John Fani Srour, MD

Dual antiplatelet therapy (DAPT) (aspirin plus a thienopyridine: clopidogrel or prasugrel) has become the standard treatment for patients with acute coronary syndromes (ACS) and after coronary stent placement (Table 1). Anticoagulant therapy with warfarin is indicated for stroke prevention in atrial fibrillation (AF), profound left ventricular dysfunction, and after mechanical heart valve replacement, as well as for treatment of deep venous thrombosis and pulmonary embolism (Table 2). It is estimated that 41% of the U.S. population over age 40 years is on some form of antiplatelet therapy,6 and 2.5 million patients, mostly elderly, are on long‐term warfarin therapy.7 More specifically, 5% of patients undergoing percutaneous coronary interventions (PCIs) also have an indication for warfarin.8 With widespread use of drug‐eluting stents (DES), the need for a longer duration of DAPT, and the increased age and complexity of hospitalized patients, the safety and challenges of triple therapy (combined DAPT and warfarin) have become more important to the practice of hospital medicine. Triple therapy may increase hospitalization rates, as the risk of major bleeding is four to five times higher than with DAPT.911 In contrast, DAPT is much less effective than warfarin alone in preventing embolic events in AF,12 and warfarin alone or in combination with aspirin (ASA) is inadequate therapy to prevent stent thrombosis. Even fewer data exist on the efficacy and safety of triple therapy in patients with mechanical valves or left ventricular dysfunction.

Hospitalists commonly care for patients on triple therapy; certain indications are appropriate and supported from the available literature while others lack evidence. Knowledge of existing practice guidelines and of supporting research studies leads to optimal management of these complicated patients, and minimizes excessive morbidity from bleeding complications or thromboembolic events such as strokes and stent thrombosis.

In the first part of this article, we present the evidence that supports current recommendations for DAPT or warfarin in specific medical conditions. We also address controversies and unanswered questions. The second part of this review focuses on the available data and provides guidance on the optimal care of patients on triple therapy.

Dual Antiplatelet Therapy Following Acute Coronary Syndromes

Table 3 summarizes key randomized trials of DAPT versus ASA alone in several clinical scenarios. The addition of clopidogrel to ASA in patients with nonST‐elevation ACS reduced the risk of adverse ischemic outcomes in the clopidogrel in unstable angina to prevent recurrent events (CURE) trial,15 as well as in its substudy, the PCI‐CURE (patients with ACS who have undergone stenting).17 In the main CURE study, the study groups diverged within the first 30 days after randomization and the benefit of DAPT persisted throughout the 12 months of the study period. DAPT is also superior to ASA in patients with ST‐elevation myocardial infarction (MI) (CLARITYTIMI 28 and COMMIT trials).13, 14 On the basis of these findings, DAPT has become the standard of care for patients with ACS. The American College of Cardiology (ACC)/American Heart Association (AHA)3 and the European Society of Cardiology18 recommend ASA treatment indefinitely for patients with ACS whether or not they underwent PCI. Clopidogrel is recommended for at least 12 months following ACS, especially for patients who receive a coronary stent.

Despite the proven efficacy of DAPT in ACS, about 15% of patients die or experience reinfarction within 30 days of diagnosis.19 The continued risk for thrombotic events could be due to delayed onset of platelet inhibition and to patient heterogeneity in responsiveness to therapy with ASA and/or clopidogrel.20 Consequently, the optimum dose for clopidogrel and ASA following ACS is uncertain. The CURRENT‐OASIS 7 trial evaluated the efficacy and safety of high‐dose clopidogrel (600‐mg loading dose, 150 mg once daily for 7 days, followed by 75 mg/d) versus standard‐dose clopidogrel (300‐mg loading dose, followed by 75 mg/d) and ASA (75‐100 mg versus 300‐325 mg/d) in patients with ACS who were treated medically, with or without stenting.21 In the overall study population as well as in patients who did not receive stenting, there was no significant difference in the combined rate of death from cardiovascular causes, MI, and stroke between patients receiving the high‐dose and the standard‐dose clopidogrel (4.2% vs 4.4%; P = .37) and high‐dose versus low‐dose ASA (4.2% vs 4.4%; P = .47). There were no significant differences in bleeding complications between the two clopidogrel treatment arms or between the high‐dose and low‐dose ASA groups.

The ACC/AHA guidelines recommend ASA, 75‐162 mg/d indefinitely after medical therapy without stenting (class I, level of evidence: A)3 and clopidogrel 75 mg/d for at least 1 month (class IA) and optimally for 1 year (class IB). Clopidogrel monotherapy is appropriate for patients with ACS who are unable to tolerate ASA due to either hypersensitivity or recent significant gastrointestinal bleeding.

As is the case after coronary stenting, interruption of DAPT soon after ACS may subject patients to high recurrence of cardiovascular events, although few data are available to support this observation. Interruption of DAPT due to bleeding complications or surgical procedures more than 1 month after ACS may be reasonable for a patient who did not receive a stent. Clinicians should restart DAPT after the surgical procedure once the bleeding risk becomes acceptable.

Dual Antiplatelet Therapy Following Coronary Stenting

Warfarin After Acute Coronary Syndromes

Warfarin with different international normalized ratio (INR) goals alone or in combination with ASA has been evaluated after ACS. In an early trial, patients with recent (mean interval 27 days) MI were treated with warfarin alone versus placebo.41 Warfarin conferred a relative risk reduction in mortality of 24% (95% CI, 4‐44%; P = .027) at the expense of major bleeding rates of 0.6%/y. In the ASPECT trial,42 moderate to high intensity anticoagulation after MI resulted in a 53% and 40% reduction in the relative risk of reinfarction (annual incidence 2.3% versus 5.1%) and cerebrovascular events (annual incidence 0.7% versus 1.2%), respectively. In the WARIS II43 and ASPECT‐244 trials, moderate intensity warfarin (INR 2.0‐2.5) in combination with low‐dose ASA, compared with ASA alone, reduced the composite occurrence of death or nonfatal reinfarction, as well as recurrent coronary occlusion after ST‐segment elevation MI. High‐intensity warfarin therapy alone (INR 3.0‐4.0 for ASPECT, 2.8‐4.2 for WARISII) reduced ischemic vascular events compared with ASA alone. Not unexpectedly, major bleeding episodes were more common among patients receiving warfarin.

No randomized trials have compared DAPT with warfarin plus ASA for patients with ACS who did not receive stents. The ACC/AHA guidelines recommend warfarin for secondary prevention following ACS (class IIb). High‐intensity warfarin alone (INR 2.5‐3.5) or moderate intensity (INR 2.0‐2.5) with low‐dose ASA (75‐81 mg/d) may be reasonable for patients at high ischemic and low bleeding risk who are intolerant of clopidogrel (level of evidence: B). Fixed dose warfarin is not recommended by the ACC/AHA primarily on the basis of the Coumadin Aspirin Reinfarction Study (CARS) results. This study of patients following MI was discontinued prematurely because of a lack of incremental benefit of reduced‐dose ASA (80 mg/d) combined with either 1 or 3 mg of warfarin daily when compared with 160 mg/d of ASA alone.

Triple Therapy for PCI and Atrial Fibrillation

AF is the most frequent indication (70%) for long‐term therapy with warfarin in patients scheduled for stent placement.10 Clinical trials have shown that warfarin alone is superior to ASA, clopidogrel, or DAPT for prevention of stroke in patients with AF.45, 46 Although warfarin is indispensable in these settings, DAPT is similarly necessary after stent implantation. As triple therapy increases the risk of bleeding, the management of patients with AF and who have received stents remains controversial. This situation is particularly problematic among patients who have received DES and may benefit from extended DAPT. No randomized trials exist to clarify the optimal treatment in these patients; and the feasibility of such studies is questionable. Small, mostly retrospective, studies (Table 4) provide limited guidance on this issue; most studies focus on bleeding events rather than the cardiovascular efficacy of triple therapy. Because of these limitations, cardiovascular societies give IIb recommendation for either triple therapy or the combination of warfarin and clopidogrel in this setting and the level of evidence is C.1, 59, 60

In the largest study to date, Nguyen et al.58 evaluated 800 patients who underwent stenting for ACS and were discharged on warfarin plus single antiplatelet agent or triple therapy as part of the GRACE registry. At 6 months, triple therapy conferred a significant reduction in stroke (0.7% versus 3.4%, P = .02) but not in death or MI. There were no differences in in‐hospital major bleeding events between the two groups (5.9% versus 4.6%; P = .46). Similarly, Sarafoff et al.53 reported no significant differences in the combined endpoint (death, MI, stent thrombosis or stroke) or bleeding complications among patients who received triple therapy or DAPT at 2 years of follow‐up. In contrast, Ruiz‐Nodar et al.52 showed that triple therapy, compared with DAPT, at discharge reduced the incidence of death (17.8% versus 27.8%; adjusted HR = 3.43; 95% CI, 1.617.54; P = .002) and major adverse cardiac events (26.5% versus 38.7%; adjusted HR = 4.9; 95% CI, 2.1711.1; P = .01), without a substantial increase in major bleeding events.

The value of combination antiplatelet therapy to prevent stent thrombosis in these patients is clearer in the study reported by Karjalainen et al.10 This case‐control study of 239 patients receiving warfarin at baseline who underwent PCI evaluated a primary endpoint of death, MI, target‐vessel revascularization, or stent thrombosis and a secondary endpoint of major bleeding and stroke to 12 months of follow‐up. Forty‐eight percent of patients received triple therapy, whereas 15.5% were discharged on DAPT. The remaining patients received warfarin plus a single antiplatelet agent. Stent thrombosis occurred more frequently among patients receiving warfarin plus ASA (15.2%) than among those receiving triple therapy (1.9%). As expected, stroke was more frequent in patients treated with DAPT (8.8%) than among those receiving triple therapy (2.8%). Major bleeding was similar between groups. Therapy with warfarin was an independent predictor of both major bleeding and major cardiac events at 1 year. This observation illustrates that the outcome of PCI in patients on chronic warfarin therapy is unsatisfactory irrespective of the antithrombotic combinations used, highlighting the need for better strategies to treat these patients.

Choice of Therapy and Management of Patients Eligible for Triple Therapy

Current guidelines for PCI do not provide guidance for patients with an indication for triple therapy due to a paucity of published evidence. Several ongoing prospective trials aim to address the management of these patients (AFCAS, ISAR‐TRIPLE). Pending further study, clinicians should consider the embolic risk (CHADS2 score), target INR, type of stent, bleeding risk, and duration of treatment when determining the appropriate antiplatelet/anticoagulant combinations. The CHADS2 score (Table 2) stratifies the risk for stroke among patients with AF,4 while the Outpatient Bleeding Risk Index (OBRI) allows estimation of bleeding risk.12, 61 The OBRI considers age > 65 years, prior stroke, prior gastrointestinal bleeding, and any of four comorbidities (recent MI, anemia, diabetes, or renal insufficiency) in order to stratify patients into three risk groups.61 Patients with three to four risk factors have a high risk of bleeding (23% at 3 months and 48% at 12 months) whereas patients with no risk factors have only a 3% risk of bleeding at 12 months. Unfortunately, advanced age and prior stroke appear in both OBRI and CHADS.

For patients with AF who are at high risk for embolic stroke (>3% per year), we recommend triple therapy for the shortest time possible, followed by warfarin and ASA indefinitely. In case of BMS, it is acceptable to shorten triple therapy duration to 1 month. The optimal duration of triple therapy for patients with DES is uncertain; recommended durations range from 3 months to 1 year.62 If the potential consequences of stent thrombosis are high due to a large amount of myocardium at risk, an extended period of triple therapy might be justified. For patients whose stroke risk is lower (CHADS2 score of 0‐1), the risk for bleeding likely outweighs any benefit from stroke prevention. In this instance, it is reasonable to use DAPT with ASA and clopidogrel for 1 month after BMS and 12 months after DES, followed by ASA, with or without warfarin, indefinitely. In a recently published study, patients with AF and a CHADS2 score of 1 had a yearly stroke risk of 1.25% while taking DAPT63; the risk of major bleeding for triple therapy is 6.1% per year.64

For patients who have a high bleeding risk, BMS are the preferred stent type as the duration of triple therapy might be limited to 4 weeks. To our knowledge, no randomized study has evaluated the outcome of patients with BMS compared with DES who also have an indication for warfarin. Because studies have suggested that clopidogrel is more effective than aspirin in preventing stent thrombosis and in reducing death or MI after coronary stenting,40, 65 warfarin and single antiplatelet therapy with clopidogrel might be a reasonable treatment option in patients with high bleeding risk. The WOEST study (NCT00769938), currently recruiting participants, is the first randomized study specifically designed to test this hypothesis.

Since gastrointestinal bleeding accounts for approximately 30‐40% of hemorrhagic events in patients on combined ASA and anticoagulant therapy, an expert consensus document recommended concomitant treatment with proton pump inhibitors (PPIs) to reduce this risk.66 In contrast, the 2009 Focused Updates of the ACC/AHA/SCAI Guidelines did not recommend the use of PPIs with DAPT in the setting of ACS.2 This is because of studies that show inhibition of platelet activation,67 and potential clinical harm,68 when clopidogrel is combined with certain PPIs that inhibit the CYP2C19 enzyme. However, to date there are no convincing randomized clinical trial data documenting an important clinical drug‐drug interaction. The U.S. Food and Drug Administration (FDA) advises that physicians avoid the use of clopidogrel in patients with impaired CYP2C19 function due to known genetic variation or due to concomitant use of drugs that inhibit CYP2C19 activity. More specifically, the FDA recommends avoiding the use of omeprazole and esomeprazole in patients taking clopidogrel.69

In particular, elderly patients have an increased risk of bleeding while receiving triple therapy. In a study of patients over age 65, 2.5% were hospitalized for bleeding in the first year after PCI, and the use of triple therapy was the strongest predictor of bleeding (more than threefold increase).70 One in five patients suffered death or MI at 1 year after hospitalization for bleeding.70 The basis for poor outcomes after hospitalization for bleeding in this population is multifactorial and may be due to the location of bleeding, associated hypercoagulable state, potential adverse impact of blood transfusion, withdrawal of warfarin therapy in patients with AF and PCI, and the premature discontinuation of DAPT. The use of nonsteroidal anti‐inflammatory drugs (NSAIDs) is common among the elderly and conferred a doubling of bleeding risk.70 Limiting the use of NSAID, the use of low‐dose ASA beyond 30 days after stent implantation, greater use of BMS, and maintaining INR at the lowest possible level (INR of 22.5) will reduce the risk for bleeding.57, 71

New Anticoagulants

Due to the high risk for bleeding with warfarin and the challenges inherent in INR monitoring, researchers have developed several novel anticoagulants whose advantages include fixed daily dosing and no need for monitoring. Dabigatran is a direct oral thrombin inhibitor that is already licensed in Europe and Canada for thromboprophylaxis after hip or knee surgery. It has also been studied in patients with AF. In the RE‐LY trial, patients with AF who received dabigatran 110 mg daily had rates of stroke and systemic embolism that were similar to those with warfarin, as well as lower rates of major hemorrhage.72 The randomized ReDEEM trial, reported at the AHA 2009 Scientific Sessions, was aimed at finding a dosage of dabigatran that achieves a good balance between clinical effectiveness and bleeding risk when combined with aspirin and clopidogrel after acute MI. Dosages ranging from 50 mg twice daily to 150 mg twice daily were all associated with 6‐month rates of bleeding lower than 2%. Hospitalists should view these encouraging results cautiously until the publication of ReDEEM trial results in a peer‐reviewed journal.

A variety of oral Xa antagonists are also being evaluated in patients with AF or ACS. These trials offer insight into triple therapy regimens that include ASA, clopidogrel, and an Xa antagonist. In a recent study of the oral Xa antagonist rivaroxaban, investigators stratified 3491 subjects with ACS according to whether they received concomitant ASA alone or ASA and clopidogrel.73 Subjects receiving ASA plus rivaroxaban had a modest increase in bleeding. Triple therapy, however, increased the composite bleeding rate from 3.5% in the DAPT group to approximately 6‐15% (low‐dose or high‐dose rivaroxaban, respectively). Rivaroxaban is currently under review by the FDA.

These novel agents might eventually replace warfarin for many or most indications for anticoagulation. It is imperative that future research compare the efficacy and risk of bleeding between triple therapy using these new agents and triple therapy with warfarin.

Conclusions

The management of patients on long‐term anticoagulation who require DAPT because of ACS or coronary stenting is challenging. DAPT may safely substitute for warfarin only for patients at low risk for a thromboembolic event (ie, low‐risk AF with low CHADS2 score). Clinicians should not interrupt warfarin in patients at higher risk (ie, intermediate to high‐risk AF, mechanical valves, or recent venous thromboembolism), even in the presence of DAPT. In these patients, triple therapy is the optimal approach following coronary stenting (and possibly during the initial period after ACS without stenting). As this approach confers a fivefold increase in bleeding complications compared with DAPT, careful monitoring of the INR, the addition of PPIs, and the exclusion of elderly patients who are at the highest risk for bleeding complications74 is recommended. The preferred duration of triple therapy after BMS in patients who require long‐term anticoagulation is 1 month, whereas the optimal duration after ACS or DES remains unresolved.

Dual antiplatelet therapy (DAPT) (aspirin plus a thienopyridine: clopidogrel or prasugrel) has become the standard treatment for patients with acute coronary syndromes (ACS) and after coronary stent placement (Table 1). Anticoagulant therapy with warfarin is indicated for stroke prevention in atrial fibrillation (AF), profound left ventricular dysfunction, and after mechanical heart valve replacement, as well as for treatment of deep venous thrombosis and pulmonary embolism (Table 2). It is estimated that 41% of the U.S. population over age 40 years is on some form of antiplatelet therapy,6 and 2.5 million patients, mostly elderly, are on long‐term warfarin therapy.7 More specifically, 5% of patients undergoing percutaneous coronary interventions (PCIs) also have an indication for warfarin.8 With widespread use of drug‐eluting stents (DES), the need for a longer duration of DAPT, and the increased age and complexity of hospitalized patients, the safety and challenges of triple therapy (combined DAPT and warfarin) have become more important to the practice of hospital medicine. Triple therapy may increase hospitalization rates, as the risk of major bleeding is four to five times higher than with DAPT.911 In contrast, DAPT is much less effective than warfarin alone in preventing embolic events in AF,12 and warfarin alone or in combination with aspirin (ASA) is inadequate therapy to prevent stent thrombosis. Even fewer data exist on the efficacy and safety of triple therapy in patients with mechanical valves or left ventricular dysfunction.

Hospitalists commonly care for patients on triple therapy; certain indications are appropriate and supported from the available literature while others lack evidence. Knowledge of existing practice guidelines and of supporting research studies leads to optimal management of these complicated patients, and minimizes excessive morbidity from bleeding complications or thromboembolic events such as strokes and stent thrombosis.

In the first part of this article, we present the evidence that supports current recommendations for DAPT or warfarin in specific medical conditions. We also address controversies and unanswered questions. The second part of this review focuses on the available data and provides guidance on the optimal care of patients on triple therapy.

Dual Antiplatelet Therapy Following Acute Coronary Syndromes

Table 3 summarizes key randomized trials of DAPT versus ASA alone in several clinical scenarios. The addition of clopidogrel to ASA in patients with nonST‐elevation ACS reduced the risk of adverse ischemic outcomes in the clopidogrel in unstable angina to prevent recurrent events (CURE) trial,15 as well as in its substudy, the PCI‐CURE (patients with ACS who have undergone stenting).17 In the main CURE study, the study groups diverged within the first 30 days after randomization and the benefit of DAPT persisted throughout the 12 months of the study period. DAPT is also superior to ASA in patients with ST‐elevation myocardial infarction (MI) (CLARITYTIMI 28 and COMMIT trials).13, 14 On the basis of these findings, DAPT has become the standard of care for patients with ACS. The American College of Cardiology (ACC)/American Heart Association (AHA)3 and the European Society of Cardiology18 recommend ASA treatment indefinitely for patients with ACS whether or not they underwent PCI. Clopidogrel is recommended for at least 12 months following ACS, especially for patients who receive a coronary stent.

Despite the proven efficacy of DAPT in ACS, about 15% of patients die or experience reinfarction within 30 days of diagnosis.19 The continued risk for thrombotic events could be due to delayed onset of platelet inhibition and to patient heterogeneity in responsiveness to therapy with ASA and/or clopidogrel.20 Consequently, the optimum dose for clopidogrel and ASA following ACS is uncertain. The CURRENT‐OASIS 7 trial evaluated the efficacy and safety of high‐dose clopidogrel (600‐mg loading dose, 150 mg once daily for 7 days, followed by 75 mg/d) versus standard‐dose clopidogrel (300‐mg loading dose, followed by 75 mg/d) and ASA (75‐100 mg versus 300‐325 mg/d) in patients with ACS who were treated medically, with or without stenting.21 In the overall study population as well as in patients who did not receive stenting, there was no significant difference in the combined rate of death from cardiovascular causes, MI, and stroke between patients receiving the high‐dose and the standard‐dose clopidogrel (4.2% vs 4.4%; P = .37) and high‐dose versus low‐dose ASA (4.2% vs 4.4%; P = .47). There were no significant differences in bleeding complications between the two clopidogrel treatment arms or between the high‐dose and low‐dose ASA groups.

The ACC/AHA guidelines recommend ASA, 75‐162 mg/d indefinitely after medical therapy without stenting (class I, level of evidence: A)3 and clopidogrel 75 mg/d for at least 1 month (class IA) and optimally for 1 year (class IB). Clopidogrel monotherapy is appropriate for patients with ACS who are unable to tolerate ASA due to either hypersensitivity or recent significant gastrointestinal bleeding.

As is the case after coronary stenting, interruption of DAPT soon after ACS may subject patients to high recurrence of cardiovascular events, although few data are available to support this observation. Interruption of DAPT due to bleeding complications or surgical procedures more than 1 month after ACS may be reasonable for a patient who did not receive a stent. Clinicians should restart DAPT after the surgical procedure once the bleeding risk becomes acceptable.

Dual Antiplatelet Therapy Following Coronary Stenting

Warfarin After Acute Coronary Syndromes

Warfarin with different international normalized ratio (INR) goals alone or in combination with ASA has been evaluated after ACS. In an early trial, patients with recent (mean interval 27 days) MI were treated with warfarin alone versus placebo.41 Warfarin conferred a relative risk reduction in mortality of 24% (95% CI, 4‐44%; P = .027) at the expense of major bleeding rates of 0.6%/y. In the ASPECT trial,42 moderate to high intensity anticoagulation after MI resulted in a 53% and 40% reduction in the relative risk of reinfarction (annual incidence 2.3% versus 5.1%) and cerebrovascular events (annual incidence 0.7% versus 1.2%), respectively. In the WARIS II43 and ASPECT‐244 trials, moderate intensity warfarin (INR 2.0‐2.5) in combination with low‐dose ASA, compared with ASA alone, reduced the composite occurrence of death or nonfatal reinfarction, as well as recurrent coronary occlusion after ST‐segment elevation MI. High‐intensity warfarin therapy alone (INR 3.0‐4.0 for ASPECT, 2.8‐4.2 for WARISII) reduced ischemic vascular events compared with ASA alone. Not unexpectedly, major bleeding episodes were more common among patients receiving warfarin.

No randomized trials have compared DAPT with warfarin plus ASA for patients with ACS who did not receive stents. The ACC/AHA guidelines recommend warfarin for secondary prevention following ACS (class IIb). High‐intensity warfarin alone (INR 2.5‐3.5) or moderate intensity (INR 2.0‐2.5) with low‐dose ASA (75‐81 mg/d) may be reasonable for patients at high ischemic and low bleeding risk who are intolerant of clopidogrel (level of evidence: B). Fixed dose warfarin is not recommended by the ACC/AHA primarily on the basis of the Coumadin Aspirin Reinfarction Study (CARS) results. This study of patients following MI was discontinued prematurely because of a lack of incremental benefit of reduced‐dose ASA (80 mg/d) combined with either 1 or 3 mg of warfarin daily when compared with 160 mg/d of ASA alone.

Triple Therapy for PCI and Atrial Fibrillation

AF is the most frequent indication (70%) for long‐term therapy with warfarin in patients scheduled for stent placement.10 Clinical trials have shown that warfarin alone is superior to ASA, clopidogrel, or DAPT for prevention of stroke in patients with AF.45, 46 Although warfarin is indispensable in these settings, DAPT is similarly necessary after stent implantation. As triple therapy increases the risk of bleeding, the management of patients with AF and who have received stents remains controversial. This situation is particularly problematic among patients who have received DES and may benefit from extended DAPT. No randomized trials exist to clarify the optimal treatment in these patients; and the feasibility of such studies is questionable. Small, mostly retrospective, studies (Table 4) provide limited guidance on this issue; most studies focus on bleeding events rather than the cardiovascular efficacy of triple therapy. Because of these limitations, cardiovascular societies give IIb recommendation for either triple therapy or the combination of warfarin and clopidogrel in this setting and the level of evidence is C.1, 59, 60

In the largest study to date, Nguyen et al.58 evaluated 800 patients who underwent stenting for ACS and were discharged on warfarin plus single antiplatelet agent or triple therapy as part of the GRACE registry. At 6 months, triple therapy conferred a significant reduction in stroke (0.7% versus 3.4%, P = .02) but not in death or MI. There were no differences in in‐hospital major bleeding events between the two groups (5.9% versus 4.6%; P = .46). Similarly, Sarafoff et al.53 reported no significant differences in the combined endpoint (death, MI, stent thrombosis or stroke) or bleeding complications among patients who received triple therapy or DAPT at 2 years of follow‐up. In contrast, Ruiz‐Nodar et al.52 showed that triple therapy, compared with DAPT, at discharge reduced the incidence of death (17.8% versus 27.8%; adjusted HR = 3.43; 95% CI, 1.617.54; P = .002) and major adverse cardiac events (26.5% versus 38.7%; adjusted HR = 4.9; 95% CI, 2.1711.1; P = .01), without a substantial increase in major bleeding events.

The value of combination antiplatelet therapy to prevent stent thrombosis in these patients is clearer in the study reported by Karjalainen et al.10 This case‐control study of 239 patients receiving warfarin at baseline who underwent PCI evaluated a primary endpoint of death, MI, target‐vessel revascularization, or stent thrombosis and a secondary endpoint of major bleeding and stroke to 12 months of follow‐up. Forty‐eight percent of patients received triple therapy, whereas 15.5% were discharged on DAPT. The remaining patients received warfarin plus a single antiplatelet agent. Stent thrombosis occurred more frequently among patients receiving warfarin plus ASA (15.2%) than among those receiving triple therapy (1.9%). As expected, stroke was more frequent in patients treated with DAPT (8.8%) than among those receiving triple therapy (2.8%). Major bleeding was similar between groups. Therapy with warfarin was an independent predictor of both major bleeding and major cardiac events at 1 year. This observation illustrates that the outcome of PCI in patients on chronic warfarin therapy is unsatisfactory irrespective of the antithrombotic combinations used, highlighting the need for better strategies to treat these patients.

Choice of Therapy and Management of Patients Eligible for Triple Therapy

Current guidelines for PCI do not provide guidance for patients with an indication for triple therapy due to a paucity of published evidence. Several ongoing prospective trials aim to address the management of these patients (AFCAS, ISAR‐TRIPLE). Pending further study, clinicians should consider the embolic risk (CHADS2 score), target INR, type of stent, bleeding risk, and duration of treatment when determining the appropriate antiplatelet/anticoagulant combinations. The CHADS2 score (Table 2) stratifies the risk for stroke among patients with AF,4 while the Outpatient Bleeding Risk Index (OBRI) allows estimation of bleeding risk.12, 61 The OBRI considers age > 65 years, prior stroke, prior gastrointestinal bleeding, and any of four comorbidities (recent MI, anemia, diabetes, or renal insufficiency) in order to stratify patients into three risk groups.61 Patients with three to four risk factors have a high risk of bleeding (23% at 3 months and 48% at 12 months) whereas patients with no risk factors have only a 3% risk of bleeding at 12 months. Unfortunately, advanced age and prior stroke appear in both OBRI and CHADS.

For patients with AF who are at high risk for embolic stroke (>3% per year), we recommend triple therapy for the shortest time possible, followed by warfarin and ASA indefinitely. In case of BMS, it is acceptable to shorten triple therapy duration to 1 month. The optimal duration of triple therapy for patients with DES is uncertain; recommended durations range from 3 months to 1 year.62 If the potential consequences of stent thrombosis are high due to a large amount of myocardium at risk, an extended period of triple therapy might be justified. For patients whose stroke risk is lower (CHADS2 score of 0‐1), the risk for bleeding likely outweighs any benefit from stroke prevention. In this instance, it is reasonable to use DAPT with ASA and clopidogrel for 1 month after BMS and 12 months after DES, followed by ASA, with or without warfarin, indefinitely. In a recently published study, patients with AF and a CHADS2 score of 1 had a yearly stroke risk of 1.25% while taking DAPT63; the risk of major bleeding for triple therapy is 6.1% per year.64

For patients who have a high bleeding risk, BMS are the preferred stent type as the duration of triple therapy might be limited to 4 weeks. To our knowledge, no randomized study has evaluated the outcome of patients with BMS compared with DES who also have an indication for warfarin. Because studies have suggested that clopidogrel is more effective than aspirin in preventing stent thrombosis and in reducing death or MI after coronary stenting,40, 65 warfarin and single antiplatelet therapy with clopidogrel might be a reasonable treatment option in patients with high bleeding risk. The WOEST study (NCT00769938), currently recruiting participants, is the first randomized study specifically designed to test this hypothesis.

Since gastrointestinal bleeding accounts for approximately 30‐40% of hemorrhagic events in patients on combined ASA and anticoagulant therapy, an expert consensus document recommended concomitant treatment with proton pump inhibitors (PPIs) to reduce this risk.66 In contrast, the 2009 Focused Updates of the ACC/AHA/SCAI Guidelines did not recommend the use of PPIs with DAPT in the setting of ACS.2 This is because of studies that show inhibition of platelet activation,67 and potential clinical harm,68 when clopidogrel is combined with certain PPIs that inhibit the CYP2C19 enzyme. However, to date there are no convincing randomized clinical trial data documenting an important clinical drug‐drug interaction. The U.S. Food and Drug Administration (FDA) advises that physicians avoid the use of clopidogrel in patients with impaired CYP2C19 function due to known genetic variation or due to concomitant use of drugs that inhibit CYP2C19 activity. More specifically, the FDA recommends avoiding the use of omeprazole and esomeprazole in patients taking clopidogrel.69

In particular, elderly patients have an increased risk of bleeding while receiving triple therapy. In a study of patients over age 65, 2.5% were hospitalized for bleeding in the first year after PCI, and the use of triple therapy was the strongest predictor of bleeding (more than threefold increase).70 One in five patients suffered death or MI at 1 year after hospitalization for bleeding.70 The basis for poor outcomes after hospitalization for bleeding in this population is multifactorial and may be due to the location of bleeding, associated hypercoagulable state, potential adverse impact of blood transfusion, withdrawal of warfarin therapy in patients with AF and PCI, and the premature discontinuation of DAPT. The use of nonsteroidal anti‐inflammatory drugs (NSAIDs) is common among the elderly and conferred a doubling of bleeding risk.70 Limiting the use of NSAID, the use of low‐dose ASA beyond 30 days after stent implantation, greater use of BMS, and maintaining INR at the lowest possible level (INR of 22.5) will reduce the risk for bleeding.57, 71

New Anticoagulants

Due to the high risk for bleeding with warfarin and the challenges inherent in INR monitoring, researchers have developed several novel anticoagulants whose advantages include fixed daily dosing and no need for monitoring. Dabigatran is a direct oral thrombin inhibitor that is already licensed in Europe and Canada for thromboprophylaxis after hip or knee surgery. It has also been studied in patients with AF. In the RE‐LY trial, patients with AF who received dabigatran 110 mg daily had rates of stroke and systemic embolism that were similar to those with warfarin, as well as lower rates of major hemorrhage.72 The randomized ReDEEM trial, reported at the AHA 2009 Scientific Sessions, was aimed at finding a dosage of dabigatran that achieves a good balance between clinical effectiveness and bleeding risk when combined with aspirin and clopidogrel after acute MI. Dosages ranging from 50 mg twice daily to 150 mg twice daily were all associated with 6‐month rates of bleeding lower than 2%. Hospitalists should view these encouraging results cautiously until the publication of ReDEEM trial results in a peer‐reviewed journal.

A variety of oral Xa antagonists are also being evaluated in patients with AF or ACS. These trials offer insight into triple therapy regimens that include ASA, clopidogrel, and an Xa antagonist. In a recent study of the oral Xa antagonist rivaroxaban, investigators stratified 3491 subjects with ACS according to whether they received concomitant ASA alone or ASA and clopidogrel.73 Subjects receiving ASA plus rivaroxaban had a modest increase in bleeding. Triple therapy, however, increased the composite bleeding rate from 3.5% in the DAPT group to approximately 6‐15% (low‐dose or high‐dose rivaroxaban, respectively). Rivaroxaban is currently under review by the FDA.

These novel agents might eventually replace warfarin for many or most indications for anticoagulation. It is imperative that future research compare the efficacy and risk of bleeding between triple therapy using these new agents and triple therapy with warfarin.

Conclusions

The management of patients on long‐term anticoagulation who require DAPT because of ACS or coronary stenting is challenging. DAPT may safely substitute for warfarin only for patients at low risk for a thromboembolic event (ie, low‐risk AF with low CHADS2 score). Clinicians should not interrupt warfarin in patients at higher risk (ie, intermediate to high‐risk AF, mechanical valves, or recent venous thromboembolism), even in the presence of DAPT. In these patients, triple therapy is the optimal approach following coronary stenting (and possibly during the initial period after ACS without stenting). As this approach confers a fivefold increase in bleeding complications compared with DAPT, careful monitoring of the INR, the addition of PPIs, and the exclusion of elderly patients who are at the highest risk for bleeding complications74 is recommended. The preferred duration of triple therapy after BMS in patients who require long‐term anticoagulation is 1 month, whereas the optimal duration after ACS or DES remains unresolved.

Dual antiplatelet therapy (DAPT) (aspirin plus a thienopyridine: clopidogrel or prasugrel) has become the standard treatment for patients with acute coronary syndromes (ACS) and after coronary stent placement (Table 1). Anticoagulant therapy with warfarin is indicated for stroke prevention in atrial fibrillation (AF), profound left ventricular dysfunction, and after mechanical heart valve replacement, as well as for treatment of deep venous thrombosis and pulmonary embolism (Table 2). It is estimated that 41% of the U.S. population over age 40 years is on some form of antiplatelet therapy,6 and 2.5 million patients, mostly elderly, are on long‐term warfarin therapy.7 More specifically, 5% of patients undergoing percutaneous coronary interventions (PCIs) also have an indication for warfarin.8 With widespread use of drug‐eluting stents (DES), the need for a longer duration of DAPT, and the increased age and complexity of hospitalized patients, the safety and challenges of triple therapy (combined DAPT and warfarin) have become more important to the practice of hospital medicine. Triple therapy may increase hospitalization rates, as the risk of major bleeding is four to five times higher than with DAPT.911 In contrast, DAPT is much less effective than warfarin alone in preventing embolic events in AF,12 and warfarin alone or in combination with aspirin (ASA) is inadequate therapy to prevent stent thrombosis. Even fewer data exist on the efficacy and safety of triple therapy in patients with mechanical valves or left ventricular dysfunction.

Hospitalists commonly care for patients on triple therapy; certain indications are appropriate and supported from the available literature while others lack evidence. Knowledge of existing practice guidelines and of supporting research studies leads to optimal management of these complicated patients, and minimizes excessive morbidity from bleeding complications or thromboembolic events such as strokes and stent thrombosis.

In the first part of this article, we present the evidence that supports current recommendations for DAPT or warfarin in specific medical conditions. We also address controversies and unanswered questions. The second part of this review focuses on the available data and provides guidance on the optimal care of patients on triple therapy.

Dual Antiplatelet Therapy Following Acute Coronary Syndromes

Table 3 summarizes key randomized trials of DAPT versus ASA alone in several clinical scenarios. The addition of clopidogrel to ASA in patients with nonST‐elevation ACS reduced the risk of adverse ischemic outcomes in the clopidogrel in unstable angina to prevent recurrent events (CURE) trial,15 as well as in its substudy, the PCI‐CURE (patients with ACS who have undergone stenting).17 In the main CURE study, the study groups diverged within the first 30 days after randomization and the benefit of DAPT persisted throughout the 12 months of the study period. DAPT is also superior to ASA in patients with ST‐elevation myocardial infarction (MI) (CLARITYTIMI 28 and COMMIT trials).13, 14 On the basis of these findings, DAPT has become the standard of care for patients with ACS. The American College of Cardiology (ACC)/American Heart Association (AHA)3 and the European Society of Cardiology18 recommend ASA treatment indefinitely for patients with ACS whether or not they underwent PCI. Clopidogrel is recommended for at least 12 months following ACS, especially for patients who receive a coronary stent.

Despite the proven efficacy of DAPT in ACS, about 15% of patients die or experience reinfarction within 30 days of diagnosis.19 The continued risk for thrombotic events could be due to delayed onset of platelet inhibition and to patient heterogeneity in responsiveness to therapy with ASA and/or clopidogrel.20 Consequently, the optimum dose for clopidogrel and ASA following ACS is uncertain. The CURRENT‐OASIS 7 trial evaluated the efficacy and safety of high‐dose clopidogrel (600‐mg loading dose, 150 mg once daily for 7 days, followed by 75 mg/d) versus standard‐dose clopidogrel (300‐mg loading dose, followed by 75 mg/d) and ASA (75‐100 mg versus 300‐325 mg/d) in patients with ACS who were treated medically, with or without stenting.21 In the overall study population as well as in patients who did not receive stenting, there was no significant difference in the combined rate of death from cardiovascular causes, MI, and stroke between patients receiving the high‐dose and the standard‐dose clopidogrel (4.2% vs 4.4%; P = .37) and high‐dose versus low‐dose ASA (4.2% vs 4.4%; P = .47). There were no significant differences in bleeding complications between the two clopidogrel treatment arms or between the high‐dose and low‐dose ASA groups.

The ACC/AHA guidelines recommend ASA, 75‐162 mg/d indefinitely after medical therapy without stenting (class I, level of evidence: A)3 and clopidogrel 75 mg/d for at least 1 month (class IA) and optimally for 1 year (class IB). Clopidogrel monotherapy is appropriate for patients with ACS who are unable to tolerate ASA due to either hypersensitivity or recent significant gastrointestinal bleeding.

As is the case after coronary stenting, interruption of DAPT soon after ACS may subject patients to high recurrence of cardiovascular events, although few data are available to support this observation. Interruption of DAPT due to bleeding complications or surgical procedures more than 1 month after ACS may be reasonable for a patient who did not receive a stent. Clinicians should restart DAPT after the surgical procedure once the bleeding risk becomes acceptable.

Dual Antiplatelet Therapy Following Coronary Stenting

Warfarin After Acute Coronary Syndromes

Warfarin with different international normalized ratio (INR) goals alone or in combination with ASA has been evaluated after ACS. In an early trial, patients with recent (mean interval 27 days) MI were treated with warfarin alone versus placebo.41 Warfarin conferred a relative risk reduction in mortality of 24% (95% CI, 4‐44%; P = .027) at the expense of major bleeding rates of 0.6%/y. In the ASPECT trial,42 moderate to high intensity anticoagulation after MI resulted in a 53% and 40% reduction in the relative risk of reinfarction (annual incidence 2.3% versus 5.1%) and cerebrovascular events (annual incidence 0.7% versus 1.2%), respectively. In the WARIS II43 and ASPECT‐244 trials, moderate intensity warfarin (INR 2.0‐2.5) in combination with low‐dose ASA, compared with ASA alone, reduced the composite occurrence of death or nonfatal reinfarction, as well as recurrent coronary occlusion after ST‐segment elevation MI. High‐intensity warfarin therapy alone (INR 3.0‐4.0 for ASPECT, 2.8‐4.2 for WARISII) reduced ischemic vascular events compared with ASA alone. Not unexpectedly, major bleeding episodes were more common among patients receiving warfarin.

No randomized trials have compared DAPT with warfarin plus ASA for patients with ACS who did not receive stents. The ACC/AHA guidelines recommend warfarin for secondary prevention following ACS (class IIb). High‐intensity warfarin alone (INR 2.5‐3.5) or moderate intensity (INR 2.0‐2.5) with low‐dose ASA (75‐81 mg/d) may be reasonable for patients at high ischemic and low bleeding risk who are intolerant of clopidogrel (level of evidence: B). Fixed dose warfarin is not recommended by the ACC/AHA primarily on the basis of the Coumadin Aspirin Reinfarction Study (CARS) results. This study of patients following MI was discontinued prematurely because of a lack of incremental benefit of reduced‐dose ASA (80 mg/d) combined with either 1 or 3 mg of warfarin daily when compared with 160 mg/d of ASA alone.

Triple Therapy for PCI and Atrial Fibrillation

AF is the most frequent indication (70%) for long‐term therapy with warfarin in patients scheduled for stent placement.10 Clinical trials have shown that warfarin alone is superior to ASA, clopidogrel, or DAPT for prevention of stroke in patients with AF.45, 46 Although warfarin is indispensable in these settings, DAPT is similarly necessary after stent implantation. As triple therapy increases the risk of bleeding, the management of patients with AF and who have received stents remains controversial. This situation is particularly problematic among patients who have received DES and may benefit from extended DAPT. No randomized trials exist to clarify the optimal treatment in these patients; and the feasibility of such studies is questionable. Small, mostly retrospective, studies (Table 4) provide limited guidance on this issue; most studies focus on bleeding events rather than the cardiovascular efficacy of triple therapy. Because of these limitations, cardiovascular societies give IIb recommendation for either triple therapy or the combination of warfarin and clopidogrel in this setting and the level of evidence is C.1, 59, 60

In the largest study to date, Nguyen et al.58 evaluated 800 patients who underwent stenting for ACS and were discharged on warfarin plus single antiplatelet agent or triple therapy as part of the GRACE registry. At 6 months, triple therapy conferred a significant reduction in stroke (0.7% versus 3.4%, P = .02) but not in death or MI. There were no differences in in‐hospital major bleeding events between the two groups (5.9% versus 4.6%; P = .46). Similarly, Sarafoff et al.53 reported no significant differences in the combined endpoint (death, MI, stent thrombosis or stroke) or bleeding complications among patients who received triple therapy or DAPT at 2 years of follow‐up. In contrast, Ruiz‐Nodar et al.52 showed that triple therapy, compared with DAPT, at discharge reduced the incidence of death (17.8% versus 27.8%; adjusted HR = 3.43; 95% CI, 1.617.54; P = .002) and major adverse cardiac events (26.5% versus 38.7%; adjusted HR = 4.9; 95% CI, 2.1711.1; P = .01), without a substantial increase in major bleeding events.

The value of combination antiplatelet therapy to prevent stent thrombosis in these patients is clearer in the study reported by Karjalainen et al.10 This case‐control study of 239 patients receiving warfarin at baseline who underwent PCI evaluated a primary endpoint of death, MI, target‐vessel revascularization, or stent thrombosis and a secondary endpoint of major bleeding and stroke to 12 months of follow‐up. Forty‐eight percent of patients received triple therapy, whereas 15.5% were discharged on DAPT. The remaining patients received warfarin plus a single antiplatelet agent. Stent thrombosis occurred more frequently among patients receiving warfarin plus ASA (15.2%) than among those receiving triple therapy (1.9%). As expected, stroke was more frequent in patients treated with DAPT (8.8%) than among those receiving triple therapy (2.8%). Major bleeding was similar between groups. Therapy with warfarin was an independent predictor of both major bleeding and major cardiac events at 1 year. This observation illustrates that the outcome of PCI in patients on chronic warfarin therapy is unsatisfactory irrespective of the antithrombotic combinations used, highlighting the need for better strategies to treat these patients.

Choice of Therapy and Management of Patients Eligible for Triple Therapy

Current guidelines for PCI do not provide guidance for patients with an indication for triple therapy due to a paucity of published evidence. Several ongoing prospective trials aim to address the management of these patients (AFCAS, ISAR‐TRIPLE). Pending further study, clinicians should consider the embolic risk (CHADS2 score), target INR, type of stent, bleeding risk, and duration of treatment when determining the appropriate antiplatelet/anticoagulant combinations. The CHADS2 score (Table 2) stratifies the risk for stroke among patients with AF,4 while the Outpatient Bleeding Risk Index (OBRI) allows estimation of bleeding risk.12, 61 The OBRI considers age > 65 years, prior stroke, prior gastrointestinal bleeding, and any of four comorbidities (recent MI, anemia, diabetes, or renal insufficiency) in order to stratify patients into three risk groups.61 Patients with three to four risk factors have a high risk of bleeding (23% at 3 months and 48% at 12 months) whereas patients with no risk factors have only a 3% risk of bleeding at 12 months. Unfortunately, advanced age and prior stroke appear in both OBRI and CHADS.

For patients with AF who are at high risk for embolic stroke (>3% per year), we recommend triple therapy for the shortest time possible, followed by warfarin and ASA indefinitely. In case of BMS, it is acceptable to shorten triple therapy duration to 1 month. The optimal duration of triple therapy for patients with DES is uncertain; recommended durations range from 3 months to 1 year.62 If the potential consequences of stent thrombosis are high due to a large amount of myocardium at risk, an extended period of triple therapy might be justified. For patients whose stroke risk is lower (CHADS2 score of 0‐1), the risk for bleeding likely outweighs any benefit from stroke prevention. In this instance, it is reasonable to use DAPT with ASA and clopidogrel for 1 month after BMS and 12 months after DES, followed by ASA, with or without warfarin, indefinitely. In a recently published study, patients with AF and a CHADS2 score of 1 had a yearly stroke risk of 1.25% while taking DAPT63; the risk of major bleeding for triple therapy is 6.1% per year.64

For patients who have a high bleeding risk, BMS are the preferred stent type as the duration of triple therapy might be limited to 4 weeks. To our knowledge, no randomized study has evaluated the outcome of patients with BMS compared with DES who also have an indication for warfarin. Because studies have suggested that clopidogrel is more effective than aspirin in preventing stent thrombosis and in reducing death or MI after coronary stenting,40, 65 warfarin and single antiplatelet therapy with clopidogrel might be a reasonable treatment option in patients with high bleeding risk. The WOEST study (NCT00769938), currently recruiting participants, is the first randomized study specifically designed to test this hypothesis.

Since gastrointestinal bleeding accounts for approximately 30‐40% of hemorrhagic events in patients on combined ASA and anticoagulant therapy, an expert consensus document recommended concomitant treatment with proton pump inhibitors (PPIs) to reduce this risk.66 In contrast, the 2009 Focused Updates of the ACC/AHA/SCAI Guidelines did not recommend the use of PPIs with DAPT in the setting of ACS.2 This is because of studies that show inhibition of platelet activation,67 and potential clinical harm,68 when clopidogrel is combined with certain PPIs that inhibit the CYP2C19 enzyme. However, to date there are no convincing randomized clinical trial data documenting an important clinical drug‐drug interaction. The U.S. Food and Drug Administration (FDA) advises that physicians avoid the use of clopidogrel in patients with impaired CYP2C19 function due to known genetic variation or due to concomitant use of drugs that inhibit CYP2C19 activity. More specifically, the FDA recommends avoiding the use of omeprazole and esomeprazole in patients taking clopidogrel.69

In particular, elderly patients have an increased risk of bleeding while receiving triple therapy. In a study of patients over age 65, 2.5% were hospitalized for bleeding in the first year after PCI, and the use of triple therapy was the strongest predictor of bleeding (more than threefold increase).70 One in five patients suffered death or MI at 1 year after hospitalization for bleeding.70 The basis for poor outcomes after hospitalization for bleeding in this population is multifactorial and may be due to the location of bleeding, associated hypercoagulable state, potential adverse impact of blood transfusion, withdrawal of warfarin therapy in patients with AF and PCI, and the premature discontinuation of DAPT. The use of nonsteroidal anti‐inflammatory drugs (NSAIDs) is common among the elderly and conferred a doubling of bleeding risk.70 Limiting the use of NSAID, the use of low‐dose ASA beyond 30 days after stent implantation, greater use of BMS, and maintaining INR at the lowest possible level (INR of 22.5) will reduce the risk for bleeding.57, 71

New Anticoagulants

Due to the high risk for bleeding with warfarin and the challenges inherent in INR monitoring, researchers have developed several novel anticoagulants whose advantages include fixed daily dosing and no need for monitoring. Dabigatran is a direct oral thrombin inhibitor that is already licensed in Europe and Canada for thromboprophylaxis after hip or knee surgery. It has also been studied in patients with AF. In the RE‐LY trial, patients with AF who received dabigatran 110 mg daily had rates of stroke and systemic embolism that were similar to those with warfarin, as well as lower rates of major hemorrhage.72 The randomized ReDEEM trial, reported at the AHA 2009 Scientific Sessions, was aimed at finding a dosage of dabigatran that achieves a good balance between clinical effectiveness and bleeding risk when combined with aspirin and clopidogrel after acute MI. Dosages ranging from 50 mg twice daily to 150 mg twice daily were all associated with 6‐month rates of bleeding lower than 2%. Hospitalists should view these encouraging results cautiously until the publication of ReDEEM trial results in a peer‐reviewed journal.

A variety of oral Xa antagonists are also being evaluated in patients with AF or ACS. These trials offer insight into triple therapy regimens that include ASA, clopidogrel, and an Xa antagonist. In a recent study of the oral Xa antagonist rivaroxaban, investigators stratified 3491 subjects with ACS according to whether they received concomitant ASA alone or ASA and clopidogrel.73 Subjects receiving ASA plus rivaroxaban had a modest increase in bleeding. Triple therapy, however, increased the composite bleeding rate from 3.5% in the DAPT group to approximately 6‐15% (low‐dose or high‐dose rivaroxaban, respectively). Rivaroxaban is currently under review by the FDA.

These novel agents might eventually replace warfarin for many or most indications for anticoagulation. It is imperative that future research compare the efficacy and risk of bleeding between triple therapy using these new agents and triple therapy with warfarin.

Conclusions

The management of patients on long‐term anticoagulation who require DAPT because of ACS or coronary stenting is challenging. DAPT may safely substitute for warfarin only for patients at low risk for a thromboembolic event (ie, low‐risk AF with low CHADS2 score). Clinicians should not interrupt warfarin in patients at higher risk (ie, intermediate to high‐risk AF, mechanical valves, or recent venous thromboembolism), even in the presence of DAPT. In these patients, triple therapy is the optimal approach following coronary stenting (and possibly during the initial period after ACS without stenting). As this approach confers a fivefold increase in bleeding complications compared with DAPT, careful monitoring of the INR, the addition of PPIs, and the exclusion of elderly patients who are at the highest risk for bleeding complications74 is recommended. The preferred duration of triple therapy after BMS in patients who require long‐term anticoagulation is 1 month, whereas the optimal duration after ACS or DES remains unresolved.

A 71‐year‐old man presented to a hospital with a one week history of fatigue, polyuria, and polydipsia. He also reported pain in his back, hips, and ribs, in addition to frequent falls, intermittent confusion, constipation, and a weight loss of 10 pounds over the last 2 weeks. He denied cough, shortness of breath, chest pain, fever, night sweats, headache, and focal weakness.

Polyuria, which is often associated with polydipsia, can be arbitrarily defined as a urine output exceeding 3 L per day. After excluding osmotic diuresis due to uncontrolled diabetes mellitus, the 3 major causes of polyuria are primary polydipsia, central diabetes insipidus, and nephrogenic diabetes insipidus. Approximately 30% to 50% of cases of central diabetes insipidus are idiopathic; however, primary or secondary brain tumors or infiltrative diseases involving the hypothalamic‐pituitary region need to be considered in this 71‐year‐old man. The most common causes of nephrogenic diabetes insipidus in adults are chronic lithium ingestion, hypokalemia, and hypercalcemia. The patient describes symptoms that can result from severe hypercalcemia, including fatigue, confusion, constipation, polyuria, and polydipsia.

The patient's past medical history included long‐standing, insulin‐requiring type 2 diabetes with associated complications including coronary artery disease, transient ischemic attacks, proliferative retinopathy, peripheral diabetic neuropathy, and nephropathy. Seven years prior to presentation, he received a cadaveric renal transplant that was complicated by BK virus (polyomavirus) nephropathy and secondary hyperparathyroidism. Three years after his transplant surgery, he developed squamous cell carcinoma of the skin, which was treated with local surgical resection. Two years after that, he developed stage I laryngeal cancer of the glottis and received laser surgery, and since then he had been considered disease‐free. He also had a history of hypertension, hypercholesterolemia, osteoporosis, and depression. His medications included aspirin, amlodipine, metoprolol succinate, valsartan, furosemide, simvastatin, insulin, prednisone, sirolimus, and sulfamethoxazole/trimethoprim. He was a married psychiatrist. He denied tobacco use and reported occasional alcohol use.

The prolonged immunosuppressive therapy that is required following organ transplantation carries a markedly increased risk of the subsequent development of malignant tumors, including cancers of the lips and skin, lymphoproliferative disorders, and bronchogenic carcinoma. Primary brain lymphoma resulting in central diabetes insipidus would be unlikely in the absence of headache or focal weakness. An increased risk of lung cancer occurs in recipients of heart and lung transplants, and to a much lesser degree, recipients of kidney transplants. However, metastatic lung cancer is less likely in the absence of respiratory symptoms and smoking history (present in approximately 90% of all lung cancers). Nephrogenic diabetes insipidus, in its mild form, is relatively common in elderly patients with acute or chronic renal insufficiency because of a reduction in maximum urinary concentrating ability. On the other hand, this alone does not explain his remaining symptoms. The instinctive diagnosis in this case is tertiary hyperparathyroidism due to progression of untreated secondary hyperparathyroidism. This causes hypercalcemia, nephrogenic diabetes insipidus, and significant bone pain related to renal osteodystrophy.

On physical exam, the patient appeared chronically ill, but was in no acute distress. He weighed 197.6 pounds and his height was 70.5 inches. He was afebrile with a blood pressure of 146/82 mm Hg, a heart rate of 76 beats per minute, a respiratory rate of 12 breaths per minute, and an oxygen saturation of 97% while breathing room air. He had no generalized lymphadenopathy. Thyroid examination was unremarkable. Examination of the lungs, heart, abdomen, and lower extremities was normal. The rectal examination revealed no masses or prostate nodules; a test for fecal occult blood was negative. He had loss of sensation to light touch and vibration in the feet with absent Achilles deep tendon reflexes. He had a poorly healing surgical wound on his forehead at the site of his prior skin cancer, but no rash or other lesions. There was no joint swelling or erythema. There were tender points over the cervical, thoracic, and lumbar spine; on multiple ribs; and on the pelvic rims.

Perhaps of greatest importance is the lack of lymphadenopathy, organomegaly, or other findings suggestive of diffuse lymphoproliferative disease. His multifocal bone tenderness is concerning for renal osteodystrophy, multiple myeloma, or primary or metastatic bone disease. Cancers in men that metastasize to the bone usually originate from the prostate, lung, kidney, or thyroid gland. In any case, his physical examination did not reveal an enlarged, asymmetric, or nodular prostate or thyroid gland. I recommend a chest film to rule out primary lung malignancy and a basic laboratory evaluation to narrow down the differential diagnosis.

A complete blood count showed a normocytic anemia with a hemoglobin of 8.7 g/dL and a hematocrit of 25%. Other laboratory tests revealed the following values: sodium, 139 mmol/L; potassium, 4.1 mmol/L; blood urea nitrogen, 70 mg/dL; creatinine, 3.5 mg/dL (most recent value 2 months ago was 1.9 mg/dL); total calcium, 13.2 mg/dL (normal range, 8.5‐10.5 mg/dL); phosphate, 5.3 mg/dL; magnesium, 2.5 mg/dL; total bilirubin, 0.5 mg/dL; alkaline phosphatase, 130 U/L; aspartate aminotransferase, 28 U/L; alanine aminotransferase, 19 U/L; albumin, 3.5 g/dL; and lactate dehydrogenase (LDH), 1258 IU/L (normal range, 105‐333 IU/L). A chest radiograph was normal.

The most important laboratory findings are severe hypercalcemia, acute on chronic renal failure, and anemia. Hypercalcemia most commonly results from malignancy or hyperparathyroidism. Less frequently, hypercalcemia may result from sarcoidosis, vitamin D intoxication, or hyperthyroidism. The degree of hypercalcemia is useful diagnostically as hyperparathyroidism commonly results in mild hypercalcemia (serum calcium concentration often below 11 mg/dL). Values above 13 mg/dL are unusual in hyperparathyroidism and are most often due to malignancy. Malignancy is often evident clinically by the time it causes hypercalcemia, and patients with hypercalcemia of malignancy are more often symptomatic than those with hyperparathyroidism. Additionally, localized bone pain and weight loss do not result from hypercalcemia itself and their presence also raises concern for malignancy.

Nonmelanoma skin cancer is the most common cancer occurring after transplantation but does not cause hypercalcemia. Squamous cancers of the head and neck can rarely cause hypercalcemia due to secretion of parathyroid hormone‐related peptide; however, his early‐stage laryngeal cancer and the expected high likelihood of cure argue against this possibility. Osteolytic metastases account for approximately 20% of cases of hypercalcemia of malignancy (Table 1). Prostate cancer rarely results in hypercalcemia since bone metastases are predominantly osteoblastic, whereas metastatic non‐small‐cell lung cancer, thyroid cancer, and kidney cancer more commonly cause hypercalcemia due to osteolytic bone lesions. The total alkaline phosphatase has been traditionally used to assess the osteoblastic component of bone remodeling. Its normal level tends to predict a negative bone scan and supports the likelihood of lytic lesions. Posttransplantation lymphoproliferative disorders, which include a wide range of syndromes, can rarely result in hypercalcemia. I am also worried about the possibility of multiple myeloma as he has the classic triad of hypercalcemia, bone pain, and subacute kidney injury.

The first purpose of the laboratory evaluation is to differentiate parathyroid hormone (PTH)‐mediated hypercalcemia (primary and tertiary hyperparathyroidism) from non‐PTH‐mediated hypercalcemia (primarily malignancy, hyperthyroidism, vitamin D intoxication, and granulomatous disease). The production of vitamin D metabolites, PTH‐related protein, or hypercalcemia from osteolysis in these latter cases results in suppressed PTH levels.

In severe elevations of calcium, the initial goals of treatment are directed toward fluid resuscitation with normal saline and, unless contraindicated, the immediate institution of bisphosphonate therapy. A loop diuretic such as furosemide is often used, but a recent review concluded that there is little evidence to support its use in this setting.

The patient was admitted and treated with intravenous saline and furosemide. Additional laboratory evaluation revealed normal levels of prostate‐specific antigen and thyroid‐stimulating hormone. PTH was 44 pg/mL (the most recent value was 906 pg/mL eight years ago; normal range, 15‐65 pg/mL) and beta‐2 microglobulin (B2M) was 8 mg/L (normal range, 0.8‐2.2 mg/L).

The normal PTH level makes tertiary hyperparathyroidism unlikely and points toward non‐PTH‐related hypercalcemia. An elevated B2M level may occur in patients with chronic graft rejection, renal tubular dysfunction, dialysis‐related amyloidosis, multiple myeloma, or lymphoma. LDH is often elevated in patients with multiple myeloma and lymphoma, but this is not a specific finding. The next laboratory test would be measurement of PTH‐related protein and vitamin D metabolites, as these tests can differentiate between the causes of non‐PTH‐mediated hypercalcemia.

Serum concentrations of the vitamin D metabolites, 25‐hydroxyvitamin D (calcidiol) and 1,25‐dihydroxyvitamin D (calcitriol), were low‐normal. PTH‐related protein was not detected.

The marked elevation of serum LDH and B2M, the relatively suppressed PTH level, combined with undetectable PTH‐related protein suggest multiple myeloma or lymphoma as the likely cause of the patient's clinical presentation. The combination of hypercalcemia and multifocal bone pain makes multiple myeloma the leading diagnosis as hypercalcemia is uncommon in patients with lymphoma, especially at the time of initial clinical presentation.

I would proceed with serum and urine protein electrophoresis (SPEP and UPEP, respectively) and a skeletal survey. If these tests do not confirm the diagnosis of multiple myeloma, I would order a noncontrast computed tomography (CT) of the chest and abdomen and a magnetic resonance imaging (MRI) of the spine. In addition, I would like to monitor his response to the intravenous saline and furosemide.

Forty‐eight hours after presentation, repeat serum calcium and creatinine levels were 11.3 mg/dL and 2.9 mg/dL, respectively. He received salmon calcitonin 4 U/kg every 12 hours. Pamidronate was avoided because of his kidney disease. His confusion resolved. He received intravenous morphine intermittently to alleviate his bone pain.

The SPEP revealed a monoclonal immunoglobulin G (IgG) lambda (light chain) spike representing roughly 3% (200 mg/dL) of total protein. His serum Ig levels were normal. The UPEP was negative for monoclonal immunoglobulin and Bence‐Jones protein. The skeletal survey revealed marked osteopenia, and the bone scan was normal. An MRI of the spine showed multiple round lesions in the cervical, thoracic, and lumbar spine (Figure 1). A CT of the chest showed similar bone lesions in the ribs and pelvis. A CT of the abdomen and chest did not suggest any primary malignancy nor did it show thoracic or abdominal lymphadenopathy.

Figure 1

The lack of lymphadenopathy, splenomegaly, or a visceral mass by CT imaging and physical examination, along with the normal PSA level, exclude most common forms of non‐Hodgkin lymphoma and bone metastasis from solid tumors. In multiple myeloma, cytokines secreted by plasma cells suppress osteoblast activity; therefore, while discrete lytic bone lesions are apparent on skeletal survey, the bone scan is typically normal. The absence of lytic lesions, normal serum immunoglobulin levels, and unremarkable UPEP make multiple myeloma or light‐chain deposition disease a less likely diagnosis.

Typically, primary lymphoma of the bone produces increased uptake with bone scanning. However, because primary lymphoma of the bone is one of the least common primary skeletal malignancies and varies widely in appearance on imaging, confident diagnosis based on imaging alone usually is not possible.

Posttransplantation lymphoproliferative disorder (PTLD) refers to a syndrome that ranges from a self‐limited form of lymphoproliferation to an aggressive disseminated disease. Although the patient is at risk for PTLD, isolated bone involvement has only rarely been reported.

Primary lymphoma of the bone and PTLD are my leading diagnoses in this patient. At this point, I recommend a bone marrow biopsy and biopsy of an easily accessible representative bone lesion with special staining for Epstein‐Barr virus (EBV) (EBV‐encoded RNA [EBER] and latent membrane protein 1 [LMP1]). I expect this test to provide a definitive diagnosis. As 95% of PTLD cases are induced by infection with EBV, information regarding pretransplantation EBV status of the patient and the donor, current EBV status of the patient, and type and intensity of immunosuppression at the time of transplantation would be very helpful to determine their likelihood.

Seventy‐two hours after presentation, his serum calcium level normalized and most of his symptoms improved. Calcitonin was discontinued, and he was maintained on oral hydration. On hospital day number 5, he underwent CT‐guided bone biopsy of the L4 vertebral body, which showed large aggregates of atypical lymphoid cells (Figure 2). These cells were predominantly B‐cells interspersed with small reactive T‐cells. The cells did not express EBV LMP1 or EBER (Figure 3). On hospital day 7, he underwent a bone marrow biopsy, which revealed similar large atypical lymphoid cells that comprised the majority of marrow space (Figure 4). By immunohistochemistry, these cells brightly expressed the pan B cell marker, CD20, and coexpressed bcl‐2. EBER and LMP1 were also negative. A flow cytometry of the bone marrow demonstrated a lambda light chain restriction within the B lymphocytes.

Figure 2

Figure 3

Figure 4

The medical records indicated that the patient had positive pretransplantation EBV serologies. He received a regimen based on sirolimus, mycophenolate mofetil, and prednisone, and did not receive high doses of induction or maintenance immunosuppressive therapy.

The biopsy results establish a diagnosis of diffuse large B‐cell lymphoma of the bone. PTLD is unlikely given his positive pretransplantation EBV status, the late onset of his disease (6 years after transplantation), the isolated bone involvement, and the negative EBER and LMP1 tests.

The patient was discharged and was readmitted 1 week later for induction chemotherapy with etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone [EPOCH]Rituxan (rituximab). Over the next several months, he received 6 cycles of chemotherapy, his hypercalcemia resolved, and his back pain improved.

Commentary

Hypercalcemia is among the most common causes of nephrogenic diabetes insipidus in adults.1 A urinary concentrating defect usually becomes clinically apparent if the plasma calcium concentration is persistently above 11 mg/dL.1 This defect is generally reversible with correction of the hypercalcemia but may persist in patients in whom interstitial nephritis has induced permanent medullary damage. The mechanism by which the concentrating defect occurs is incompletely understood but may be related to impairments in sodium chloride reabsorption in the thick ascending limb and in the ability of antidiuretic hormone to increase water permeability in the collecting tubules.1

Although hypercalcemia in otherwise healthy outpatients is usually due to primary hyperparathyroidism, malignancy is more often responsible for hypercalcemia in hospitalized patients.2 While the signs and symptoms of hypercalcemia are similar regardless of the cause, several clinical features may help distinguish the etiology of hypercalcemia. For instance, the presence of tachycardia, warm skin, thinning of the hair, stare and lid lag, and widened pulse pressure points toward hypercalcemia related to hyperthyroidism. In addition, risk factors and comorbidities guide the diagnostic process. For example, low‐level hypercalcemia in an asymptomatic postmenopausal woman with a normal physical examination suggests primary hyperparathyroidism. In contrast, hypercalcemia in a transplant patient raises concern of malignancy including PTLDs.3, 4

PTLDs are uncommon causes of hypercalcemia but are among the most serious and potentially fatal complications of chronic immunosuppression in transplant recipients.5 They occur in 1.9% of patients after kidney transplantation. The lymphoproliferative disorders occurring after transplantation have different characteristics from those that occur in the general population. Non‐Hodgkin lymphoma accounts for 65% of lymphomas in the general population, compared to 93% in transplant recipients.5, 6 The pathogenesis of PTLD appears to be related to B cell proliferation induced by infection with EBV in the setting of chronic immunosuppression.6 Therefore, there is an increased frequency of PTLD among transplant recipients who are EBV seronegative at the time of operation. These patients, who have no preoperative immunity to EBV, usually acquire the infection from the donor. The level of immunosuppression (intensity and type) influences PTLD rates as well. The disease typically occurs within 12 months after transplantation and in two‐thirds of cases involves extranodal sites. Among these sites, the gastrointestinal tract is involved in about 26% of cases and central nervous system in about 27%. Isolated bone involvement is exceedingly rare.5, 6

Primary lymphoma of the bone is another rare cause of hypercalcemia and accounts for less than 5% of all primary bone tumors.7 The majority of cases are of the non‐Hodgkin's type, characterized as diffuse large B‐cell lymphomas, with peak occurrence in the sixth to seventh decades of life.8 The classic imaging findings of primary lymphoma of the bone are a solitary metadiaphyseal lesion with a layered periosteal reaction on plain radiographs, and corresponding surrounding soft‐tissue mass on MRI.9 Less commonly, primary lymphoma of the bone can be multifocal with diffuse osseous involvement and variable radiographic appearances, as in this case. Most series have reported that the long bones are affected most frequently (especially the femur), although a large series showed equal numbers of cases presenting in the long bones and the spine.712

In order to diagnose primary lymphoma of the bone, it is necessary to exclude nodal or disseminated disease by physical examination and imaging. As plain films are often normal, bone scan or MRI of clinically affected areas is necessary to establish disease extent.9 Distinguishing primary bone lymphomas (PLB) from other bone tumors is important because PLB has a better response to therapy and a better prognosis.10, 11

Randomized trials addressing treatment options for primary lymphoma of bone are not available. Historically, PLB was treated with radiotherapy alone with good local control. However, the rate of distant relapses was relatively high. Currently, chemotherapy with or without radiation therapy is preferred; 5‐year survival is approximately 70% after combined therapy.10, 11

In this case, symptomatic hypercalcemia, a history of transplantation, marked elevation of both LDH and B2M, and a normal PTH level all pointed toward the correct diagnosis of malignancy. Low or normal levels of vitamin D metabolites and PTH‐related protein occur in 20% of patients with hypercalcemia caused by malignancy.13, 14 Diffuse osteopenia on skeletal survey is a prominent feature of renal osteodystrophy or osteoporosis related to chronic corticosteroid use. However, in a patient with diffuse osteopenia and hypercalcemia, clinicians must consider multiple myeloma and other lymphoproliferative disorders; the absence of osteoblastic or osteolytic lesions and a normal alkaline phosphatase do not rule out these diagnoses. When the results of serum and urine protein electrophoresis exclude multiple myeloma, the next investigation should be a bone biopsy to exclude PLB, an uncommon cause of anemia, hypercalcemia, and osteopenic, painful bones.

Key Points for Hospitalists

• 1

  Normal total alkaline phosphatase does not exclude primary or metastatic bone malignancy. While a normal level tends to predict a negative bone scan, further diagnostic tests are needed to exclude bone malignancy if high clinical suspicion exists.

• 2

  The degree of hypercalcemia is useful diagnostically; values above 13 mg/dL are most often due to malignancy.

• 3

  Hypercalcemia in transplant patients deserves special attention due to an increased risk of malignancy, including squamous cancers of the lips and skin, lymphoproliferative disorders, and bronchogenic carcinoma.

• 4

  While rare, consider primary lymphoma of the bone in patients with hypercalcemia and bone pain, along with the more common diagnoses of multiple myeloma and metastatic bone disease.

A 71‐year‐old man presented to a hospital with a one week history of fatigue, polyuria, and polydipsia. He also reported pain in his back, hips, and ribs, in addition to frequent falls, intermittent confusion, constipation, and a weight loss of 10 pounds over the last 2 weeks. He denied cough, shortness of breath, chest pain, fever, night sweats, headache, and focal weakness.

Polyuria, which is often associated with polydipsia, can be arbitrarily defined as a urine output exceeding 3 L per day. After excluding osmotic diuresis due to uncontrolled diabetes mellitus, the 3 major causes of polyuria are primary polydipsia, central diabetes insipidus, and nephrogenic diabetes insipidus. Approximately 30% to 50% of cases of central diabetes insipidus are idiopathic; however, primary or secondary brain tumors or infiltrative diseases involving the hypothalamic‐pituitary region need to be considered in this 71‐year‐old man. The most common causes of nephrogenic diabetes insipidus in adults are chronic lithium ingestion, hypokalemia, and hypercalcemia. The patient describes symptoms that can result from severe hypercalcemia, including fatigue, confusion, constipation, polyuria, and polydipsia.

The patient's past medical history included long‐standing, insulin‐requiring type 2 diabetes with associated complications including coronary artery disease, transient ischemic attacks, proliferative retinopathy, peripheral diabetic neuropathy, and nephropathy. Seven years prior to presentation, he received a cadaveric renal transplant that was complicated by BK virus (polyomavirus) nephropathy and secondary hyperparathyroidism. Three years after his transplant surgery, he developed squamous cell carcinoma of the skin, which was treated with local surgical resection. Two years after that, he developed stage I laryngeal cancer of the glottis and received laser surgery, and since then he had been considered disease‐free. He also had a history of hypertension, hypercholesterolemia, osteoporosis, and depression. His medications included aspirin, amlodipine, metoprolol succinate, valsartan, furosemide, simvastatin, insulin, prednisone, sirolimus, and sulfamethoxazole/trimethoprim. He was a married psychiatrist. He denied tobacco use and reported occasional alcohol use.

The prolonged immunosuppressive therapy that is required following organ transplantation carries a markedly increased risk of the subsequent development of malignant tumors, including cancers of the lips and skin, lymphoproliferative disorders, and bronchogenic carcinoma. Primary brain lymphoma resulting in central diabetes insipidus would be unlikely in the absence of headache or focal weakness. An increased risk of lung cancer occurs in recipients of heart and lung transplants, and to a much lesser degree, recipients of kidney transplants. However, metastatic lung cancer is less likely in the absence of respiratory symptoms and smoking history (present in approximately 90% of all lung cancers). Nephrogenic diabetes insipidus, in its mild form, is relatively common in elderly patients with acute or chronic renal insufficiency because of a reduction in maximum urinary concentrating ability. On the other hand, this alone does not explain his remaining symptoms. The instinctive diagnosis in this case is tertiary hyperparathyroidism due to progression of untreated secondary hyperparathyroidism. This causes hypercalcemia, nephrogenic diabetes insipidus, and significant bone pain related to renal osteodystrophy.

On physical exam, the patient appeared chronically ill, but was in no acute distress. He weighed 197.6 pounds and his height was 70.5 inches. He was afebrile with a blood pressure of 146/82 mm Hg, a heart rate of 76 beats per minute, a respiratory rate of 12 breaths per minute, and an oxygen saturation of 97% while breathing room air. He had no generalized lymphadenopathy. Thyroid examination was unremarkable. Examination of the lungs, heart, abdomen, and lower extremities was normal. The rectal examination revealed no masses or prostate nodules; a test for fecal occult blood was negative. He had loss of sensation to light touch and vibration in the feet with absent Achilles deep tendon reflexes. He had a poorly healing surgical wound on his forehead at the site of his prior skin cancer, but no rash or other lesions. There was no joint swelling or erythema. There were tender points over the cervical, thoracic, and lumbar spine; on multiple ribs; and on the pelvic rims.

Perhaps of greatest importance is the lack of lymphadenopathy, organomegaly, or other findings suggestive of diffuse lymphoproliferative disease. His multifocal bone tenderness is concerning for renal osteodystrophy, multiple myeloma, or primary or metastatic bone disease. Cancers in men that metastasize to the bone usually originate from the prostate, lung, kidney, or thyroid gland. In any case, his physical examination did not reveal an enlarged, asymmetric, or nodular prostate or thyroid gland. I recommend a chest film to rule out primary lung malignancy and a basic laboratory evaluation to narrow down the differential diagnosis.

A complete blood count showed a normocytic anemia with a hemoglobin of 8.7 g/dL and a hematocrit of 25%. Other laboratory tests revealed the following values: sodium, 139 mmol/L; potassium, 4.1 mmol/L; blood urea nitrogen, 70 mg/dL; creatinine, 3.5 mg/dL (most recent value 2 months ago was 1.9 mg/dL); total calcium, 13.2 mg/dL (normal range, 8.5‐10.5 mg/dL); phosphate, 5.3 mg/dL; magnesium, 2.5 mg/dL; total bilirubin, 0.5 mg/dL; alkaline phosphatase, 130 U/L; aspartate aminotransferase, 28 U/L; alanine aminotransferase, 19 U/L; albumin, 3.5 g/dL; and lactate dehydrogenase (LDH), 1258 IU/L (normal range, 105‐333 IU/L). A chest radiograph was normal.

The most important laboratory findings are severe hypercalcemia, acute on chronic renal failure, and anemia. Hypercalcemia most commonly results from malignancy or hyperparathyroidism. Less frequently, hypercalcemia may result from sarcoidosis, vitamin D intoxication, or hyperthyroidism. The degree of hypercalcemia is useful diagnostically as hyperparathyroidism commonly results in mild hypercalcemia (serum calcium concentration often below 11 mg/dL). Values above 13 mg/dL are unusual in hyperparathyroidism and are most often due to malignancy. Malignancy is often evident clinically by the time it causes hypercalcemia, and patients with hypercalcemia of malignancy are more often symptomatic than those with hyperparathyroidism. Additionally, localized bone pain and weight loss do not result from hypercalcemia itself and their presence also raises concern for malignancy.

Nonmelanoma skin cancer is the most common cancer occurring after transplantation but does not cause hypercalcemia. Squamous cancers of the head and neck can rarely cause hypercalcemia due to secretion of parathyroid hormone‐related peptide; however, his early‐stage laryngeal cancer and the expected high likelihood of cure argue against this possibility. Osteolytic metastases account for approximately 20% of cases of hypercalcemia of malignancy (Table 1). Prostate cancer rarely results in hypercalcemia since bone metastases are predominantly osteoblastic, whereas metastatic non‐small‐cell lung cancer, thyroid cancer, and kidney cancer more commonly cause hypercalcemia due to osteolytic bone lesions. The total alkaline phosphatase has been traditionally used to assess the osteoblastic component of bone remodeling. Its normal level tends to predict a negative bone scan and supports the likelihood of lytic lesions. Posttransplantation lymphoproliferative disorders, which include a wide range of syndromes, can rarely result in hypercalcemia. I am also worried about the possibility of multiple myeloma as he has the classic triad of hypercalcemia, bone pain, and subacute kidney injury.

The first purpose of the laboratory evaluation is to differentiate parathyroid hormone (PTH)‐mediated hypercalcemia (primary and tertiary hyperparathyroidism) from non‐PTH‐mediated hypercalcemia (primarily malignancy, hyperthyroidism, vitamin D intoxication, and granulomatous disease). The production of vitamin D metabolites, PTH‐related protein, or hypercalcemia from osteolysis in these latter cases results in suppressed PTH levels.

In severe elevations of calcium, the initial goals of treatment are directed toward fluid resuscitation with normal saline and, unless contraindicated, the immediate institution of bisphosphonate therapy. A loop diuretic such as furosemide is often used, but a recent review concluded that there is little evidence to support its use in this setting.

The patient was admitted and treated with intravenous saline and furosemide. Additional laboratory evaluation revealed normal levels of prostate‐specific antigen and thyroid‐stimulating hormone. PTH was 44 pg/mL (the most recent value was 906 pg/mL eight years ago; normal range, 15‐65 pg/mL) and beta‐2 microglobulin (B2M) was 8 mg/L (normal range, 0.8‐2.2 mg/L).

The normal PTH level makes tertiary hyperparathyroidism unlikely and points toward non‐PTH‐related hypercalcemia. An elevated B2M level may occur in patients with chronic graft rejection, renal tubular dysfunction, dialysis‐related amyloidosis, multiple myeloma, or lymphoma. LDH is often elevated in patients with multiple myeloma and lymphoma, but this is not a specific finding. The next laboratory test would be measurement of PTH‐related protein and vitamin D metabolites, as these tests can differentiate between the causes of non‐PTH‐mediated hypercalcemia.

Serum concentrations of the vitamin D metabolites, 25‐hydroxyvitamin D (calcidiol) and 1,25‐dihydroxyvitamin D (calcitriol), were low‐normal. PTH‐related protein was not detected.

The marked elevation of serum LDH and B2M, the relatively suppressed PTH level, combined with undetectable PTH‐related protein suggest multiple myeloma or lymphoma as the likely cause of the patient's clinical presentation. The combination of hypercalcemia and multifocal bone pain makes multiple myeloma the leading diagnosis as hypercalcemia is uncommon in patients with lymphoma, especially at the time of initial clinical presentation.

I would proceed with serum and urine protein electrophoresis (SPEP and UPEP, respectively) and a skeletal survey. If these tests do not confirm the diagnosis of multiple myeloma, I would order a noncontrast computed tomography (CT) of the chest and abdomen and a magnetic resonance imaging (MRI) of the spine. In addition, I would like to monitor his response to the intravenous saline and furosemide.

Forty‐eight hours after presentation, repeat serum calcium and creatinine levels were 11.3 mg/dL and 2.9 mg/dL, respectively. He received salmon calcitonin 4 U/kg every 12 hours. Pamidronate was avoided because of his kidney disease. His confusion resolved. He received intravenous morphine intermittently to alleviate his bone pain.

The SPEP revealed a monoclonal immunoglobulin G (IgG) lambda (light chain) spike representing roughly 3% (200 mg/dL) of total protein. His serum Ig levels were normal. The UPEP was negative for monoclonal immunoglobulin and Bence‐Jones protein. The skeletal survey revealed marked osteopenia, and the bone scan was normal. An MRI of the spine showed multiple round lesions in the cervical, thoracic, and lumbar spine (Figure 1). A CT of the chest showed similar bone lesions in the ribs and pelvis. A CT of the abdomen and chest did not suggest any primary malignancy nor did it show thoracic or abdominal lymphadenopathy.

Figure 1

The lack of lymphadenopathy, splenomegaly, or a visceral mass by CT imaging and physical examination, along with the normal PSA level, exclude most common forms of non‐Hodgkin lymphoma and bone metastasis from solid tumors. In multiple myeloma, cytokines secreted by plasma cells suppress osteoblast activity; therefore, while discrete lytic bone lesions are apparent on skeletal survey, the bone scan is typically normal. The absence of lytic lesions, normal serum immunoglobulin levels, and unremarkable UPEP make multiple myeloma or light‐chain deposition disease a less likely diagnosis.

Typically, primary lymphoma of the bone produces increased uptake with bone scanning. However, because primary lymphoma of the bone is one of the least common primary skeletal malignancies and varies widely in appearance on imaging, confident diagnosis based on imaging alone usually is not possible.

Posttransplantation lymphoproliferative disorder (PTLD) refers to a syndrome that ranges from a self‐limited form of lymphoproliferation to an aggressive disseminated disease. Although the patient is at risk for PTLD, isolated bone involvement has only rarely been reported.

Primary lymphoma of the bone and PTLD are my leading diagnoses in this patient. At this point, I recommend a bone marrow biopsy and biopsy of an easily accessible representative bone lesion with special staining for Epstein‐Barr virus (EBV) (EBV‐encoded RNA [EBER] and latent membrane protein 1 [LMP1]). I expect this test to provide a definitive diagnosis. As 95% of PTLD cases are induced by infection with EBV, information regarding pretransplantation EBV status of the patient and the donor, current EBV status of the patient, and type and intensity of immunosuppression at the time of transplantation would be very helpful to determine their likelihood.

Seventy‐two hours after presentation, his serum calcium level normalized and most of his symptoms improved. Calcitonin was discontinued, and he was maintained on oral hydration. On hospital day number 5, he underwent CT‐guided bone biopsy of the L4 vertebral body, which showed large aggregates of atypical lymphoid cells (Figure 2). These cells were predominantly B‐cells interspersed with small reactive T‐cells. The cells did not express EBV LMP1 or EBER (Figure 3). On hospital day 7, he underwent a bone marrow biopsy, which revealed similar large atypical lymphoid cells that comprised the majority of marrow space (Figure 4). By immunohistochemistry, these cells brightly expressed the pan B cell marker, CD20, and coexpressed bcl‐2. EBER and LMP1 were also negative. A flow cytometry of the bone marrow demonstrated a lambda light chain restriction within the B lymphocytes.

Figure 2

Figure 3

Figure 4

The medical records indicated that the patient had positive pretransplantation EBV serologies. He received a regimen based on sirolimus, mycophenolate mofetil, and prednisone, and did not receive high doses of induction or maintenance immunosuppressive therapy.

The biopsy results establish a diagnosis of diffuse large B‐cell lymphoma of the bone. PTLD is unlikely given his positive pretransplantation EBV status, the late onset of his disease (6 years after transplantation), the isolated bone involvement, and the negative EBER and LMP1 tests.

The patient was discharged and was readmitted 1 week later for induction chemotherapy with etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone [EPOCH]Rituxan (rituximab). Over the next several months, he received 6 cycles of chemotherapy, his hypercalcemia resolved, and his back pain improved.

Commentary

Hypercalcemia is among the most common causes of nephrogenic diabetes insipidus in adults.1 A urinary concentrating defect usually becomes clinically apparent if the plasma calcium concentration is persistently above 11 mg/dL.1 This defect is generally reversible with correction of the hypercalcemia but may persist in patients in whom interstitial nephritis has induced permanent medullary damage. The mechanism by which the concentrating defect occurs is incompletely understood but may be related to impairments in sodium chloride reabsorption in the thick ascending limb and in the ability of antidiuretic hormone to increase water permeability in the collecting tubules.1

Although hypercalcemia in otherwise healthy outpatients is usually due to primary hyperparathyroidism, malignancy is more often responsible for hypercalcemia in hospitalized patients.2 While the signs and symptoms of hypercalcemia are similar regardless of the cause, several clinical features may help distinguish the etiology of hypercalcemia. For instance, the presence of tachycardia, warm skin, thinning of the hair, stare and lid lag, and widened pulse pressure points toward hypercalcemia related to hyperthyroidism. In addition, risk factors and comorbidities guide the diagnostic process. For example, low‐level hypercalcemia in an asymptomatic postmenopausal woman with a normal physical examination suggests primary hyperparathyroidism. In contrast, hypercalcemia in a transplant patient raises concern of malignancy including PTLDs.3, 4

PTLDs are uncommon causes of hypercalcemia but are among the most serious and potentially fatal complications of chronic immunosuppression in transplant recipients.5 They occur in 1.9% of patients after kidney transplantation. The lymphoproliferative disorders occurring after transplantation have different characteristics from those that occur in the general population. Non‐Hodgkin lymphoma accounts for 65% of lymphomas in the general population, compared to 93% in transplant recipients.5, 6 The pathogenesis of PTLD appears to be related to B cell proliferation induced by infection with EBV in the setting of chronic immunosuppression.6 Therefore, there is an increased frequency of PTLD among transplant recipients who are EBV seronegative at the time of operation. These patients, who have no preoperative immunity to EBV, usually acquire the infection from the donor. The level of immunosuppression (intensity and type) influences PTLD rates as well. The disease typically occurs within 12 months after transplantation and in two‐thirds of cases involves extranodal sites. Among these sites, the gastrointestinal tract is involved in about 26% of cases and central nervous system in about 27%. Isolated bone involvement is exceedingly rare.5, 6

Primary lymphoma of the bone is another rare cause of hypercalcemia and accounts for less than 5% of all primary bone tumors.7 The majority of cases are of the non‐Hodgkin's type, characterized as diffuse large B‐cell lymphomas, with peak occurrence in the sixth to seventh decades of life.8 The classic imaging findings of primary lymphoma of the bone are a solitary metadiaphyseal lesion with a layered periosteal reaction on plain radiographs, and corresponding surrounding soft‐tissue mass on MRI.9 Less commonly, primary lymphoma of the bone can be multifocal with diffuse osseous involvement and variable radiographic appearances, as in this case. Most series have reported that the long bones are affected most frequently (especially the femur), although a large series showed equal numbers of cases presenting in the long bones and the spine.712

In order to diagnose primary lymphoma of the bone, it is necessary to exclude nodal or disseminated disease by physical examination and imaging. As plain films are often normal, bone scan or MRI of clinically affected areas is necessary to establish disease extent.9 Distinguishing primary bone lymphomas (PLB) from other bone tumors is important because PLB has a better response to therapy and a better prognosis.10, 11

Randomized trials addressing treatment options for primary lymphoma of bone are not available. Historically, PLB was treated with radiotherapy alone with good local control. However, the rate of distant relapses was relatively high. Currently, chemotherapy with or without radiation therapy is preferred; 5‐year survival is approximately 70% after combined therapy.10, 11

In this case, symptomatic hypercalcemia, a history of transplantation, marked elevation of both LDH and B2M, and a normal PTH level all pointed toward the correct diagnosis of malignancy. Low or normal levels of vitamin D metabolites and PTH‐related protein occur in 20% of patients with hypercalcemia caused by malignancy.13, 14 Diffuse osteopenia on skeletal survey is a prominent feature of renal osteodystrophy or osteoporosis related to chronic corticosteroid use. However, in a patient with diffuse osteopenia and hypercalcemia, clinicians must consider multiple myeloma and other lymphoproliferative disorders; the absence of osteoblastic or osteolytic lesions and a normal alkaline phosphatase do not rule out these diagnoses. When the results of serum and urine protein electrophoresis exclude multiple myeloma, the next investigation should be a bone biopsy to exclude PLB, an uncommon cause of anemia, hypercalcemia, and osteopenic, painful bones.

Key Points for Hospitalists

• 1

  Normal total alkaline phosphatase does not exclude primary or metastatic bone malignancy. While a normal level tends to predict a negative bone scan, further diagnostic tests are needed to exclude bone malignancy if high clinical suspicion exists.

• 2

  The degree of hypercalcemia is useful diagnostically; values above 13 mg/dL are most often due to malignancy.

• 3

  Hypercalcemia in transplant patients deserves special attention due to an increased risk of malignancy, including squamous cancers of the lips and skin, lymphoproliferative disorders, and bronchogenic carcinoma.

• 4

  While rare, consider primary lymphoma of the bone in patients with hypercalcemia and bone pain, along with the more common diagnoses of multiple myeloma and metastatic bone disease.

A 71‐year‐old man presented to a hospital with a one week history of fatigue, polyuria, and polydipsia. He also reported pain in his back, hips, and ribs, in addition to frequent falls, intermittent confusion, constipation, and a weight loss of 10 pounds over the last 2 weeks. He denied cough, shortness of breath, chest pain, fever, night sweats, headache, and focal weakness.

Polyuria, which is often associated with polydipsia, can be arbitrarily defined as a urine output exceeding 3 L per day. After excluding osmotic diuresis due to uncontrolled diabetes mellitus, the 3 major causes of polyuria are primary polydipsia, central diabetes insipidus, and nephrogenic diabetes insipidus. Approximately 30% to 50% of cases of central diabetes insipidus are idiopathic; however, primary or secondary brain tumors or infiltrative diseases involving the hypothalamic‐pituitary region need to be considered in this 71‐year‐old man. The most common causes of nephrogenic diabetes insipidus in adults are chronic lithium ingestion, hypokalemia, and hypercalcemia. The patient describes symptoms that can result from severe hypercalcemia, including fatigue, confusion, constipation, polyuria, and polydipsia.

The patient's past medical history included long‐standing, insulin‐requiring type 2 diabetes with associated complications including coronary artery disease, transient ischemic attacks, proliferative retinopathy, peripheral diabetic neuropathy, and nephropathy. Seven years prior to presentation, he received a cadaveric renal transplant that was complicated by BK virus (polyomavirus) nephropathy and secondary hyperparathyroidism. Three years after his transplant surgery, he developed squamous cell carcinoma of the skin, which was treated with local surgical resection. Two years after that, he developed stage I laryngeal cancer of the glottis and received laser surgery, and since then he had been considered disease‐free. He also had a history of hypertension, hypercholesterolemia, osteoporosis, and depression. His medications included aspirin, amlodipine, metoprolol succinate, valsartan, furosemide, simvastatin, insulin, prednisone, sirolimus, and sulfamethoxazole/trimethoprim. He was a married psychiatrist. He denied tobacco use and reported occasional alcohol use.

The prolonged immunosuppressive therapy that is required following organ transplantation carries a markedly increased risk of the subsequent development of malignant tumors, including cancers of the lips and skin, lymphoproliferative disorders, and bronchogenic carcinoma. Primary brain lymphoma resulting in central diabetes insipidus would be unlikely in the absence of headache or focal weakness. An increased risk of lung cancer occurs in recipients of heart and lung transplants, and to a much lesser degree, recipients of kidney transplants. However, metastatic lung cancer is less likely in the absence of respiratory symptoms and smoking history (present in approximately 90% of all lung cancers). Nephrogenic diabetes insipidus, in its mild form, is relatively common in elderly patients with acute or chronic renal insufficiency because of a reduction in maximum urinary concentrating ability. On the other hand, this alone does not explain his remaining symptoms. The instinctive diagnosis in this case is tertiary hyperparathyroidism due to progression of untreated secondary hyperparathyroidism. This causes hypercalcemia, nephrogenic diabetes insipidus, and significant bone pain related to renal osteodystrophy.

On physical exam, the patient appeared chronically ill, but was in no acute distress. He weighed 197.6 pounds and his height was 70.5 inches. He was afebrile with a blood pressure of 146/82 mm Hg, a heart rate of 76 beats per minute, a respiratory rate of 12 breaths per minute, and an oxygen saturation of 97% while breathing room air. He had no generalized lymphadenopathy. Thyroid examination was unremarkable. Examination of the lungs, heart, abdomen, and lower extremities was normal. The rectal examination revealed no masses or prostate nodules; a test for fecal occult blood was negative. He had loss of sensation to light touch and vibration in the feet with absent Achilles deep tendon reflexes. He had a poorly healing surgical wound on his forehead at the site of his prior skin cancer, but no rash or other lesions. There was no joint swelling or erythema. There were tender points over the cervical, thoracic, and lumbar spine; on multiple ribs; and on the pelvic rims.

Perhaps of greatest importance is the lack of lymphadenopathy, organomegaly, or other findings suggestive of diffuse lymphoproliferative disease. His multifocal bone tenderness is concerning for renal osteodystrophy, multiple myeloma, or primary or metastatic bone disease. Cancers in men that metastasize to the bone usually originate from the prostate, lung, kidney, or thyroid gland. In any case, his physical examination did not reveal an enlarged, asymmetric, or nodular prostate or thyroid gland. I recommend a chest film to rule out primary lung malignancy and a basic laboratory evaluation to narrow down the differential diagnosis.

A complete blood count showed a normocytic anemia with a hemoglobin of 8.7 g/dL and a hematocrit of 25%. Other laboratory tests revealed the following values: sodium, 139 mmol/L; potassium, 4.1 mmol/L; blood urea nitrogen, 70 mg/dL; creatinine, 3.5 mg/dL (most recent value 2 months ago was 1.9 mg/dL); total calcium, 13.2 mg/dL (normal range, 8.5‐10.5 mg/dL); phosphate, 5.3 mg/dL; magnesium, 2.5 mg/dL; total bilirubin, 0.5 mg/dL; alkaline phosphatase, 130 U/L; aspartate aminotransferase, 28 U/L; alanine aminotransferase, 19 U/L; albumin, 3.5 g/dL; and lactate dehydrogenase (LDH), 1258 IU/L (normal range, 105‐333 IU/L). A chest radiograph was normal.

The most important laboratory findings are severe hypercalcemia, acute on chronic renal failure, and anemia. Hypercalcemia most commonly results from malignancy or hyperparathyroidism. Less frequently, hypercalcemia may result from sarcoidosis, vitamin D intoxication, or hyperthyroidism. The degree of hypercalcemia is useful diagnostically as hyperparathyroidism commonly results in mild hypercalcemia (serum calcium concentration often below 11 mg/dL). Values above 13 mg/dL are unusual in hyperparathyroidism and are most often due to malignancy. Malignancy is often evident clinically by the time it causes hypercalcemia, and patients with hypercalcemia of malignancy are more often symptomatic than those with hyperparathyroidism. Additionally, localized bone pain and weight loss do not result from hypercalcemia itself and their presence also raises concern for malignancy.

Nonmelanoma skin cancer is the most common cancer occurring after transplantation but does not cause hypercalcemia. Squamous cancers of the head and neck can rarely cause hypercalcemia due to secretion of parathyroid hormone‐related peptide; however, his early‐stage laryngeal cancer and the expected high likelihood of cure argue against this possibility. Osteolytic metastases account for approximately 20% of cases of hypercalcemia of malignancy (Table 1). Prostate cancer rarely results in hypercalcemia since bone metastases are predominantly osteoblastic, whereas metastatic non‐small‐cell lung cancer, thyroid cancer, and kidney cancer more commonly cause hypercalcemia due to osteolytic bone lesions. The total alkaline phosphatase has been traditionally used to assess the osteoblastic component of bone remodeling. Its normal level tends to predict a negative bone scan and supports the likelihood of lytic lesions. Posttransplantation lymphoproliferative disorders, which include a wide range of syndromes, can rarely result in hypercalcemia. I am also worried about the possibility of multiple myeloma as he has the classic triad of hypercalcemia, bone pain, and subacute kidney injury.

The first purpose of the laboratory evaluation is to differentiate parathyroid hormone (PTH)‐mediated hypercalcemia (primary and tertiary hyperparathyroidism) from non‐PTH‐mediated hypercalcemia (primarily malignancy, hyperthyroidism, vitamin D intoxication, and granulomatous disease). The production of vitamin D metabolites, PTH‐related protein, or hypercalcemia from osteolysis in these latter cases results in suppressed PTH levels.

In severe elevations of calcium, the initial goals of treatment are directed toward fluid resuscitation with normal saline and, unless contraindicated, the immediate institution of bisphosphonate therapy. A loop diuretic such as furosemide is often used, but a recent review concluded that there is little evidence to support its use in this setting.

The patient was admitted and treated with intravenous saline and furosemide. Additional laboratory evaluation revealed normal levels of prostate‐specific antigen and thyroid‐stimulating hormone. PTH was 44 pg/mL (the most recent value was 906 pg/mL eight years ago; normal range, 15‐65 pg/mL) and beta‐2 microglobulin (B2M) was 8 mg/L (normal range, 0.8‐2.2 mg/L).

The normal PTH level makes tertiary hyperparathyroidism unlikely and points toward non‐PTH‐related hypercalcemia. An elevated B2M level may occur in patients with chronic graft rejection, renal tubular dysfunction, dialysis‐related amyloidosis, multiple myeloma, or lymphoma. LDH is often elevated in patients with multiple myeloma and lymphoma, but this is not a specific finding. The next laboratory test would be measurement of PTH‐related protein and vitamin D metabolites, as these tests can differentiate between the causes of non‐PTH‐mediated hypercalcemia.

Serum concentrations of the vitamin D metabolites, 25‐hydroxyvitamin D (calcidiol) and 1,25‐dihydroxyvitamin D (calcitriol), were low‐normal. PTH‐related protein was not detected.

The marked elevation of serum LDH and B2M, the relatively suppressed PTH level, combined with undetectable PTH‐related protein suggest multiple myeloma or lymphoma as the likely cause of the patient's clinical presentation. The combination of hypercalcemia and multifocal bone pain makes multiple myeloma the leading diagnosis as hypercalcemia is uncommon in patients with lymphoma, especially at the time of initial clinical presentation.

I would proceed with serum and urine protein electrophoresis (SPEP and UPEP, respectively) and a skeletal survey. If these tests do not confirm the diagnosis of multiple myeloma, I would order a noncontrast computed tomography (CT) of the chest and abdomen and a magnetic resonance imaging (MRI) of the spine. In addition, I would like to monitor his response to the intravenous saline and furosemide.

Forty‐eight hours after presentation, repeat serum calcium and creatinine levels were 11.3 mg/dL and 2.9 mg/dL, respectively. He received salmon calcitonin 4 U/kg every 12 hours. Pamidronate was avoided because of his kidney disease. His confusion resolved. He received intravenous morphine intermittently to alleviate his bone pain.

The SPEP revealed a monoclonal immunoglobulin G (IgG) lambda (light chain) spike representing roughly 3% (200 mg/dL) of total protein. His serum Ig levels were normal. The UPEP was negative for monoclonal immunoglobulin and Bence‐Jones protein. The skeletal survey revealed marked osteopenia, and the bone scan was normal. An MRI of the spine showed multiple round lesions in the cervical, thoracic, and lumbar spine (Figure 1). A CT of the chest showed similar bone lesions in the ribs and pelvis. A CT of the abdomen and chest did not suggest any primary malignancy nor did it show thoracic or abdominal lymphadenopathy.

Figure 1

The lack of lymphadenopathy, splenomegaly, or a visceral mass by CT imaging and physical examination, along with the normal PSA level, exclude most common forms of non‐Hodgkin lymphoma and bone metastasis from solid tumors. In multiple myeloma, cytokines secreted by plasma cells suppress osteoblast activity; therefore, while discrete lytic bone lesions are apparent on skeletal survey, the bone scan is typically normal. The absence of lytic lesions, normal serum immunoglobulin levels, and unremarkable UPEP make multiple myeloma or light‐chain deposition disease a less likely diagnosis.

Typically, primary lymphoma of the bone produces increased uptake with bone scanning. However, because primary lymphoma of the bone is one of the least common primary skeletal malignancies and varies widely in appearance on imaging, confident diagnosis based on imaging alone usually is not possible.

Posttransplantation lymphoproliferative disorder (PTLD) refers to a syndrome that ranges from a self‐limited form of lymphoproliferation to an aggressive disseminated disease. Although the patient is at risk for PTLD, isolated bone involvement has only rarely been reported.

Primary lymphoma of the bone and PTLD are my leading diagnoses in this patient. At this point, I recommend a bone marrow biopsy and biopsy of an easily accessible representative bone lesion with special staining for Epstein‐Barr virus (EBV) (EBV‐encoded RNA [EBER] and latent membrane protein 1 [LMP1]). I expect this test to provide a definitive diagnosis. As 95% of PTLD cases are induced by infection with EBV, information regarding pretransplantation EBV status of the patient and the donor, current EBV status of the patient, and type and intensity of immunosuppression at the time of transplantation would be very helpful to determine their likelihood.

Seventy‐two hours after presentation, his serum calcium level normalized and most of his symptoms improved. Calcitonin was discontinued, and he was maintained on oral hydration. On hospital day number 5, he underwent CT‐guided bone biopsy of the L4 vertebral body, which showed large aggregates of atypical lymphoid cells (Figure 2). These cells were predominantly B‐cells interspersed with small reactive T‐cells. The cells did not express EBV LMP1 or EBER (Figure 3). On hospital day 7, he underwent a bone marrow biopsy, which revealed similar large atypical lymphoid cells that comprised the majority of marrow space (Figure 4). By immunohistochemistry, these cells brightly expressed the pan B cell marker, CD20, and coexpressed bcl‐2. EBER and LMP1 were also negative. A flow cytometry of the bone marrow demonstrated a lambda light chain restriction within the B lymphocytes.

Figure 2

Figure 3

Figure 4

The medical records indicated that the patient had positive pretransplantation EBV serologies. He received a regimen based on sirolimus, mycophenolate mofetil, and prednisone, and did not receive high doses of induction or maintenance immunosuppressive therapy.

The biopsy results establish a diagnosis of diffuse large B‐cell lymphoma of the bone. PTLD is unlikely given his positive pretransplantation EBV status, the late onset of his disease (6 years after transplantation), the isolated bone involvement, and the negative EBER and LMP1 tests.

The patient was discharged and was readmitted 1 week later for induction chemotherapy with etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone [EPOCH]Rituxan (rituximab). Over the next several months, he received 6 cycles of chemotherapy, his hypercalcemia resolved, and his back pain improved.

Commentary

Hypercalcemia is among the most common causes of nephrogenic diabetes insipidus in adults.1 A urinary concentrating defect usually becomes clinically apparent if the plasma calcium concentration is persistently above 11 mg/dL.1 This defect is generally reversible with correction of the hypercalcemia but may persist in patients in whom interstitial nephritis has induced permanent medullary damage. The mechanism by which the concentrating defect occurs is incompletely understood but may be related to impairments in sodium chloride reabsorption in the thick ascending limb and in the ability of antidiuretic hormone to increase water permeability in the collecting tubules.1

Although hypercalcemia in otherwise healthy outpatients is usually due to primary hyperparathyroidism, malignancy is more often responsible for hypercalcemia in hospitalized patients.2 While the signs and symptoms of hypercalcemia are similar regardless of the cause, several clinical features may help distinguish the etiology of hypercalcemia. For instance, the presence of tachycardia, warm skin, thinning of the hair, stare and lid lag, and widened pulse pressure points toward hypercalcemia related to hyperthyroidism. In addition, risk factors and comorbidities guide the diagnostic process. For example, low‐level hypercalcemia in an asymptomatic postmenopausal woman with a normal physical examination suggests primary hyperparathyroidism. In contrast, hypercalcemia in a transplant patient raises concern of malignancy including PTLDs.3, 4

PTLDs are uncommon causes of hypercalcemia but are among the most serious and potentially fatal complications of chronic immunosuppression in transplant recipients.5 They occur in 1.9% of patients after kidney transplantation. The lymphoproliferative disorders occurring after transplantation have different characteristics from those that occur in the general population. Non‐Hodgkin lymphoma accounts for 65% of lymphomas in the general population, compared to 93% in transplant recipients.5, 6 The pathogenesis of PTLD appears to be related to B cell proliferation induced by infection with EBV in the setting of chronic immunosuppression.6 Therefore, there is an increased frequency of PTLD among transplant recipients who are EBV seronegative at the time of operation. These patients, who have no preoperative immunity to EBV, usually acquire the infection from the donor. The level of immunosuppression (intensity and type) influences PTLD rates as well. The disease typically occurs within 12 months after transplantation and in two‐thirds of cases involves extranodal sites. Among these sites, the gastrointestinal tract is involved in about 26% of cases and central nervous system in about 27%. Isolated bone involvement is exceedingly rare.5, 6

Primary lymphoma of the bone is another rare cause of hypercalcemia and accounts for less than 5% of all primary bone tumors.7 The majority of cases are of the non‐Hodgkin's type, characterized as diffuse large B‐cell lymphomas, with peak occurrence in the sixth to seventh decades of life.8 The classic imaging findings of primary lymphoma of the bone are a solitary metadiaphyseal lesion with a layered periosteal reaction on plain radiographs, and corresponding surrounding soft‐tissue mass on MRI.9 Less commonly, primary lymphoma of the bone can be multifocal with diffuse osseous involvement and variable radiographic appearances, as in this case. Most series have reported that the long bones are affected most frequently (especially the femur), although a large series showed equal numbers of cases presenting in the long bones and the spine.712

In order to diagnose primary lymphoma of the bone, it is necessary to exclude nodal or disseminated disease by physical examination and imaging. As plain films are often normal, bone scan or MRI of clinically affected areas is necessary to establish disease extent.9 Distinguishing primary bone lymphomas (PLB) from other bone tumors is important because PLB has a better response to therapy and a better prognosis.10, 11

Randomized trials addressing treatment options for primary lymphoma of bone are not available. Historically, PLB was treated with radiotherapy alone with good local control. However, the rate of distant relapses was relatively high. Currently, chemotherapy with or without radiation therapy is preferred; 5‐year survival is approximately 70% after combined therapy.10, 11

In this case, symptomatic hypercalcemia, a history of transplantation, marked elevation of both LDH and B2M, and a normal PTH level all pointed toward the correct diagnosis of malignancy. Low or normal levels of vitamin D metabolites and PTH‐related protein occur in 20% of patients with hypercalcemia caused by malignancy.13, 14 Diffuse osteopenia on skeletal survey is a prominent feature of renal osteodystrophy or osteoporosis related to chronic corticosteroid use. However, in a patient with diffuse osteopenia and hypercalcemia, clinicians must consider multiple myeloma and other lymphoproliferative disorders; the absence of osteoblastic or osteolytic lesions and a normal alkaline phosphatase do not rule out these diagnoses. When the results of serum and urine protein electrophoresis exclude multiple myeloma, the next investigation should be a bone biopsy to exclude PLB, an uncommon cause of anemia, hypercalcemia, and osteopenic, painful bones.

Key Points for Hospitalists

• 1

  Normal total alkaline phosphatase does not exclude primary or metastatic bone malignancy. While a normal level tends to predict a negative bone scan, further diagnostic tests are needed to exclude bone malignancy if high clinical suspicion exists.

• 2

  The degree of hypercalcemia is useful diagnostically; values above 13 mg/dL are most often due to malignancy.

• 3

  Hypercalcemia in transplant patients deserves special attention due to an increased risk of malignancy, including squamous cancers of the lips and skin, lymphoproliferative disorders, and bronchogenic carcinoma.

• 4

  While rare, consider primary lymphoma of the bone in patients with hypercalcemia and bone pain, along with the more common diagnoses of multiple myeloma and metastatic bone disease.