, the Food and Drug Administration mandated that the four manufacturers of long-acting beta-agonists available in the United States conduct postmarketing safety analyses of these agents. The current trial is AstraZeneca’s response to the mandate, said Stephen P. Peters, MD, PhD, of Wake Forest University, Winston-Salem N.C., and his associates.

They assessed patients aged 12 years and older who had taken daily asthma medication for at least 1 year before enrollment and had a history of at least one exacerbation during that year. These participants were enrolled at 534 medical centers in 25 countries during 2011-2015 and randomly assigned to receive either budesonide plus formoterol (5,846 patients) or budesonide alone (5,847 patients) through an inhaler twice daily for 26 weeks. The primary endpoint was a composite of asthma-related death, intubation, and hospitalization.

A total of 43 patients in the combined-therapy group had 49 serious asthma-related events, while 40 patients in the budesonide-only group had 45 such events. This is a nonsignificant difference and establishes the noninferiority of the combined treatment regarding this outcome, the investigators said (N Engl J Med. 2016 Sept 1. doi: 10.1056/NEJMoa1511190).

In addition, 539 (9.2%) of the patients in the combined-therapy group reported 637 asthma exacerbations, while 633 in the budesonide-only group had 762 exacerbations. Thus, the risk of having an asthma exacerbation was 16.5% lower with combined therapy (HR, 0.84).

Both study groups had a clinically relevant improvement in asthma control as measured by the ACQ-6, and the combined therapy yielded a significantly greater benefit. The percentage of patients who had a clinically relevant improvement in asthma control at the conclusion of treatment also favored budesonide plus formoterol (58.7% vs. 54.4%). And the combined-therapy group also had a greater mean number of symptom-free days, had fewer night-time awakenings, and used fewer doses of rescue medications, Dr. Peters and his associates said.

Given that asthma-related deaths are rare, none of the four individual manufacturer-sponsored postmarketing studies required by the FDA can be powered for a separate analysis of that endpoint. “Any between-group differences in asthma-related death will need to be evaluated in the context of pooled data from the four studies, once they are all completed,” the investigators added.

Dr. Peters and his associates reported ties to numerous industry sources.

Adding formoterol to budesonide in a fixed-dose combination does not increase serous asthma-related events in adolescents and adults, according to a report published online Sept. 1 in the New England Journal of Medicine.

This finding from a multicenter randomized double-blind clinical trial involving 11,693 patients should allay safety concerns about adding long-acting beta-agonists to inhaled glucocorticoids in moderate to severe asthma. Previously, two large studies linked such additive therapy to increased asthma-related deaths and other serious outcomes, but other clinical trials and numerous meta-analyses found no such increase.

©MattZ90/thinkstockphotos.com

In 2009, the Food and Drug Administration mandated that the four manufacturers of long-acting beta-agonists available in the United States conduct postmarketing safety analyses of these agents. The current trial is AstraZeneca’s response to the mandate, said Stephen P. Peters, MD, PhD, of Wake Forest University, Winston-Salem N.C., and his associates.

They assessed patients aged 12 years and older who had taken daily asthma medication for at least 1 year before enrollment and had a history of at least one exacerbation during that year. These participants were enrolled at 534 medical centers in 25 countries during 2011-2015 and randomly assigned to receive either budesonide plus formoterol (5,846 patients) or budesonide alone (5,847 patients) through an inhaler twice daily for 26 weeks. The primary endpoint was a composite of asthma-related death, intubation, and hospitalization.

A total of 43 patients in the combined-therapy group had 49 serious asthma-related events, while 40 patients in the budesonide-only group had 45 such events. This is a nonsignificant difference and establishes the noninferiority of the combined treatment regarding this outcome, the investigators said (N Engl J Med. 2016 Sept 1. doi: 10.1056/NEJMoa1511190).

In addition, 539 (9.2%) of the patients in the combined-therapy group reported 637 asthma exacerbations, while 633 in the budesonide-only group had 762 exacerbations. Thus, the risk of having an asthma exacerbation was 16.5% lower with combined therapy (HR, 0.84).

Both study groups had a clinically relevant improvement in asthma control as measured by the ACQ-6, and the combined therapy yielded a significantly greater benefit. The percentage of patients who had a clinically relevant improvement in asthma control at the conclusion of treatment also favored budesonide plus formoterol (58.7% vs. 54.4%). And the combined-therapy group also had a greater mean number of symptom-free days, had fewer night-time awakenings, and used fewer doses of rescue medications, Dr. Peters and his associates said.

Given that asthma-related deaths are rare, none of the four individual manufacturer-sponsored postmarketing studies required by the FDA can be powered for a separate analysis of that endpoint. “Any between-group differences in asthma-related death will need to be evaluated in the context of pooled data from the four studies, once they are all completed,” the investigators added.

Dr. Peters and his associates reported ties to numerous industry sources.

The serotype B meningococcal vaccines MenB-FHbp and MenB-4C are safe and can be administered to healthy people aged 10-25 years, according to a policy statement from the American Academy of Pediatrics Committee on Infectious Diseases.

The AAP recommends that people older than 10 years at increased risk for serogroup B meningococcal disease (category A) should receive MenB vaccines regularly. Category A includes people with persistent complement component deficiencies, people with anatomic or functional asplenia, and healthy people at increased risk because of a disease outbreak.

HUNG KUO CHUN (Thinkstockphotos)

Young adults aged 16-23 years old may receive a vaccination, but it is not routinely recommended (category B), with a preferred vaccination age between 16 and 18 years.

Annual incidence of serogroup B meningococcal disease in people aged 11-24 years in the United States is about 50-60 cases per year, and a routine vaccination program would prevent 15-29 cases and 2-5 deaths per year, the researchers noted. The cost of routine vaccination in the general population would range from $3.7 million per quality-adjusted life year (QALY) to $9.4 million per QALY.

Both MenB-FHbp and MenB-4C have been safely administered in clinical trials, with no deaths related to either vaccine. Data on duration of immunogenicity and proportion of MenB strains covered by vaccines in different geographic regions remain incomplete, and both vaccine manufacturers must complete postmarketing studies to determine overall vaccine effectiveness.

“Pediatricians are encouraged to discuss the availability of the MenB vaccines with families. Discussion should include the low incidence of MenB disease and the unknown efficacy of the vaccines... The treating clinician should discuss the benefits, risks, and costs with patients and their families and then work with them to determine what is in their best interest,” the AAP committee noted.

Find the full study in Pediatrics (doi: 10.1542/peds.2016-1890).

[email protected]

The serotype B meningococcal vaccines MenB-FHbp and MenB-4C are safe and can be administered to healthy people aged 10-25 years, according to a policy statement from the American Academy of Pediatrics Committee on Infectious Diseases.

The AAP recommends that people older than 10 years at increased risk for serogroup B meningococcal disease (category A) should receive MenB vaccines regularly. Category A includes people with persistent complement component deficiencies, people with anatomic or functional asplenia, and healthy people at increased risk because of a disease outbreak.

HUNG KUO CHUN (Thinkstockphotos)

Young adults aged 16-23 years old may receive a vaccination, but it is not routinely recommended (category B), with a preferred vaccination age between 16 and 18 years.

Annual incidence of serogroup B meningococcal disease in people aged 11-24 years in the United States is about 50-60 cases per year, and a routine vaccination program would prevent 15-29 cases and 2-5 deaths per year, the researchers noted. The cost of routine vaccination in the general population would range from $3.7 million per quality-adjusted life year (QALY) to $9.4 million per QALY.

Both MenB-FHbp and MenB-4C have been safely administered in clinical trials, with no deaths related to either vaccine. Data on duration of immunogenicity and proportion of MenB strains covered by vaccines in different geographic regions remain incomplete, and both vaccine manufacturers must complete postmarketing studies to determine overall vaccine effectiveness.

“Pediatricians are encouraged to discuss the availability of the MenB vaccines with families. Discussion should include the low incidence of MenB disease and the unknown efficacy of the vaccines... The treating clinician should discuss the benefits, risks, and costs with patients and their families and then work with them to determine what is in their best interest,” the AAP committee noted.

Find the full study in Pediatrics (doi: 10.1542/peds.2016-1890).

[email protected]

The serotype B meningococcal vaccines MenB-FHbp and MenB-4C are safe and can be administered to healthy people aged 10-25 years, according to a policy statement from the American Academy of Pediatrics Committee on Infectious Diseases.

The AAP recommends that people older than 10 years at increased risk for serogroup B meningococcal disease (category A) should receive MenB vaccines regularly. Category A includes people with persistent complement component deficiencies, people with anatomic or functional asplenia, and healthy people at increased risk because of a disease outbreak.

HUNG KUO CHUN (Thinkstockphotos)

Young adults aged 16-23 years old may receive a vaccination, but it is not routinely recommended (category B), with a preferred vaccination age between 16 and 18 years.

Annual incidence of serogroup B meningococcal disease in people aged 11-24 years in the United States is about 50-60 cases per year, and a routine vaccination program would prevent 15-29 cases and 2-5 deaths per year, the researchers noted. The cost of routine vaccination in the general population would range from $3.7 million per quality-adjusted life year (QALY) to $9.4 million per QALY.

Both MenB-FHbp and MenB-4C have been safely administered in clinical trials, with no deaths related to either vaccine. Data on duration of immunogenicity and proportion of MenB strains covered by vaccines in different geographic regions remain incomplete, and both vaccine manufacturers must complete postmarketing studies to determine overall vaccine effectiveness.

“Pediatricians are encouraged to discuss the availability of the MenB vaccines with families. Discussion should include the low incidence of MenB disease and the unknown efficacy of the vaccines... The treating clinician should discuss the benefits, risks, and costs with patients and their families and then work with them to determine what is in their best interest,” the AAP committee noted.

Find the full study in Pediatrics (doi: 10.1542/peds.2016-1890).

[email protected]

Papulopustular rosacea (PPR) is characterized by centrofacial papules, pustules, erythema, and occasionally telangiectasia.^1,2 A myriad of factors, including genetic predisposition³ and environmental triggers,⁴ have been associated with dysregulated inflammatory responses,⁵ contributing to the disease pathogenesis and symptoms. Inflammation associated with PPR may decrease skin barrier function, increase transepidermal water loss, and reduce stratum corneum hydration,^6,7 resulting in heightened skin sensitivity, pain, burning, and/or stinging.^5,8

Azelaic acid (AzA), which historically has only been available in gel or cream formulations, is well established for the treatment of rosacea⁹; however, these formulations have been associated with application-site adverse events (AEs)(eg, burning, erythema, irritation), limited cosmetic acceptability, and reduced compliance or efficacy.¹⁰

For select skin conditions, active agents delivered in foam vehicles may offer superior tolerability with improved outcomes.¹¹ An AzA foam 15% formulation was approved for the treatment of mild to moderate PPR. Primary outcomes from a phase 3 trial demonstrated the efficacy and safety of AzA foam in improving inflammatory lesion counts (ILCs) and disease severity in participants with PPR. The trial also evaluated additional secondary end points, including the effect of AzA foam on erythema, inflammatory lesions, treatment response, and other manifestations of PPR.¹² The current study evaluated investigator-reported efficacy outcomes for these secondary end points for AzA foam 15% versus vehicle foam.

Methods

Study Design

This phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was conducted from September 2012 to January 2014 at 48 US study centers comparing the efficacy of AzA foam versus vehicle foam in patients with PPR. Eligible participants were 18 years and older with PPR rated as moderate or severe according to investigator global assessment (IGA), plus 12 to 50 inflammatory lesions and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication was applied in 0.5-g doses twice daily until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to IGA and nominal change in ILC—were previously reported.¹²

Investigator-Reported Secondary Efficacy Outcomes

The secondary efficacy end points were grouped change in erythema rating, grouped change in telangiectasia rating, grouped change in IGA score, therapeutic response rate according to IGA, percentage change in ILC from baseline, and facial skin color rating at EoT.

Grouped change for all secondary end points was measured as improved, no change, or worsened relative to baseline. For grouped change in erythema and telangiectasia ratings, a participant was considered improved if the rating at the postbaseline visit was lower than the baseline rating, no change if the postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline. For grouped change in IGA score, a participant was considered improved if a responder showed at least a 1-step improvement postbaseline compared to baseline, no change if postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline.

For the therapeutic response rate, a participant was considered a treatment responder if the IGA score improved from baseline and resulted in clear, minimal, or mild disease severity at EoT.

Safety

Adverse events also were assessed.

Statistical Analyses

Secondary efficacy and safety end points were assessed for all randomized participants who were dispensed the study medication. Missing data were imputed using last observation carried forward.

For the percentage change in ILC from baseline, therapeutic response rate, and grouped change in erythema rating, confirmatory analyses were conducted in a hierarchical manner (in the order listed), with testing stopped as soon as a null hypothesis of superior treatment effect could not be rejected. Analyses without significance level were exploratory. The Cochran-Mantel-Haenszel van Elteren test stratified by study center was used for grouped change in erythema rating (1-tailed, 2.5%) and IGA score (2-tailed, 5%); Wilcoxon rank sum tests also were performed. Percentage change in ILC from baseline was evaluated using the Student t test and F test of analysis of covariance (1-tailed, 2.5%). Therapeutic response rate was evaluated using the Cochran-Mantel-Haenszel van Elteren test stratified by study center and the Pearson χ² test. Facial skin color and grouped change in telangiectasia rating were evaluated using the Wilcoxon rank sum test.

Adverse events beginning or worsening after the first dose of the study drug were considered treatment emergent and were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1. Statistical analyses were performed using SAS software version 9.2.

Results

Study Participants

The study included 961 total participants; 483 were randomized to the AzA foam group and 478 to the vehicle group (Figure 1). Overall, 803 participants completed follow-up; however, week 16 results for the efficacy outcomes include data for 4 additional patients (2 per study arm) who did not formally meet all requirements for follow-up completion. The mean age was 51.5 years, and the majority of the participants were white and female (Table 1). Most participants (86.8%) had moderate PPR at baseline, with the remaining rated as having severe disease (13.2%). The majority (76.4%) had more than 14 inflammatory lesions with moderate (76.4%) or severe (15.1%) erythema at baseline.

Efficacy

Significantly more participants in the AzA group than in the vehicle group showed an improved erythema rating at EoT (61.5% vs 51.3%; P<.001)(Figure 2), with more participants in the AzA group showing improvement at weeks 4 (P=.022) and 8 (P=.002).

A significantly greater mean percentage reduction in ILC from baseline to EoT was observed in the AzA group versus the vehicle group (61.6% vs 50.8%; P<.001)(Figure 3), and between-group differences were observed at week 4 (P<.001), week 8 (P=.003), and week 16 (end of study/follow-up)(P=.002).

A significantly higher proportion of participants treated with AzA foam versus vehicle were considered responders at week 12/EoT (66.3% vs 54.4%; P<.001)(Figure 4). Differences in responder rate also were observed at week 4 (P=.026) and week 8 (P=.026).

Differences in grouped change in IGA score were observed between groups at every evaluation during the treatment phase (Figure 5). Specifically, IGA score was improved at week 12/EoT relative to baseline in 71.2% of participants in the AzA group versus 58.8% in the vehicle group (P<.001).

For grouped change in telangiectasia rating at EoT, the majority of participants in both treatment groups showed no change (Table 2). Regarding facial skin color, the majority of participants in both the AzA and vehicle treatment groups (80.1% and 78.7%, respectively) showed normal skin color compared to nontreated skin EoT; no between-group differences were detected for facial skin color rating (P=.315, Wilcoxon rank sum test).

Safety

The incidence of drug-related AEs was greater in the AzA group than the vehicle group (7.7% vs 4.8%)(Table 3). Drug-related AEs occurring in at least 1% of the AzA group were pain at application site (eg, tenderness, stinging, burning)(AzA group, 3.5%; vehicle group, 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). A single drug-related AE of severe intensity (ie, application-site dermatitis) was observed in the vehicle group; all other drug-related AEs were mild or moderate. The incidence of withdrawals due to AEs was lower in the AzA group than the vehicle group (1.2% vs 2.5%). This AE profile correlated with a treatment compliance (the percentage of expected doses that were actually administered) of 97.0% in the AzA group and 95.9% in the vehicle group. One participant in the vehicle group died due to head trauma unrelated to administration of the study drug.

Comment

The results of this study further support the efficacy of AzA foam for the treatment of PPR. The percentage reduction in ILC was consistent with nominal decreases in ILC, a coprimary efficacy end point of this study.¹² Almost two-thirds of participants treated with AzA foam achieved a therapeutic response, indicating that many participants who did not strictly achieve the primary outcome of therapeutic success nevertheless attained notable reductions in disease severity. The number of participants who showed any improvement on the IGA scale increased throughout the course of treatment (63.8% AzA foam vs 55.0% vehicle at week 8) up to EoT (71.2% vs 58.8%)(Figure 5). In addition, the number of participants showing any improvement at week 8 (63.8% AzA foam vs 55.0% vehicle)(Figure 5) was comparable to the number of participants achieving therapeutic response at week 12/EoT (66.3% vs 54.4%)(Figure 4). These data suggest that increasing time of treatment increases the likelihood of achieving better results.

Erythema also appeared to respond to AzA foam, with 10.2% more participants in the AzA group demonstrating improvement at week 12/EoT compared to vehicle. The difference in grouped change in erythema rating also was statistically significant and favored AzA foam, sustained up to 4 weeks after EoT.

The outcomes for percentage change in ILC, therapeutic response rate, and grouped change in erythema rating consequently led to the rejection of all 3 null hypotheses in hierarchical confirmatory analyses, underscoring the benefits of AzA foam treatment.

The therapeutic effects of AzA foam were apparent at the first postbaseline evaluation and persisted throughout treatment. Differences favoring AzA foam were observed at every on-treatment evaluation for grouped change in erythema rating, percentage change in ILC, therapeutic response rate, and grouped change in IGA score. Symptoms showed minimal resurgence after treatment cessation, and there were no signs of disease flare-up within the 4 weeks of observational follow-up. In addition, the percentage reduction in ILC remained higher in the AzA foam group during follow-up.

These results also show that AzA foam was well tolerated with a low incidence of discontinuation because of drug-related AEs. No serious drug-related AEs were reported for this study or in the preceding phase 2 trial.^12,13 Although not directly evaluated, the low incidence of cutaneous AEs suggests that AzA foam may be better tolerated than prior formulations of AzA^14,15 and correlates with high compliance observed during the study.¹² Azelaic acid foam appeared to have minimal to no effect on skin color, with more than 88% of participants reporting barely visible or no skin lightening.

Interestingly, the vehicle foam showed appreciable efficacy independent of AzA. Improvements in erythema were recorded in approximately half of the vehicle group at week 12/EoT. A similar proportion attained a therapeutic response, and ILC was reduced by 50.8% at week 12/EoT. Comparable results also were evident in the vehicle group for the primary end points of this study.¹² Vehicles in dermatologic trials frequently exert effects on diseased skin^16,17 via a skin care regimen effect (eg, moisturization and other vehicle-related effects that may improve skin barrier integrity and function) and thus should not be regarded as placebo controls. The mechanism underlying this efficacy may be due to the impact of vehicle composition on skin barrier integrity and transepidermal water loss.¹⁸ The hydrophilic emulsion or other constituents of AzA foam (eg, fatty alcohols) may play a role.

A notable strength of our study is detailed clinical characterization using carefully chosen parameters and preplanned analyses that complement the primary end points. As the latter are often driven by regulatory requirements, opportunities to characterize other outcomes of interest to clinicians may be missed. The additional analyses reported here hopefully will aid dermatologists in both assessing the role of AzA foam in the treatment armamentarium for PPR and counseling patients.

Because participants with lighter skin pigmentation dominated our study population, the impact of AzA foam among patients with darker skin complexions is unknown. Although AzA is unlikely to cause hypopigmentation in normal undiseased skin, patients should be monitored for early signs of hypopigmentation.^19,20 Our data also do not allow assessment of the differential effect, if any, of AzA foam on erythema of different etiologies in PPR, as corresponding information was not collected in the trial.

Conclusion

Azelaic acid foam 15% combines a well-established treatment of PPR with new vehicle technology to deliver effective therapy across multiple disease dimensions. In addition, the vehicle foam appears to demonstrate inherent therapeutic properties independent of AzA. The availability of this novel, efficacious, and well-tolerated option for PPR has the potential to improve patient care, reduce disease burden, and minimize unnecessary costs through increased tolerability and compliance.²¹

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Papulopustular rosacea (PPR) is characterized by centrofacial papules, pustules, erythema, and occasionally telangiectasia.^1,2 A myriad of factors, including genetic predisposition³ and environmental triggers,⁴ have been associated with dysregulated inflammatory responses,⁵ contributing to the disease pathogenesis and symptoms. Inflammation associated with PPR may decrease skin barrier function, increase transepidermal water loss, and reduce stratum corneum hydration,^6,7 resulting in heightened skin sensitivity, pain, burning, and/or stinging.^5,8

Azelaic acid (AzA), which historically has only been available in gel or cream formulations, is well established for the treatment of rosacea⁹; however, these formulations have been associated with application-site adverse events (AEs)(eg, burning, erythema, irritation), limited cosmetic acceptability, and reduced compliance or efficacy.¹⁰

For select skin conditions, active agents delivered in foam vehicles may offer superior tolerability with improved outcomes.¹¹ An AzA foam 15% formulation was approved for the treatment of mild to moderate PPR. Primary outcomes from a phase 3 trial demonstrated the efficacy and safety of AzA foam in improving inflammatory lesion counts (ILCs) and disease severity in participants with PPR. The trial also evaluated additional secondary end points, including the effect of AzA foam on erythema, inflammatory lesions, treatment response, and other manifestations of PPR.¹² The current study evaluated investigator-reported efficacy outcomes for these secondary end points for AzA foam 15% versus vehicle foam.

Methods

Study Design

This phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was conducted from September 2012 to January 2014 at 48 US study centers comparing the efficacy of AzA foam versus vehicle foam in patients with PPR. Eligible participants were 18 years and older with PPR rated as moderate or severe according to investigator global assessment (IGA), plus 12 to 50 inflammatory lesions and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication was applied in 0.5-g doses twice daily until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to IGA and nominal change in ILC—were previously reported.¹²

Investigator-Reported Secondary Efficacy Outcomes

The secondary efficacy end points were grouped change in erythema rating, grouped change in telangiectasia rating, grouped change in IGA score, therapeutic response rate according to IGA, percentage change in ILC from baseline, and facial skin color rating at EoT.

Grouped change for all secondary end points was measured as improved, no change, or worsened relative to baseline. For grouped change in erythema and telangiectasia ratings, a participant was considered improved if the rating at the postbaseline visit was lower than the baseline rating, no change if the postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline. For grouped change in IGA score, a participant was considered improved if a responder showed at least a 1-step improvement postbaseline compared to baseline, no change if postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline.

For the therapeutic response rate, a participant was considered a treatment responder if the IGA score improved from baseline and resulted in clear, minimal, or mild disease severity at EoT.

Safety

Adverse events also were assessed.

Statistical Analyses

Secondary efficacy and safety end points were assessed for all randomized participants who were dispensed the study medication. Missing data were imputed using last observation carried forward.

For the percentage change in ILC from baseline, therapeutic response rate, and grouped change in erythema rating, confirmatory analyses were conducted in a hierarchical manner (in the order listed), with testing stopped as soon as a null hypothesis of superior treatment effect could not be rejected. Analyses without significance level were exploratory. The Cochran-Mantel-Haenszel van Elteren test stratified by study center was used for grouped change in erythema rating (1-tailed, 2.5%) and IGA score (2-tailed, 5%); Wilcoxon rank sum tests also were performed. Percentage change in ILC from baseline was evaluated using the Student t test and F test of analysis of covariance (1-tailed, 2.5%). Therapeutic response rate was evaluated using the Cochran-Mantel-Haenszel van Elteren test stratified by study center and the Pearson χ² test. Facial skin color and grouped change in telangiectasia rating were evaluated using the Wilcoxon rank sum test.

Adverse events beginning or worsening after the first dose of the study drug were considered treatment emergent and were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1. Statistical analyses were performed using SAS software version 9.2.

Results

Study Participants

The study included 961 total participants; 483 were randomized to the AzA foam group and 478 to the vehicle group (Figure 1). Overall, 803 participants completed follow-up; however, week 16 results for the efficacy outcomes include data for 4 additional patients (2 per study arm) who did not formally meet all requirements for follow-up completion. The mean age was 51.5 years, and the majority of the participants were white and female (Table 1). Most participants (86.8%) had moderate PPR at baseline, with the remaining rated as having severe disease (13.2%). The majority (76.4%) had more than 14 inflammatory lesions with moderate (76.4%) or severe (15.1%) erythema at baseline.

Efficacy

Significantly more participants in the AzA group than in the vehicle group showed an improved erythema rating at EoT (61.5% vs 51.3%; P<.001)(Figure 2), with more participants in the AzA group showing improvement at weeks 4 (P=.022) and 8 (P=.002).

A significantly greater mean percentage reduction in ILC from baseline to EoT was observed in the AzA group versus the vehicle group (61.6% vs 50.8%; P<.001)(Figure 3), and between-group differences were observed at week 4 (P<.001), week 8 (P=.003), and week 16 (end of study/follow-up)(P=.002).

A significantly higher proportion of participants treated with AzA foam versus vehicle were considered responders at week 12/EoT (66.3% vs 54.4%; P<.001)(Figure 4). Differences in responder rate also were observed at week 4 (P=.026) and week 8 (P=.026).

Differences in grouped change in IGA score were observed between groups at every evaluation during the treatment phase (Figure 5). Specifically, IGA score was improved at week 12/EoT relative to baseline in 71.2% of participants in the AzA group versus 58.8% in the vehicle group (P<.001).

For grouped change in telangiectasia rating at EoT, the majority of participants in both treatment groups showed no change (Table 2). Regarding facial skin color, the majority of participants in both the AzA and vehicle treatment groups (80.1% and 78.7%, respectively) showed normal skin color compared to nontreated skin EoT; no between-group differences were detected for facial skin color rating (P=.315, Wilcoxon rank sum test).

Safety

The incidence of drug-related AEs was greater in the AzA group than the vehicle group (7.7% vs 4.8%)(Table 3). Drug-related AEs occurring in at least 1% of the AzA group were pain at application site (eg, tenderness, stinging, burning)(AzA group, 3.5%; vehicle group, 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). A single drug-related AE of severe intensity (ie, application-site dermatitis) was observed in the vehicle group; all other drug-related AEs were mild or moderate. The incidence of withdrawals due to AEs was lower in the AzA group than the vehicle group (1.2% vs 2.5%). This AE profile correlated with a treatment compliance (the percentage of expected doses that were actually administered) of 97.0% in the AzA group and 95.9% in the vehicle group. One participant in the vehicle group died due to head trauma unrelated to administration of the study drug.

Comment

The results of this study further support the efficacy of AzA foam for the treatment of PPR. The percentage reduction in ILC was consistent with nominal decreases in ILC, a coprimary efficacy end point of this study.¹² Almost two-thirds of participants treated with AzA foam achieved a therapeutic response, indicating that many participants who did not strictly achieve the primary outcome of therapeutic success nevertheless attained notable reductions in disease severity. The number of participants who showed any improvement on the IGA scale increased throughout the course of treatment (63.8% AzA foam vs 55.0% vehicle at week 8) up to EoT (71.2% vs 58.8%)(Figure 5). In addition, the number of participants showing any improvement at week 8 (63.8% AzA foam vs 55.0% vehicle)(Figure 5) was comparable to the number of participants achieving therapeutic response at week 12/EoT (66.3% vs 54.4%)(Figure 4). These data suggest that increasing time of treatment increases the likelihood of achieving better results.

Erythema also appeared to respond to AzA foam, with 10.2% more participants in the AzA group demonstrating improvement at week 12/EoT compared to vehicle. The difference in grouped change in erythema rating also was statistically significant and favored AzA foam, sustained up to 4 weeks after EoT.

The outcomes for percentage change in ILC, therapeutic response rate, and grouped change in erythema rating consequently led to the rejection of all 3 null hypotheses in hierarchical confirmatory analyses, underscoring the benefits of AzA foam treatment.

The therapeutic effects of AzA foam were apparent at the first postbaseline evaluation and persisted throughout treatment. Differences favoring AzA foam were observed at every on-treatment evaluation for grouped change in erythema rating, percentage change in ILC, therapeutic response rate, and grouped change in IGA score. Symptoms showed minimal resurgence after treatment cessation, and there were no signs of disease flare-up within the 4 weeks of observational follow-up. In addition, the percentage reduction in ILC remained higher in the AzA foam group during follow-up.

These results also show that AzA foam was well tolerated with a low incidence of discontinuation because of drug-related AEs. No serious drug-related AEs were reported for this study or in the preceding phase 2 trial.^12,13 Although not directly evaluated, the low incidence of cutaneous AEs suggests that AzA foam may be better tolerated than prior formulations of AzA^14,15 and correlates with high compliance observed during the study.¹² Azelaic acid foam appeared to have minimal to no effect on skin color, with more than 88% of participants reporting barely visible or no skin lightening.

Interestingly, the vehicle foam showed appreciable efficacy independent of AzA. Improvements in erythema were recorded in approximately half of the vehicle group at week 12/EoT. A similar proportion attained a therapeutic response, and ILC was reduced by 50.8% at week 12/EoT. Comparable results also were evident in the vehicle group for the primary end points of this study.¹² Vehicles in dermatologic trials frequently exert effects on diseased skin^16,17 via a skin care regimen effect (eg, moisturization and other vehicle-related effects that may improve skin barrier integrity and function) and thus should not be regarded as placebo controls. The mechanism underlying this efficacy may be due to the impact of vehicle composition on skin barrier integrity and transepidermal water loss.¹⁸ The hydrophilic emulsion or other constituents of AzA foam (eg, fatty alcohols) may play a role.

A notable strength of our study is detailed clinical characterization using carefully chosen parameters and preplanned analyses that complement the primary end points. As the latter are often driven by regulatory requirements, opportunities to characterize other outcomes of interest to clinicians may be missed. The additional analyses reported here hopefully will aid dermatologists in both assessing the role of AzA foam in the treatment armamentarium for PPR and counseling patients.

Because participants with lighter skin pigmentation dominated our study population, the impact of AzA foam among patients with darker skin complexions is unknown. Although AzA is unlikely to cause hypopigmentation in normal undiseased skin, patients should be monitored for early signs of hypopigmentation.^19,20 Our data also do not allow assessment of the differential effect, if any, of AzA foam on erythema of different etiologies in PPR, as corresponding information was not collected in the trial.

Conclusion

Azelaic acid foam 15% combines a well-established treatment of PPR with new vehicle technology to deliver effective therapy across multiple disease dimensions. In addition, the vehicle foam appears to demonstrate inherent therapeutic properties independent of AzA. The availability of this novel, efficacious, and well-tolerated option for PPR has the potential to improve patient care, reduce disease burden, and minimize unnecessary costs through increased tolerability and compliance.²¹

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.

Papulopustular rosacea (PPR) is characterized by centrofacial papules, pustules, erythema, and occasionally telangiectasia.^1,2 A myriad of factors, including genetic predisposition³ and environmental triggers,⁴ have been associated with dysregulated inflammatory responses,⁵ contributing to the disease pathogenesis and symptoms. Inflammation associated with PPR may decrease skin barrier function, increase transepidermal water loss, and reduce stratum corneum hydration,^6,7 resulting in heightened skin sensitivity, pain, burning, and/or stinging.^5,8

Azelaic acid (AzA), which historically has only been available in gel or cream formulations, is well established for the treatment of rosacea⁹; however, these formulations have been associated with application-site adverse events (AEs)(eg, burning, erythema, irritation), limited cosmetic acceptability, and reduced compliance or efficacy.¹⁰

For select skin conditions, active agents delivered in foam vehicles may offer superior tolerability with improved outcomes.¹¹ An AzA foam 15% formulation was approved for the treatment of mild to moderate PPR. Primary outcomes from a phase 3 trial demonstrated the efficacy and safety of AzA foam in improving inflammatory lesion counts (ILCs) and disease severity in participants with PPR. The trial also evaluated additional secondary end points, including the effect of AzA foam on erythema, inflammatory lesions, treatment response, and other manifestations of PPR.¹² The current study evaluated investigator-reported efficacy outcomes for these secondary end points for AzA foam 15% versus vehicle foam.

Methods

Study Design

This phase 3 multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical trial was conducted from September 2012 to January 2014 at 48 US study centers comparing the efficacy of AzA foam versus vehicle foam in patients with PPR. Eligible participants were 18 years and older with PPR rated as moderate or severe according to investigator global assessment (IGA), plus 12 to 50 inflammatory lesions and persistent erythema with or without telangiectasia. Exclusion criteria included known nonresponse to AzA, current or prior use (within 6 weeks of randomization) of noninvestigational products to treat rosacea, and presence of other dermatoses that could interfere with rosacea evaluation.

Participants were randomized into the AzA foam or vehicle group (1:1 ratio). The study medication was applied in 0.5-g doses twice daily until the end of treatment (EoT) at 12 weeks. Efficacy and safety parameters were evaluated at baseline and at 4, 8, and 12 weeks of treatment, and at a follow-up visit 4 weeks after EoT (week 16).

Results for the coprimary efficacy end points—therapeutic success rate according to IGA and nominal change in ILC—were previously reported.¹²

Investigator-Reported Secondary Efficacy Outcomes

The secondary efficacy end points were grouped change in erythema rating, grouped change in telangiectasia rating, grouped change in IGA score, therapeutic response rate according to IGA, percentage change in ILC from baseline, and facial skin color rating at EoT.

Grouped change for all secondary end points was measured as improved, no change, or worsened relative to baseline. For grouped change in erythema and telangiectasia ratings, a participant was considered improved if the rating at the postbaseline visit was lower than the baseline rating, no change if the postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline. For grouped change in IGA score, a participant was considered improved if a responder showed at least a 1-step improvement postbaseline compared to baseline, no change if postbaseline and baseline ratings were identical, and worsened if the postbaseline rating was higher than at baseline.

For the therapeutic response rate, a participant was considered a treatment responder if the IGA score improved from baseline and resulted in clear, minimal, or mild disease severity at EoT.

Safety

Adverse events also were assessed.

Statistical Analyses

Secondary efficacy and safety end points were assessed for all randomized participants who were dispensed the study medication. Missing data were imputed using last observation carried forward.

For the percentage change in ILC from baseline, therapeutic response rate, and grouped change in erythema rating, confirmatory analyses were conducted in a hierarchical manner (in the order listed), with testing stopped as soon as a null hypothesis of superior treatment effect could not be rejected. Analyses without significance level were exploratory. The Cochran-Mantel-Haenszel van Elteren test stratified by study center was used for grouped change in erythema rating (1-tailed, 2.5%) and IGA score (2-tailed, 5%); Wilcoxon rank sum tests also were performed. Percentage change in ILC from baseline was evaluated using the Student t test and F test of analysis of covariance (1-tailed, 2.5%). Therapeutic response rate was evaluated using the Cochran-Mantel-Haenszel van Elteren test stratified by study center and the Pearson χ² test. Facial skin color and grouped change in telangiectasia rating were evaluated using the Wilcoxon rank sum test.

Adverse events beginning or worsening after the first dose of the study drug were considered treatment emergent and were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.1. Statistical analyses were performed using SAS software version 9.2.

Results

Study Participants

The study included 961 total participants; 483 were randomized to the AzA foam group and 478 to the vehicle group (Figure 1). Overall, 803 participants completed follow-up; however, week 16 results for the efficacy outcomes include data for 4 additional patients (2 per study arm) who did not formally meet all requirements for follow-up completion. The mean age was 51.5 years, and the majority of the participants were white and female (Table 1). Most participants (86.8%) had moderate PPR at baseline, with the remaining rated as having severe disease (13.2%). The majority (76.4%) had more than 14 inflammatory lesions with moderate (76.4%) or severe (15.1%) erythema at baseline.

Efficacy

Significantly more participants in the AzA group than in the vehicle group showed an improved erythema rating at EoT (61.5% vs 51.3%; P<.001)(Figure 2), with more participants in the AzA group showing improvement at weeks 4 (P=.022) and 8 (P=.002).

A significantly greater mean percentage reduction in ILC from baseline to EoT was observed in the AzA group versus the vehicle group (61.6% vs 50.8%; P<.001)(Figure 3), and between-group differences were observed at week 4 (P<.001), week 8 (P=.003), and week 16 (end of study/follow-up)(P=.002).

A significantly higher proportion of participants treated with AzA foam versus vehicle were considered responders at week 12/EoT (66.3% vs 54.4%; P<.001)(Figure 4). Differences in responder rate also were observed at week 4 (P=.026) and week 8 (P=.026).

Differences in grouped change in IGA score were observed between groups at every evaluation during the treatment phase (Figure 5). Specifically, IGA score was improved at week 12/EoT relative to baseline in 71.2% of participants in the AzA group versus 58.8% in the vehicle group (P<.001).

For grouped change in telangiectasia rating at EoT, the majority of participants in both treatment groups showed no change (Table 2). Regarding facial skin color, the majority of participants in both the AzA and vehicle treatment groups (80.1% and 78.7%, respectively) showed normal skin color compared to nontreated skin EoT; no between-group differences were detected for facial skin color rating (P=.315, Wilcoxon rank sum test).

Safety

The incidence of drug-related AEs was greater in the AzA group than the vehicle group (7.7% vs 4.8%)(Table 3). Drug-related AEs occurring in at least 1% of the AzA group were pain at application site (eg, tenderness, stinging, burning)(AzA group, 3.5%; vehicle group, 1.3%), application-site pruritus (1.4% vs 0.4%), and application-site dryness (1.0% vs 0.6%). A single drug-related AE of severe intensity (ie, application-site dermatitis) was observed in the vehicle group; all other drug-related AEs were mild or moderate. The incidence of withdrawals due to AEs was lower in the AzA group than the vehicle group (1.2% vs 2.5%). This AE profile correlated with a treatment compliance (the percentage of expected doses that were actually administered) of 97.0% in the AzA group and 95.9% in the vehicle group. One participant in the vehicle group died due to head trauma unrelated to administration of the study drug.

Comment

The results of this study further support the efficacy of AzA foam for the treatment of PPR. The percentage reduction in ILC was consistent with nominal decreases in ILC, a coprimary efficacy end point of this study.¹² Almost two-thirds of participants treated with AzA foam achieved a therapeutic response, indicating that many participants who did not strictly achieve the primary outcome of therapeutic success nevertheless attained notable reductions in disease severity. The number of participants who showed any improvement on the IGA scale increased throughout the course of treatment (63.8% AzA foam vs 55.0% vehicle at week 8) up to EoT (71.2% vs 58.8%)(Figure 5). In addition, the number of participants showing any improvement at week 8 (63.8% AzA foam vs 55.0% vehicle)(Figure 5) was comparable to the number of participants achieving therapeutic response at week 12/EoT (66.3% vs 54.4%)(Figure 4). These data suggest that increasing time of treatment increases the likelihood of achieving better results.

Erythema also appeared to respond to AzA foam, with 10.2% more participants in the AzA group demonstrating improvement at week 12/EoT compared to vehicle. The difference in grouped change in erythema rating also was statistically significant and favored AzA foam, sustained up to 4 weeks after EoT.

The outcomes for percentage change in ILC, therapeutic response rate, and grouped change in erythema rating consequently led to the rejection of all 3 null hypotheses in hierarchical confirmatory analyses, underscoring the benefits of AzA foam treatment.

The therapeutic effects of AzA foam were apparent at the first postbaseline evaluation and persisted throughout treatment. Differences favoring AzA foam were observed at every on-treatment evaluation for grouped change in erythema rating, percentage change in ILC, therapeutic response rate, and grouped change in IGA score. Symptoms showed minimal resurgence after treatment cessation, and there were no signs of disease flare-up within the 4 weeks of observational follow-up. In addition, the percentage reduction in ILC remained higher in the AzA foam group during follow-up.

These results also show that AzA foam was well tolerated with a low incidence of discontinuation because of drug-related AEs. No serious drug-related AEs were reported for this study or in the preceding phase 2 trial.^12,13 Although not directly evaluated, the low incidence of cutaneous AEs suggests that AzA foam may be better tolerated than prior formulations of AzA^14,15 and correlates with high compliance observed during the study.¹² Azelaic acid foam appeared to have minimal to no effect on skin color, with more than 88% of participants reporting barely visible or no skin lightening.

Interestingly, the vehicle foam showed appreciable efficacy independent of AzA. Improvements in erythema were recorded in approximately half of the vehicle group at week 12/EoT. A similar proportion attained a therapeutic response, and ILC was reduced by 50.8% at week 12/EoT. Comparable results also were evident in the vehicle group for the primary end points of this study.¹² Vehicles in dermatologic trials frequently exert effects on diseased skin^16,17 via a skin care regimen effect (eg, moisturization and other vehicle-related effects that may improve skin barrier integrity and function) and thus should not be regarded as placebo controls. The mechanism underlying this efficacy may be due to the impact of vehicle composition on skin barrier integrity and transepidermal water loss.¹⁸ The hydrophilic emulsion or other constituents of AzA foam (eg, fatty alcohols) may play a role.

A notable strength of our study is detailed clinical characterization using carefully chosen parameters and preplanned analyses that complement the primary end points. As the latter are often driven by regulatory requirements, opportunities to characterize other outcomes of interest to clinicians may be missed. The additional analyses reported here hopefully will aid dermatologists in both assessing the role of AzA foam in the treatment armamentarium for PPR and counseling patients.

Because participants with lighter skin pigmentation dominated our study population, the impact of AzA foam among patients with darker skin complexions is unknown. Although AzA is unlikely to cause hypopigmentation in normal undiseased skin, patients should be monitored for early signs of hypopigmentation.^19,20 Our data also do not allow assessment of the differential effect, if any, of AzA foam on erythema of different etiologies in PPR, as corresponding information was not collected in the trial.

Conclusion

Azelaic acid foam 15% combines a well-established treatment of PPR with new vehicle technology to deliver effective therapy across multiple disease dimensions. In addition, the vehicle foam appears to demonstrate inherent therapeutic properties independent of AzA. The availability of this novel, efficacious, and well-tolerated option for PPR has the potential to improve patient care, reduce disease burden, and minimize unnecessary costs through increased tolerability and compliance.²¹

Acknowledgment

Editorial support through inVentiv Medical Communications (New York, New York) was provided by Bayer Pharmaceuticals.