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What’s best when a patient doesn’t respond to the maximum dose of an antidepressant?
FIRST, CONSIDER POSSIBLE CAUSES OF THE INADEQUATE RESPONSE, then weigh treatment options in light of the characteristics of the individual patient and therapy. When managing a patient with nonpsychotic depression and inadequate response to the maximum dose of a single antidepressant, the physician should first identify factors that may contribute to the poor response, such as suboptimal dosage resulting from nonadherence, inadequate duration of therapy, and comorbid medical and psychiatric conditions (strength of recommendation [SOR]: C, expert opinion).
The literature supports several treatment alternatives, including augmentation with cognitive therapy, switch therapy, and combination-augmentation therapy; not enough studies exist to recommend the best treatment. All options reviewed produced a 20% to 50% remission rate (SOR: B, systematic reviews and randomized controlled trials [RCTs]).
Physicians should consider the patient’s clinical history and preferences, along with drug toxicity, potential drug interactions, and cost when making treatment decisions (SOR: C, expert opinion).
Evidence summary
A recent study randomized 158 patients who didn’t respond to antidepressant therapy to either cognitive therapy with clinical management or clinical management alone.1 The cognitive therapy group had a 29% cumulative relapse rate at 68 weeks, compared with 47% in the clinical management control group (number needed to treat [NNT]=6).
A crossover RCT compared 12 weeks of the cognitive behavioral analysis system of psychotherapy (CBASP) in 61 patients who had failed to respond to a 12-week course of nefazodone with 12 weeks of nefazodone treatment in 79 patients who hadn’t responded to 12 weeks of CBASP.2 Remission rates were comparable in the 2 crossover groups (28% for nefazodone vs 25% for CBASP; P=.92).
Drugs may produce a faster response
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial compared augmentation with as many as 16 sessions of cognitive therapy with pharmacologic augmentation and switch strategy among 65 patients who had failed to respond to 14 weeks of citalopram.3
The investigators concluded that augmentation with cognitive therapy or pharmacologic therapy was equally effective, but pharmacologic augmentation produced a more rapid response (mean time to first remission for cognitive therapy=53.3 days, compared with 40.1 days for pharmacologic therapy; P=.022). Patients who were switched to cognitive therapy had similar outcomes to patients who were switched to alternative antidepressants (remission rates=25% and 27.9%, respectively; P=.6881), but reported fewer adverse effects (0% vs 48%).
When an SSRI fails…
A recent systematic review of 8 RCTs (including STAR*D) and 23 open studies concluded that after a first failure of a selective serotonin reuptake inhibitor (SSRI), any switch within or between classes of antidepressant is legitimate and equally effective.4
Switching within the same class of antidepressant. The STAR*D study, an unblinded RCT, reported that patients (N=238; median age 41 years) who were switched to sertraline (as much as 200 mg per day for 14 weeks) when they didn’t tolerate or respond adequately to citalopram had remission rates of 17.6% on the Hamilton Rating Scale for Depression (HAM-D) and 26.6% on the Quick Inventory of Depressive Symptomatology (QIDS).5
Switching to a different class of antidepressant. In a multisite study, outpatients who failed to respond to 12-week, double-blind treatment with either sertraline (n=117) or imipramine (n=51) were randomized to an additional 12 weeks of double-blinded treatment with the alternate medication. Investigators reported a 60% response rate in the sertraline switch group and a 44% response rate in the imipramine switch group.6
In the STAR*D study, patients who didn’t tolerate or failed to respond to as many as 12 weeks of citalopram were switched to sustained-release (SR) bupropion, sertraline, or extended-release (ER) venlafaxine for as long as 14 weeks.5 The bupropion-SR switch group (n=239, up to 400 mg per day) had remission rates of 21.3% (HAM-D) and 25.5% (QIDS); the sertraline switch group (n=238, up to 200 mg per day) had remission rates of 17.6% (HAM-D) and 26.6% (QIDS); and the venlafaxine-ER switch group (n=250, up to 375 mg per day) had remission rates of 24.8% (HAM-D) and 25% (QIDS). There were no clinically or statistically significant differences among the groups.
Response declines with multiple switches
Patients who didn’t respond to this treatment arm and were switched again to either mirtazapine (n=114, as much as 60 mg per day) or nortriptyline (n=121, as much as 200 mg per day) had a much less favorable response (mirtazapine 12.3% vs nortriptyline 19.8%; NNT nortriptyline-mirtazapine=13).7
Patients who failed to respond to this treatment arm were randomized to either tranylcypromine (n=58, mean 36.9 mg per day) or venlafaxine plus mirtazapine (n=51, mean 210.3 and 35.7 mg per day, respectively). Both groups had low remission rates (tranylcypromine 6.9%, venlafaxine plus mirtazapine 13.7%; NNT venlafaxine plus mirtazapine-tranylcypromine=15).8
Lithium and T3 augmentation both work
A 1999 systematic review of 9 double-blind RCTs (N=234) reported that patients treated with lithium augmentation (250-1200 mg per day, or a serum level of ≥0.5 mmol/L for ≥2 weeks) had a 45% improvement in depressive symptoms (HAM-D), whereas the placebo group showed 18% improvement (NNT=3.7; 95% confidence interval [CI], 2.6-6.6).9 An updated meta-analysis of 10 RCTs confirmed the efficacy of lithium augmentation compared with placebo (41% vs 14.4% improvement; NNT=5).10
Recently, the STAR*D study (N=142) reported that augmentation with either lithium or triiodothyronine (T3) after 2 antidepressant failures was equally effective (lithium response 15.9%; T3 response 24.7%; NNT T3-lithium=11; P=.43). However, lithium was more often associated with side effects (number needed to harm [NNH]=7; P=.045).11
Bupropion and buspirone augmentation are comparable
An unblinded RCT found that patients who failed to respond to citalopram responded when augmented with either bupropion-SR or buspirone.12 After 8 weeks of treatment, the bupropion-SR group (n=565, as much as 400 mg per day) had remission rates of 29.7% (HAM-D) and 39.9% (QIDS); the buspirone group (n=286, as much as 60 mg per day) had remission rates of 30.1% (HAM-D) and 26.9% (QIDS) (NNT buspirone-bupropion-SR=10). However, the bupropion-SR group had a lower dropout rate because of intolerance (12.5% vs 20.6%; NNH=12; P<.009).
Augmentation with atypical antipsychotics works
A recent meta-analysis of 10 RCTs (N=1500 outpatients) assessed the effectiveness of augmenting various antidepressants with atypical antipsychotic agents (olanzapine, risperidone, and quetiapine) for treatment-resistant major depressive disorder.13 The pooled remission and response rates favored augmentation with atypical antipsychotics over adjunctive placebo (47% vs 22.3% and 67.2% vs 35.4%, respectively).
Another randomized study of 362 patients with incomplete response to standard antidepressant treatment found adjunctive aripiprazole was effective and well tolerated (mean change in Montgomery-Åsberg Depression Rating Scale score: –8.8 in the aripiprazole group vs –5.8 in the placebo group; P<.001).14
Agents that aren’t recommended
Expert review doesn’t recommend routine use of other agents that have been studied for augmentation therapy, including dopaminergic drugs, pyschostimulants, modafinil, anticonvulsants, inositol, opiates, estrogen, dehydroepiandrosterone, folate and S-adenosylmethionine, tryptophan, omega-3 fatty acid, pindolol, and monoamine oxidase inhibitors.15
Recommendations
The Institute for Clinical Systems Improvement16 and the American Psychiatric Association17 recommend evaluating the dose and duration of medication, the patient’s adherence to medication, and the accuracy of diagnosis or impact of comorbidities for patients who don’t respond adequately to treatment. Physicians also may consider other strategies, including switch therapy, augmentation therapies, psychotherapy, and electroconvulsive therapy.
1. Paykel ES, Scott J, Teasdale JD, et al. Prevention of relapse in residual depression by cognitive therapy: a controlled trial. Arch Gen Psychiatry. 1999;56:829-835.
2. Schatzberg AF, Rush AJ, Arnow BA, et al. Chronic depression: medication (nefazodone) or psychotherapy (CBASP) is effective when the other is not. Arch Gen Psychiatry. 2005;62:513-520.
3. Thase ME, Friedman ES, Biggs MM, et al. Cognitive therapy versus medication in augmentation and switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry. 2007;164:739-752.
4. Ruhe HG, Huyser J, Swinkels JA, et al. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry. 2006;67:1836-1855.
5. Rush AJ, Trevedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231-1242.
6. Thase ME, Rush AJ, Howard RH, et al. Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression. Arch Gen Psychiatry. 2002;59:233-239.
7. Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006;163:1161-1172.
8. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163:1531-1541.
9. Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol. 1999;19:427-434.
10. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized placebo-controlled trials. J Clin Psychiatry. 2007;68:935-940.
11. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: a STAR*D Report. Am J Psychiatry. 2006;163:1519-1530.
12. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243-1252.
13. Papakostas GI, Shelton RC, Smith J, et al. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007;68:826-831.
14. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68:843-853.
15. Fava M. Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 18):S4-S11.
16. Institute for Clinical Systems Improvement (ICSI) Depression, Major, in Adults in Primary Care. Bloomington, Minn: Institute for Clinical System Improvement (ICSI); 2009. Available at: http://www.icsi.org/guidelines_and_more/gl_os_prot/behavioral_health/depression_5/depression__major__in_adults_in_primary_care_4.html. Accessed November 9, 2009.
17. American Psychiatric Association Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(suppl 4):S1-S45.
FIRST, CONSIDER POSSIBLE CAUSES OF THE INADEQUATE RESPONSE, then weigh treatment options in light of the characteristics of the individual patient and therapy. When managing a patient with nonpsychotic depression and inadequate response to the maximum dose of a single antidepressant, the physician should first identify factors that may contribute to the poor response, such as suboptimal dosage resulting from nonadherence, inadequate duration of therapy, and comorbid medical and psychiatric conditions (strength of recommendation [SOR]: C, expert opinion).
The literature supports several treatment alternatives, including augmentation with cognitive therapy, switch therapy, and combination-augmentation therapy; not enough studies exist to recommend the best treatment. All options reviewed produced a 20% to 50% remission rate (SOR: B, systematic reviews and randomized controlled trials [RCTs]).
Physicians should consider the patient’s clinical history and preferences, along with drug toxicity, potential drug interactions, and cost when making treatment decisions (SOR: C, expert opinion).
Evidence summary
A recent study randomized 158 patients who didn’t respond to antidepressant therapy to either cognitive therapy with clinical management or clinical management alone.1 The cognitive therapy group had a 29% cumulative relapse rate at 68 weeks, compared with 47% in the clinical management control group (number needed to treat [NNT]=6).
A crossover RCT compared 12 weeks of the cognitive behavioral analysis system of psychotherapy (CBASP) in 61 patients who had failed to respond to a 12-week course of nefazodone with 12 weeks of nefazodone treatment in 79 patients who hadn’t responded to 12 weeks of CBASP.2 Remission rates were comparable in the 2 crossover groups (28% for nefazodone vs 25% for CBASP; P=.92).
Drugs may produce a faster response
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial compared augmentation with as many as 16 sessions of cognitive therapy with pharmacologic augmentation and switch strategy among 65 patients who had failed to respond to 14 weeks of citalopram.3
The investigators concluded that augmentation with cognitive therapy or pharmacologic therapy was equally effective, but pharmacologic augmentation produced a more rapid response (mean time to first remission for cognitive therapy=53.3 days, compared with 40.1 days for pharmacologic therapy; P=.022). Patients who were switched to cognitive therapy had similar outcomes to patients who were switched to alternative antidepressants (remission rates=25% and 27.9%, respectively; P=.6881), but reported fewer adverse effects (0% vs 48%).
When an SSRI fails…
A recent systematic review of 8 RCTs (including STAR*D) and 23 open studies concluded that after a first failure of a selective serotonin reuptake inhibitor (SSRI), any switch within or between classes of antidepressant is legitimate and equally effective.4
Switching within the same class of antidepressant. The STAR*D study, an unblinded RCT, reported that patients (N=238; median age 41 years) who were switched to sertraline (as much as 200 mg per day for 14 weeks) when they didn’t tolerate or respond adequately to citalopram had remission rates of 17.6% on the Hamilton Rating Scale for Depression (HAM-D) and 26.6% on the Quick Inventory of Depressive Symptomatology (QIDS).5
Switching to a different class of antidepressant. In a multisite study, outpatients who failed to respond to 12-week, double-blind treatment with either sertraline (n=117) or imipramine (n=51) were randomized to an additional 12 weeks of double-blinded treatment with the alternate medication. Investigators reported a 60% response rate in the sertraline switch group and a 44% response rate in the imipramine switch group.6
In the STAR*D study, patients who didn’t tolerate or failed to respond to as many as 12 weeks of citalopram were switched to sustained-release (SR) bupropion, sertraline, or extended-release (ER) venlafaxine for as long as 14 weeks.5 The bupropion-SR switch group (n=239, up to 400 mg per day) had remission rates of 21.3% (HAM-D) and 25.5% (QIDS); the sertraline switch group (n=238, up to 200 mg per day) had remission rates of 17.6% (HAM-D) and 26.6% (QIDS); and the venlafaxine-ER switch group (n=250, up to 375 mg per day) had remission rates of 24.8% (HAM-D) and 25% (QIDS). There were no clinically or statistically significant differences among the groups.
Response declines with multiple switches
Patients who didn’t respond to this treatment arm and were switched again to either mirtazapine (n=114, as much as 60 mg per day) or nortriptyline (n=121, as much as 200 mg per day) had a much less favorable response (mirtazapine 12.3% vs nortriptyline 19.8%; NNT nortriptyline-mirtazapine=13).7
Patients who failed to respond to this treatment arm were randomized to either tranylcypromine (n=58, mean 36.9 mg per day) or venlafaxine plus mirtazapine (n=51, mean 210.3 and 35.7 mg per day, respectively). Both groups had low remission rates (tranylcypromine 6.9%, venlafaxine plus mirtazapine 13.7%; NNT venlafaxine plus mirtazapine-tranylcypromine=15).8
Lithium and T3 augmentation both work
A 1999 systematic review of 9 double-blind RCTs (N=234) reported that patients treated with lithium augmentation (250-1200 mg per day, or a serum level of ≥0.5 mmol/L for ≥2 weeks) had a 45% improvement in depressive symptoms (HAM-D), whereas the placebo group showed 18% improvement (NNT=3.7; 95% confidence interval [CI], 2.6-6.6).9 An updated meta-analysis of 10 RCTs confirmed the efficacy of lithium augmentation compared with placebo (41% vs 14.4% improvement; NNT=5).10
Recently, the STAR*D study (N=142) reported that augmentation with either lithium or triiodothyronine (T3) after 2 antidepressant failures was equally effective (lithium response 15.9%; T3 response 24.7%; NNT T3-lithium=11; P=.43). However, lithium was more often associated with side effects (number needed to harm [NNH]=7; P=.045).11
Bupropion and buspirone augmentation are comparable
An unblinded RCT found that patients who failed to respond to citalopram responded when augmented with either bupropion-SR or buspirone.12 After 8 weeks of treatment, the bupropion-SR group (n=565, as much as 400 mg per day) had remission rates of 29.7% (HAM-D) and 39.9% (QIDS); the buspirone group (n=286, as much as 60 mg per day) had remission rates of 30.1% (HAM-D) and 26.9% (QIDS) (NNT buspirone-bupropion-SR=10). However, the bupropion-SR group had a lower dropout rate because of intolerance (12.5% vs 20.6%; NNH=12; P<.009).
Augmentation with atypical antipsychotics works
A recent meta-analysis of 10 RCTs (N=1500 outpatients) assessed the effectiveness of augmenting various antidepressants with atypical antipsychotic agents (olanzapine, risperidone, and quetiapine) for treatment-resistant major depressive disorder.13 The pooled remission and response rates favored augmentation with atypical antipsychotics over adjunctive placebo (47% vs 22.3% and 67.2% vs 35.4%, respectively).
Another randomized study of 362 patients with incomplete response to standard antidepressant treatment found adjunctive aripiprazole was effective and well tolerated (mean change in Montgomery-Åsberg Depression Rating Scale score: –8.8 in the aripiprazole group vs –5.8 in the placebo group; P<.001).14
Agents that aren’t recommended
Expert review doesn’t recommend routine use of other agents that have been studied for augmentation therapy, including dopaminergic drugs, pyschostimulants, modafinil, anticonvulsants, inositol, opiates, estrogen, dehydroepiandrosterone, folate and S-adenosylmethionine, tryptophan, omega-3 fatty acid, pindolol, and monoamine oxidase inhibitors.15
Recommendations
The Institute for Clinical Systems Improvement16 and the American Psychiatric Association17 recommend evaluating the dose and duration of medication, the patient’s adherence to medication, and the accuracy of diagnosis or impact of comorbidities for patients who don’t respond adequately to treatment. Physicians also may consider other strategies, including switch therapy, augmentation therapies, psychotherapy, and electroconvulsive therapy.
FIRST, CONSIDER POSSIBLE CAUSES OF THE INADEQUATE RESPONSE, then weigh treatment options in light of the characteristics of the individual patient and therapy. When managing a patient with nonpsychotic depression and inadequate response to the maximum dose of a single antidepressant, the physician should first identify factors that may contribute to the poor response, such as suboptimal dosage resulting from nonadherence, inadequate duration of therapy, and comorbid medical and psychiatric conditions (strength of recommendation [SOR]: C, expert opinion).
The literature supports several treatment alternatives, including augmentation with cognitive therapy, switch therapy, and combination-augmentation therapy; not enough studies exist to recommend the best treatment. All options reviewed produced a 20% to 50% remission rate (SOR: B, systematic reviews and randomized controlled trials [RCTs]).
Physicians should consider the patient’s clinical history and preferences, along with drug toxicity, potential drug interactions, and cost when making treatment decisions (SOR: C, expert opinion).
Evidence summary
A recent study randomized 158 patients who didn’t respond to antidepressant therapy to either cognitive therapy with clinical management or clinical management alone.1 The cognitive therapy group had a 29% cumulative relapse rate at 68 weeks, compared with 47% in the clinical management control group (number needed to treat [NNT]=6).
A crossover RCT compared 12 weeks of the cognitive behavioral analysis system of psychotherapy (CBASP) in 61 patients who had failed to respond to a 12-week course of nefazodone with 12 weeks of nefazodone treatment in 79 patients who hadn’t responded to 12 weeks of CBASP.2 Remission rates were comparable in the 2 crossover groups (28% for nefazodone vs 25% for CBASP; P=.92).
Drugs may produce a faster response
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial compared augmentation with as many as 16 sessions of cognitive therapy with pharmacologic augmentation and switch strategy among 65 patients who had failed to respond to 14 weeks of citalopram.3
The investigators concluded that augmentation with cognitive therapy or pharmacologic therapy was equally effective, but pharmacologic augmentation produced a more rapid response (mean time to first remission for cognitive therapy=53.3 days, compared with 40.1 days for pharmacologic therapy; P=.022). Patients who were switched to cognitive therapy had similar outcomes to patients who were switched to alternative antidepressants (remission rates=25% and 27.9%, respectively; P=.6881), but reported fewer adverse effects (0% vs 48%).
When an SSRI fails…
A recent systematic review of 8 RCTs (including STAR*D) and 23 open studies concluded that after a first failure of a selective serotonin reuptake inhibitor (SSRI), any switch within or between classes of antidepressant is legitimate and equally effective.4
Switching within the same class of antidepressant. The STAR*D study, an unblinded RCT, reported that patients (N=238; median age 41 years) who were switched to sertraline (as much as 200 mg per day for 14 weeks) when they didn’t tolerate or respond adequately to citalopram had remission rates of 17.6% on the Hamilton Rating Scale for Depression (HAM-D) and 26.6% on the Quick Inventory of Depressive Symptomatology (QIDS).5
Switching to a different class of antidepressant. In a multisite study, outpatients who failed to respond to 12-week, double-blind treatment with either sertraline (n=117) or imipramine (n=51) were randomized to an additional 12 weeks of double-blinded treatment with the alternate medication. Investigators reported a 60% response rate in the sertraline switch group and a 44% response rate in the imipramine switch group.6
In the STAR*D study, patients who didn’t tolerate or failed to respond to as many as 12 weeks of citalopram were switched to sustained-release (SR) bupropion, sertraline, or extended-release (ER) venlafaxine for as long as 14 weeks.5 The bupropion-SR switch group (n=239, up to 400 mg per day) had remission rates of 21.3% (HAM-D) and 25.5% (QIDS); the sertraline switch group (n=238, up to 200 mg per day) had remission rates of 17.6% (HAM-D) and 26.6% (QIDS); and the venlafaxine-ER switch group (n=250, up to 375 mg per day) had remission rates of 24.8% (HAM-D) and 25% (QIDS). There were no clinically or statistically significant differences among the groups.
Response declines with multiple switches
Patients who didn’t respond to this treatment arm and were switched again to either mirtazapine (n=114, as much as 60 mg per day) or nortriptyline (n=121, as much as 200 mg per day) had a much less favorable response (mirtazapine 12.3% vs nortriptyline 19.8%; NNT nortriptyline-mirtazapine=13).7
Patients who failed to respond to this treatment arm were randomized to either tranylcypromine (n=58, mean 36.9 mg per day) or venlafaxine plus mirtazapine (n=51, mean 210.3 and 35.7 mg per day, respectively). Both groups had low remission rates (tranylcypromine 6.9%, venlafaxine plus mirtazapine 13.7%; NNT venlafaxine plus mirtazapine-tranylcypromine=15).8
Lithium and T3 augmentation both work
A 1999 systematic review of 9 double-blind RCTs (N=234) reported that patients treated with lithium augmentation (250-1200 mg per day, or a serum level of ≥0.5 mmol/L for ≥2 weeks) had a 45% improvement in depressive symptoms (HAM-D), whereas the placebo group showed 18% improvement (NNT=3.7; 95% confidence interval [CI], 2.6-6.6).9 An updated meta-analysis of 10 RCTs confirmed the efficacy of lithium augmentation compared with placebo (41% vs 14.4% improvement; NNT=5).10
Recently, the STAR*D study (N=142) reported that augmentation with either lithium or triiodothyronine (T3) after 2 antidepressant failures was equally effective (lithium response 15.9%; T3 response 24.7%; NNT T3-lithium=11; P=.43). However, lithium was more often associated with side effects (number needed to harm [NNH]=7; P=.045).11
Bupropion and buspirone augmentation are comparable
An unblinded RCT found that patients who failed to respond to citalopram responded when augmented with either bupropion-SR or buspirone.12 After 8 weeks of treatment, the bupropion-SR group (n=565, as much as 400 mg per day) had remission rates of 29.7% (HAM-D) and 39.9% (QIDS); the buspirone group (n=286, as much as 60 mg per day) had remission rates of 30.1% (HAM-D) and 26.9% (QIDS) (NNT buspirone-bupropion-SR=10). However, the bupropion-SR group had a lower dropout rate because of intolerance (12.5% vs 20.6%; NNH=12; P<.009).
Augmentation with atypical antipsychotics works
A recent meta-analysis of 10 RCTs (N=1500 outpatients) assessed the effectiveness of augmenting various antidepressants with atypical antipsychotic agents (olanzapine, risperidone, and quetiapine) for treatment-resistant major depressive disorder.13 The pooled remission and response rates favored augmentation with atypical antipsychotics over adjunctive placebo (47% vs 22.3% and 67.2% vs 35.4%, respectively).
Another randomized study of 362 patients with incomplete response to standard antidepressant treatment found adjunctive aripiprazole was effective and well tolerated (mean change in Montgomery-Åsberg Depression Rating Scale score: –8.8 in the aripiprazole group vs –5.8 in the placebo group; P<.001).14
Agents that aren’t recommended
Expert review doesn’t recommend routine use of other agents that have been studied for augmentation therapy, including dopaminergic drugs, pyschostimulants, modafinil, anticonvulsants, inositol, opiates, estrogen, dehydroepiandrosterone, folate and S-adenosylmethionine, tryptophan, omega-3 fatty acid, pindolol, and monoamine oxidase inhibitors.15
Recommendations
The Institute for Clinical Systems Improvement16 and the American Psychiatric Association17 recommend evaluating the dose and duration of medication, the patient’s adherence to medication, and the accuracy of diagnosis or impact of comorbidities for patients who don’t respond adequately to treatment. Physicians also may consider other strategies, including switch therapy, augmentation therapies, psychotherapy, and electroconvulsive therapy.
1. Paykel ES, Scott J, Teasdale JD, et al. Prevention of relapse in residual depression by cognitive therapy: a controlled trial. Arch Gen Psychiatry. 1999;56:829-835.
2. Schatzberg AF, Rush AJ, Arnow BA, et al. Chronic depression: medication (nefazodone) or psychotherapy (CBASP) is effective when the other is not. Arch Gen Psychiatry. 2005;62:513-520.
3. Thase ME, Friedman ES, Biggs MM, et al. Cognitive therapy versus medication in augmentation and switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry. 2007;164:739-752.
4. Ruhe HG, Huyser J, Swinkels JA, et al. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry. 2006;67:1836-1855.
5. Rush AJ, Trevedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231-1242.
6. Thase ME, Rush AJ, Howard RH, et al. Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression. Arch Gen Psychiatry. 2002;59:233-239.
7. Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006;163:1161-1172.
8. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163:1531-1541.
9. Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol. 1999;19:427-434.
10. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized placebo-controlled trials. J Clin Psychiatry. 2007;68:935-940.
11. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: a STAR*D Report. Am J Psychiatry. 2006;163:1519-1530.
12. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243-1252.
13. Papakostas GI, Shelton RC, Smith J, et al. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007;68:826-831.
14. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68:843-853.
15. Fava M. Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 18):S4-S11.
16. Institute for Clinical Systems Improvement (ICSI) Depression, Major, in Adults in Primary Care. Bloomington, Minn: Institute for Clinical System Improvement (ICSI); 2009. Available at: http://www.icsi.org/guidelines_and_more/gl_os_prot/behavioral_health/depression_5/depression__major__in_adults_in_primary_care_4.html. Accessed November 9, 2009.
17. American Psychiatric Association Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(suppl 4):S1-S45.
1. Paykel ES, Scott J, Teasdale JD, et al. Prevention of relapse in residual depression by cognitive therapy: a controlled trial. Arch Gen Psychiatry. 1999;56:829-835.
2. Schatzberg AF, Rush AJ, Arnow BA, et al. Chronic depression: medication (nefazodone) or psychotherapy (CBASP) is effective when the other is not. Arch Gen Psychiatry. 2005;62:513-520.
3. Thase ME, Friedman ES, Biggs MM, et al. Cognitive therapy versus medication in augmentation and switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry. 2007;164:739-752.
4. Ruhe HG, Huyser J, Swinkels JA, et al. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry. 2006;67:1836-1855.
5. Rush AJ, Trevedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231-1242.
6. Thase ME, Rush AJ, Howard RH, et al. Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression. Arch Gen Psychiatry. 2002;59:233-239.
7. Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006;163:1161-1172.
8. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163:1531-1541.
9. Bauer M, Dopfmer S. Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies. J Clin Psychopharmacol. 1999;19:427-434.
10. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized placebo-controlled trials. J Clin Psychiatry. 2007;68:935-940.
11. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: a STAR*D Report. Am J Psychiatry. 2006;163:1519-1530.
12. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243-1252.
13. Papakostas GI, Shelton RC, Smith J, et al. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007;68:826-831.
14. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68:843-853.
15. Fava M. Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry. 2001;62(suppl 18):S4-S11.
16. Institute for Clinical Systems Improvement (ICSI) Depression, Major, in Adults in Primary Care. Bloomington, Minn: Institute for Clinical System Improvement (ICSI); 2009. Available at: http://www.icsi.org/guidelines_and_more/gl_os_prot/behavioral_health/depression_5/depression__major__in_adults_in_primary_care_4.html. Accessed November 9, 2009.
17. American Psychiatric Association Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(suppl 4):S1-S45.
Evidence-based answers from the Family Physicians Inquiries Network
Which medications can be split without compromising efficacy and safety?
Split tablets of lisinopril are as effective as whole tablets of the same dose for hypertension (SOR: B, based on small randomized crossover study). Similarly, split tablets of atorvastatin, lovastatin, and simvastatin are no less effective for lowering cholesterol (SOR: B, based on retrospective cohort studies). Extended-release, enteric-coated, or tablets that cannot be split accurately are not appropriate for splitting (SOR: C, based on observational studies); the accuracy of splitting also depends on device used and user skill (SOR: C, based on observational study) (TABLE).
Splitting scored tablets is efficacious and safe, but cost savings are often limited
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado Health Sciences Center, Denver
The theoretical benefit of tablet-splitting is reduced prescription cost. Splitting scored tablets is already FDA-approved as safe and efficacious. However, the cost savings garnered by splitting these types of tablets is often limited. The biggest savings comes from splitting flat-priced tablets (costs of different dosage strengths are equal/similar), but these tablets are not usually scored. Splitting unscored tablets is considered “off-label” because each split tablet dose may not have equal drug strength. However, splitting drugs with a long half-life and wide therapeutic index—such as those used to treat chronic asymptomatic conditions like hypertension or dyslipidemia—should pose minimal risk.
Be aware that recommending tablet-splitting to insured patients solely to spare them a copay—instructing a patient to take a half tablet to make a 30-day paid prescription cover 60 days—may be considered insurance fraud. However, this is not an issue for patients without prescription coverage.
TABLE
Questions to consider before tablet-splitting
| If you answer “NO” to any of these questions, reconsider the appropriateness of recommending tablet-splitting to a patient |
|---|
| Medication characteristics |
|
| *Some tablets without scoring may be split easily with tablet-splitting device. |
| Patient characteristics |
|
Evidence summary
Few studies have looked at the clinical effects of pill-splitting. A randomized trial (n=29) evaluated tablet-splitting by patients taking lisinopril for hypertension.1 Patients were randomized to split tablets or whole tablets for 2 weeks, then crossed over to the other group for 2 weeks. There was no difference in blood pressures between groups.
A retrospective study of simvastatin evaluated 1098 patients taking whole tablets and 1098 patients converted to split tablets of the same dose.2 There was no difference in average final low-density lipoprotein (LDL) cholesterol (111±30 mg/dL vs 112±32 mg/dL) or mean ala-nine aminotransferase (ALT) level.
Another retrospective study evaluated tablet-splitting by 512 patients taking statins (atorvastatin, lovastatin, simvastatin).3 Cholesterol values after 12 or more weeks on a stable whole-tablet dose were compared with those 6 to 52 weeks after initiating tablet-splitting; no significant change was seen in total cholesterol or triglycerides. There was a statistically significant decrease in LDL (102±28 vs 97±29 mg/dL, P<.001), an increase in high-density lipoprotein (HDL) cholesterol (46±12 vs 48±12 mg/dL, P<.001), and an increase in aspartate aminotransferase (AST) (26±8 vs 28±10 units/L, P<.001), which was attributed to higher medication dosage from accidental ingestion of whole tablets and to diet and lifestyle modifications. Another retrospective evaluation of 109 patients with split atorvastatin or simvastatin found no significant difference in total cholesterol or LDL values after initiating the tablet-splitting program.4
Thirty patients aged 50 years or older, half of whom received instruction and a demonstration, evaluated 2 tablet-splitters with different blade positions and types of guide.5 One device (Apex Pill Splitter) produced more accurate results by 10% to 20% (P value not provided) with metoprolol, warfarin, and lisinopril tablets. Instructed patients were 1% to 10% more accurate, as were those with experience splitting warfarin tablets (P=.003).
In another study, 94 healthy volunteers (mean age, 46.2 years) each split 10 hydrochlorothiazide 25 mg tablets by hand. Forty-one percent of the split products were more than 10% off ideal weight; 12% of tablets were more than 20% off.6 Manufacturing regulations require that medication doses vary by less than 10% of the nominal dose. Another study using 5 medications found that 0% to 44% of split tablets deviated from ideal weight by 20%, depending on tablet shape.7
Surveys of patient acceptance of tablet-splitting report varied rates (3%*#8211;74%),3,6 In 1 study,1 89% and 97% said they would split tablets to save money for themselves or their health facility, respectively.
Experts recommend assessing patients for their physical (dexterity, strength, visual acuity) and cognitive ability to split tablets, as well as whether doing so saves money.8
Recommendations from others
The American Medical Society and American Pharmacists Association oppose mandatory tablet-splitting and recommend against splitting tablets that are modified-release, combination products, unscored, film-coated, friable, or dose-critical.
1. Rindone JP. Evaluation of tablet-splitting in patients taking lisinopril for hypertension. J Clin Outcomes Management 2000;7:22-24.
2. Parra D, Beckey NP, Raval HS, et al. Effect of splitting simvastatin tablets for control of low-density lipoprotein cholesterol. Am J Cardiol 2005;95:1481-1483.
3. Gee M, Hasson NK, Hahn T, Ryono R. Effects of tablet-splitting program in patients taking HMG-Coa reductase inhibitors: analysis of clinical effects, patient satisfaction, compliance, and cost avoidance. J Managed Care Pharm 2002;8:453-458.
4. Duncan MC, Castle SS, Streetman DS. Effect of tablet splitting on serum cholesterol concentrations. Ann Pharmacother 2002;36:205-209.
5. Peek BT, Al-Achi A, Coombs SJ. Accuracy of tablet splitting by elderly patients. JAMA 2002;399:451-452.
6. McDevitt JT, Gurst AH, Chen Y. Accuracy of tablet splitting. Pharmacotherapy 1998;18:193-197.
7. Gupta P, Gupta K. Broken tablets: does the sum of the parts equal the whole? Am J Health Syst Pharm 1988;45:1498.-
8. Tablet splitting: evaluating appropriateness for patients. J Am Pharm Assoc 2004;44:324-325.
Split tablets of lisinopril are as effective as whole tablets of the same dose for hypertension (SOR: B, based on small randomized crossover study). Similarly, split tablets of atorvastatin, lovastatin, and simvastatin are no less effective for lowering cholesterol (SOR: B, based on retrospective cohort studies). Extended-release, enteric-coated, or tablets that cannot be split accurately are not appropriate for splitting (SOR: C, based on observational studies); the accuracy of splitting also depends on device used and user skill (SOR: C, based on observational study) (TABLE).
Splitting scored tablets is efficacious and safe, but cost savings are often limited
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado Health Sciences Center, Denver
The theoretical benefit of tablet-splitting is reduced prescription cost. Splitting scored tablets is already FDA-approved as safe and efficacious. However, the cost savings garnered by splitting these types of tablets is often limited. The biggest savings comes from splitting flat-priced tablets (costs of different dosage strengths are equal/similar), but these tablets are not usually scored. Splitting unscored tablets is considered “off-label” because each split tablet dose may not have equal drug strength. However, splitting drugs with a long half-life and wide therapeutic index—such as those used to treat chronic asymptomatic conditions like hypertension or dyslipidemia—should pose minimal risk.
Be aware that recommending tablet-splitting to insured patients solely to spare them a copay—instructing a patient to take a half tablet to make a 30-day paid prescription cover 60 days—may be considered insurance fraud. However, this is not an issue for patients without prescription coverage.
TABLE
Questions to consider before tablet-splitting
| If you answer “NO” to any of these questions, reconsider the appropriateness of recommending tablet-splitting to a patient |
|---|
| Medication characteristics |
|
| *Some tablets without scoring may be split easily with tablet-splitting device. |
| Patient characteristics |
|
Evidence summary
Few studies have looked at the clinical effects of pill-splitting. A randomized trial (n=29) evaluated tablet-splitting by patients taking lisinopril for hypertension.1 Patients were randomized to split tablets or whole tablets for 2 weeks, then crossed over to the other group for 2 weeks. There was no difference in blood pressures between groups.
A retrospective study of simvastatin evaluated 1098 patients taking whole tablets and 1098 patients converted to split tablets of the same dose.2 There was no difference in average final low-density lipoprotein (LDL) cholesterol (111±30 mg/dL vs 112±32 mg/dL) or mean ala-nine aminotransferase (ALT) level.
Another retrospective study evaluated tablet-splitting by 512 patients taking statins (atorvastatin, lovastatin, simvastatin).3 Cholesterol values after 12 or more weeks on a stable whole-tablet dose were compared with those 6 to 52 weeks after initiating tablet-splitting; no significant change was seen in total cholesterol or triglycerides. There was a statistically significant decrease in LDL (102±28 vs 97±29 mg/dL, P<.001), an increase in high-density lipoprotein (HDL) cholesterol (46±12 vs 48±12 mg/dL, P<.001), and an increase in aspartate aminotransferase (AST) (26±8 vs 28±10 units/L, P<.001), which was attributed to higher medication dosage from accidental ingestion of whole tablets and to diet and lifestyle modifications. Another retrospective evaluation of 109 patients with split atorvastatin or simvastatin found no significant difference in total cholesterol or LDL values after initiating the tablet-splitting program.4
Thirty patients aged 50 years or older, half of whom received instruction and a demonstration, evaluated 2 tablet-splitters with different blade positions and types of guide.5 One device (Apex Pill Splitter) produced more accurate results by 10% to 20% (P value not provided) with metoprolol, warfarin, and lisinopril tablets. Instructed patients were 1% to 10% more accurate, as were those with experience splitting warfarin tablets (P=.003).
In another study, 94 healthy volunteers (mean age, 46.2 years) each split 10 hydrochlorothiazide 25 mg tablets by hand. Forty-one percent of the split products were more than 10% off ideal weight; 12% of tablets were more than 20% off.6 Manufacturing regulations require that medication doses vary by less than 10% of the nominal dose. Another study using 5 medications found that 0% to 44% of split tablets deviated from ideal weight by 20%, depending on tablet shape.7
Surveys of patient acceptance of tablet-splitting report varied rates (3%*#8211;74%),3,6 In 1 study,1 89% and 97% said they would split tablets to save money for themselves or their health facility, respectively.
Experts recommend assessing patients for their physical (dexterity, strength, visual acuity) and cognitive ability to split tablets, as well as whether doing so saves money.8
Recommendations from others
The American Medical Society and American Pharmacists Association oppose mandatory tablet-splitting and recommend against splitting tablets that are modified-release, combination products, unscored, film-coated, friable, or dose-critical.
Split tablets of lisinopril are as effective as whole tablets of the same dose for hypertension (SOR: B, based on small randomized crossover study). Similarly, split tablets of atorvastatin, lovastatin, and simvastatin are no less effective for lowering cholesterol (SOR: B, based on retrospective cohort studies). Extended-release, enteric-coated, or tablets that cannot be split accurately are not appropriate for splitting (SOR: C, based on observational studies); the accuracy of splitting also depends on device used and user skill (SOR: C, based on observational study) (TABLE).
Splitting scored tablets is efficacious and safe, but cost savings are often limited
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado Health Sciences Center, Denver
The theoretical benefit of tablet-splitting is reduced prescription cost. Splitting scored tablets is already FDA-approved as safe and efficacious. However, the cost savings garnered by splitting these types of tablets is often limited. The biggest savings comes from splitting flat-priced tablets (costs of different dosage strengths are equal/similar), but these tablets are not usually scored. Splitting unscored tablets is considered “off-label” because each split tablet dose may not have equal drug strength. However, splitting drugs with a long half-life and wide therapeutic index—such as those used to treat chronic asymptomatic conditions like hypertension or dyslipidemia—should pose minimal risk.
Be aware that recommending tablet-splitting to insured patients solely to spare them a copay—instructing a patient to take a half tablet to make a 30-day paid prescription cover 60 days—may be considered insurance fraud. However, this is not an issue for patients without prescription coverage.
TABLE
Questions to consider before tablet-splitting
| If you answer “NO” to any of these questions, reconsider the appropriateness of recommending tablet-splitting to a patient |
|---|
| Medication characteristics |
|
| *Some tablets without scoring may be split easily with tablet-splitting device. |
| Patient characteristics |
|
Evidence summary
Few studies have looked at the clinical effects of pill-splitting. A randomized trial (n=29) evaluated tablet-splitting by patients taking lisinopril for hypertension.1 Patients were randomized to split tablets or whole tablets for 2 weeks, then crossed over to the other group for 2 weeks. There was no difference in blood pressures between groups.
A retrospective study of simvastatin evaluated 1098 patients taking whole tablets and 1098 patients converted to split tablets of the same dose.2 There was no difference in average final low-density lipoprotein (LDL) cholesterol (111±30 mg/dL vs 112±32 mg/dL) or mean ala-nine aminotransferase (ALT) level.
Another retrospective study evaluated tablet-splitting by 512 patients taking statins (atorvastatin, lovastatin, simvastatin).3 Cholesterol values after 12 or more weeks on a stable whole-tablet dose were compared with those 6 to 52 weeks after initiating tablet-splitting; no significant change was seen in total cholesterol or triglycerides. There was a statistically significant decrease in LDL (102±28 vs 97±29 mg/dL, P<.001), an increase in high-density lipoprotein (HDL) cholesterol (46±12 vs 48±12 mg/dL, P<.001), and an increase in aspartate aminotransferase (AST) (26±8 vs 28±10 units/L, P<.001), which was attributed to higher medication dosage from accidental ingestion of whole tablets and to diet and lifestyle modifications. Another retrospective evaluation of 109 patients with split atorvastatin or simvastatin found no significant difference in total cholesterol or LDL values after initiating the tablet-splitting program.4
Thirty patients aged 50 years or older, half of whom received instruction and a demonstration, evaluated 2 tablet-splitters with different blade positions and types of guide.5 One device (Apex Pill Splitter) produced more accurate results by 10% to 20% (P value not provided) with metoprolol, warfarin, and lisinopril tablets. Instructed patients were 1% to 10% more accurate, as were those with experience splitting warfarin tablets (P=.003).
In another study, 94 healthy volunteers (mean age, 46.2 years) each split 10 hydrochlorothiazide 25 mg tablets by hand. Forty-one percent of the split products were more than 10% off ideal weight; 12% of tablets were more than 20% off.6 Manufacturing regulations require that medication doses vary by less than 10% of the nominal dose. Another study using 5 medications found that 0% to 44% of split tablets deviated from ideal weight by 20%, depending on tablet shape.7
Surveys of patient acceptance of tablet-splitting report varied rates (3%*#8211;74%),3,6 In 1 study,1 89% and 97% said they would split tablets to save money for themselves or their health facility, respectively.
Experts recommend assessing patients for their physical (dexterity, strength, visual acuity) and cognitive ability to split tablets, as well as whether doing so saves money.8
Recommendations from others
The American Medical Society and American Pharmacists Association oppose mandatory tablet-splitting and recommend against splitting tablets that are modified-release, combination products, unscored, film-coated, friable, or dose-critical.
1. Rindone JP. Evaluation of tablet-splitting in patients taking lisinopril for hypertension. J Clin Outcomes Management 2000;7:22-24.
2. Parra D, Beckey NP, Raval HS, et al. Effect of splitting simvastatin tablets for control of low-density lipoprotein cholesterol. Am J Cardiol 2005;95:1481-1483.
3. Gee M, Hasson NK, Hahn T, Ryono R. Effects of tablet-splitting program in patients taking HMG-Coa reductase inhibitors: analysis of clinical effects, patient satisfaction, compliance, and cost avoidance. J Managed Care Pharm 2002;8:453-458.
4. Duncan MC, Castle SS, Streetman DS. Effect of tablet splitting on serum cholesterol concentrations. Ann Pharmacother 2002;36:205-209.
5. Peek BT, Al-Achi A, Coombs SJ. Accuracy of tablet splitting by elderly patients. JAMA 2002;399:451-452.
6. McDevitt JT, Gurst AH, Chen Y. Accuracy of tablet splitting. Pharmacotherapy 1998;18:193-197.
7. Gupta P, Gupta K. Broken tablets: does the sum of the parts equal the whole? Am J Health Syst Pharm 1988;45:1498.-
8. Tablet splitting: evaluating appropriateness for patients. J Am Pharm Assoc 2004;44:324-325.
1. Rindone JP. Evaluation of tablet-splitting in patients taking lisinopril for hypertension. J Clin Outcomes Management 2000;7:22-24.
2. Parra D, Beckey NP, Raval HS, et al. Effect of splitting simvastatin tablets for control of low-density lipoprotein cholesterol. Am J Cardiol 2005;95:1481-1483.
3. Gee M, Hasson NK, Hahn T, Ryono R. Effects of tablet-splitting program in patients taking HMG-Coa reductase inhibitors: analysis of clinical effects, patient satisfaction, compliance, and cost avoidance. J Managed Care Pharm 2002;8:453-458.
4. Duncan MC, Castle SS, Streetman DS. Effect of tablet splitting on serum cholesterol concentrations. Ann Pharmacother 2002;36:205-209.
5. Peek BT, Al-Achi A, Coombs SJ. Accuracy of tablet splitting by elderly patients. JAMA 2002;399:451-452.
6. McDevitt JT, Gurst AH, Chen Y. Accuracy of tablet splitting. Pharmacotherapy 1998;18:193-197.
7. Gupta P, Gupta K. Broken tablets: does the sum of the parts equal the whole? Am J Health Syst Pharm 1988;45:1498.-
8. Tablet splitting: evaluating appropriateness for patients. J Am Pharm Assoc 2004;44:324-325.
Evidence-based answers from the Family Physicians Inquiries Network
When should COX-2 selective NSAIDs be used for osteoarthritis and rheumatoid arthritis?
Cyclo-oxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs) are as effective as acetaminophen and nonselective NSAIDs in treating of osteoarthritis, and are equally effective in reducing pain and inflammation and improving of joint function for patients with rheumatoid arthritis, when compared with nonselective NSAIDs. The COX-2 selective NSAIDs also have a better gastrointestinal safety profile in short-term (6–12 month) treatment (strength of recommendation [SOR]: A, based on meta-analysis of randomized controlled trials with patient-oriented outcomes).
However, with recent growing concern of the cardiovascular safety of COX-2 selective NSAIDs, it is imperative to select appropriate patients by considering benefit vs risks, which include serious gastrointestinal bleeding (TABLE 1), history of intolerance to nonselective NSAID, cardiovascular disease or associated risks, renal disease, patient’s preference, and cost.
Nonselective NSAIDs with misoprostol or a PPI instead of COX-2 inhibitor is a reasonable strategy
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado at Denver and Health Sciences Center, Denver, Colo
Although celecoxib is an effective NSAID, rofecoxib and lumericoxib are the only COX-2 selective inhibitors that definitively reduce gastrointestinal (GI) ulcerations/complications compared with nonselective NSAID therapy.1,2 However, neither of these are on the market. Data from the CLASS study showed no reduced risk of GI ulcerations/complications with celecoxib vs ibuprofen or diclofenac among patients receiving low-dose aspirin.3 Low-dose aspirin reduces cardiovascular events for patients with moderate or high cardiovascular risk (Framingham scores ≥10%). Therefore, using nonselective NSAID therapy in combination with either misoprostol or a proton pump inhibitor (eg, omeprazole) instead of celecoxib, is a reasonable and proven strategy to provide NSAID therapy for patients on low-dose aspirin who are at high risk for NSAID-associated gastropathy.
Evidence summary
A Cochrane review4 (6 randomized controlled trials, N=1689, mean duration 5.8 weeks) assessed the efficacy and safety of acetaminophen in the management of osteoarthritis, comparing it with placebo and NSAIDs. Acetaminophen was superior to placebo in pain reduction and global assessment (number needed to treat [NNT]=2) with a similar safety profile. NSAIDs were better than acetaminophen in pain reduction, patient (NNT=6) and physician global assessment (NNT=17), but no better for functional improvement. Compared with nonselective NSAIDs, acetaminophen led to fewer withdrawals (number needed to harm [NNH]=20) and fewer GI adverse events (NNH=9), but there was no statistical difference when compared with COX-2 selective NSAIDs.
Another Cochrane review5 (26 randomized controlled trials) found that rofecoxib (Vioxx) was more effective than placebo (NNT=5), and equally effective with other NSAIDs in the management of osteoarthritis. They reported fewer GI adverse events (endoscopically observed gastric erosion and ulcers) with rofecoxib than with other NSAIDs—naproxen (Naprosyn), ibuprofen (Motrin), diclofenac (Cataflam), nabumetone (Relafen), diclofenac/misoprostol (Arthrotec), and nimesulide. However, the withdrawal rate due to adverse events and the increase in blood pressure and edema were significantly greater with rofecoxib than placebo at 6 weeks.
Two Cochrane reviews6-7 confirmed the efficacy of celecoxib (Celebrex) and rofecoxib in treating of rheumatoid arthritis. One review included 2 RCTs (N=8734) with a placebo arm (8 weeks) and naproxen arm (9 months).7 The rofecoxib groups (25 mg, 50 mg) had more responders than the placebo group (NNT=8 and 6 respectively). Compared with naproxen (1 g), no difference was seen in efficacy in the OMERACT outcomes (Outcome Measures for Rheumatoid Arthritis Clinical Trials), but all combined GI adverse events (perforation, ulcer, obstruction, bleeding, and all episodes of GI bleeding) were significantly reduced at 9 months (NNH=20). The withdrawals were the same in the 3 groups. Compared with placebo, the rofecoxib groups had similar incidence of elevated blood pressure and edema (NNH=50 and 100, respectively). Compared with the naproxen group, no difference was seen in renal adverse events, but total cardiovascular thrombotic events (NNH=200) and nonfatal MI (NNH=300) increased at 9 months in the 50 mg rofecoxib group.
Similar cardiovascular adverse events were reported in the APPROVE trial.9 In this study, patients taking rofecoxib 25 mg daily for 18 months had increased total thrombotic events (MI, stroke, peripheral arterial and venous thrombosis, and pulmonary embolism) when compared with placebo (NNH=63). A recent study also raised the same concern of increased cardiovascular adverse events with celecoxib.10 This study demonstrated an increase risk of cardiovascular events (combined death, myocardial infarction, stroke, and heart failure) for patients taking celecoxib 200 mg twice a day (NNH=77) or 400 mg twice a day (NNH=42).
Many patients taking low-dose aspirin for cardioprotection also frequently require treatment of pain and inflammation with a NSAID. Even low-dose aspirin (75 mg/d) is known to be associated with increased GI toxicity (ulcers and hemorrhages).11 A recent double-blind, randomized placebo-controlled trial found that 12 weeks of treatment with a combination of low-dose aspirin and a COX-2 selective NSAID (rofecoxib) had more than twice the incidence of endoscopically confirmed gastric and duodenal ulcers, compared with aspirin alone, and no difference with a nonselective NSAID.12 This has raised the safety concern of concomitant use of a COX-2 selective NSAID with low-dose aspirin.
TABLE 1
Prediction of serious gastrointestinal bleeding
| RISK FACTORS PRESENT | RISK OF GI BLEEDING |
|---|---|
| 0 factor | 0.4 % |
| Any 1 factor | 1.0 % |
| All 4 factors | 9.0 % |
| Risk factors include age >75 years, history of peptic ulcer disease, history of gastrointestinal bleeding, history of cardiovascular disease | |
| Source: Silverstein et al, Ann Intern Med 1995.8 | |
Recommendations from others
The American Pain Society recommends that for patients with osteoarthritis, acetaminophen is the drug of choice for mild pain.13 For moderate to severe pain and or inflammation, a COX-2 selective NSAID is the first choice, unless the patient is at significant risk for hypertension or renal disorder. For patients with active rheumatoid arthritis and moderate to severe pain with or without inflammation, a COX-2 selective NSAID should be used concomitantly with a disease-modifying antirheumatic drug (DMARD), unless contraindicated by existing uncontrolled hypertension and renal disease. It further recommends that for a person who is at risk for a cardiovascular event, an aspirin (75–160 mg/d), should be given along with a COX-2 selective NSAID.
The American College of Rheumatology recommends that a COX-2 selective NSAID should be considered for a person with osteoarthritis and pain not relieved by an adequate dose of acetaminophen (not to exceed 4 g/d).14,15 The COX-2 selective NSAID is particularly advantageous for those who have higher risk factors for adverse GI events (TABLE 2). For a person with rheumatoid arthritis, in addition to DMARDs, NSAIDs (salicylates, nonselective NSAID, or COX-2 selective NSAID) should be used to reduce joint pain and swelling and improve joint function. Patients with additional risks for cardiovascular events should be cautioned about use of a COX-2 selective NSAID.
A recent AHRQ report on managing osteoarthritis underscores the importance of physician-patient partnership and patient’s self management of osteoarthritis, and recommends acetaminophen (up to 4 g/day) as the drug of choice.16 It further cautions the injudicious use of NSAIDs because of its greater GI toxicity when compared with acetaminophen, and its higher medical costs.
TABLE 2
Risk factors for upper gastrointestinal adverse events
| Age ≥65 years |
| Comorbid medical conditions |
| Oral glucocorticoids |
| History of peptic ulcer disease |
| History of upper gastrointestinal bleeding |
| Anticoagulants |
| Source: American College of Rheumatology, Arthritis Rheum 2000.12 |
1. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520-1528.
2. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364:665-674.
3. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247-1255.
4. Towheed TE, Judd MG, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2003;(2):CD004257.-
5. Garner SE, Fidan DD, Frankish RR, Maxwell LJ. Rofecoxib for osteoarthritis. Cochrane Database Syst Rev 2005;(1):CD005115.-
6. Garner S, Fidan D, Frankish R, et al. Celecoxib for rheumatoid arthritis. Cochrane Database Syst Rev 2002;(4):CD003831.-
7. Garner SE, Fidan DD, Frankish RR, et al. Rofecoxib for rheumatoid arthritis. Cochrane Database Syst Rev 2005;(1):CD003685.-
8. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduced serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-249.
9. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092-1102.
10. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-1080.
11. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-1187.
12. Laine L, Maller ES, Yu C, Quan H, Simon T. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: A double-blind trial. Gastroenterology 2004;127:395-402.
13. Simon LS, Lipman AG, Jacox AK, et al. Pain in Osteoarthritis, Rheumatoid Arthritis and Juvenile Chronic Arthritis. 2nd ed. Glenview, Ill: American Pain Society; 2002.
14. American College of Rheumatology (ACR) Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;43:1905-1915.
15. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum 2002;46:328-346.
16. Managing Osteoarthritis: Helping the Elderly Maintain Function and Mobility. Issue 4, AHRQ Pub. No 02-0023, May 2002. Agency for Healthcare Research and Quality. Available at: www.ahrq.gov/research/osteoria/osteoria.htm#self-manage.
Cyclo-oxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs) are as effective as acetaminophen and nonselective NSAIDs in treating of osteoarthritis, and are equally effective in reducing pain and inflammation and improving of joint function for patients with rheumatoid arthritis, when compared with nonselective NSAIDs. The COX-2 selective NSAIDs also have a better gastrointestinal safety profile in short-term (6–12 month) treatment (strength of recommendation [SOR]: A, based on meta-analysis of randomized controlled trials with patient-oriented outcomes).
However, with recent growing concern of the cardiovascular safety of COX-2 selective NSAIDs, it is imperative to select appropriate patients by considering benefit vs risks, which include serious gastrointestinal bleeding (TABLE 1), history of intolerance to nonselective NSAID, cardiovascular disease or associated risks, renal disease, patient’s preference, and cost.
Nonselective NSAIDs with misoprostol or a PPI instead of COX-2 inhibitor is a reasonable strategy
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado at Denver and Health Sciences Center, Denver, Colo
Although celecoxib is an effective NSAID, rofecoxib and lumericoxib are the only COX-2 selective inhibitors that definitively reduce gastrointestinal (GI) ulcerations/complications compared with nonselective NSAID therapy.1,2 However, neither of these are on the market. Data from the CLASS study showed no reduced risk of GI ulcerations/complications with celecoxib vs ibuprofen or diclofenac among patients receiving low-dose aspirin.3 Low-dose aspirin reduces cardiovascular events for patients with moderate or high cardiovascular risk (Framingham scores ≥10%). Therefore, using nonselective NSAID therapy in combination with either misoprostol or a proton pump inhibitor (eg, omeprazole) instead of celecoxib, is a reasonable and proven strategy to provide NSAID therapy for patients on low-dose aspirin who are at high risk for NSAID-associated gastropathy.
Evidence summary
A Cochrane review4 (6 randomized controlled trials, N=1689, mean duration 5.8 weeks) assessed the efficacy and safety of acetaminophen in the management of osteoarthritis, comparing it with placebo and NSAIDs. Acetaminophen was superior to placebo in pain reduction and global assessment (number needed to treat [NNT]=2) with a similar safety profile. NSAIDs were better than acetaminophen in pain reduction, patient (NNT=6) and physician global assessment (NNT=17), but no better for functional improvement. Compared with nonselective NSAIDs, acetaminophen led to fewer withdrawals (number needed to harm [NNH]=20) and fewer GI adverse events (NNH=9), but there was no statistical difference when compared with COX-2 selective NSAIDs.
Another Cochrane review5 (26 randomized controlled trials) found that rofecoxib (Vioxx) was more effective than placebo (NNT=5), and equally effective with other NSAIDs in the management of osteoarthritis. They reported fewer GI adverse events (endoscopically observed gastric erosion and ulcers) with rofecoxib than with other NSAIDs—naproxen (Naprosyn), ibuprofen (Motrin), diclofenac (Cataflam), nabumetone (Relafen), diclofenac/misoprostol (Arthrotec), and nimesulide. However, the withdrawal rate due to adverse events and the increase in blood pressure and edema were significantly greater with rofecoxib than placebo at 6 weeks.
Two Cochrane reviews6-7 confirmed the efficacy of celecoxib (Celebrex) and rofecoxib in treating of rheumatoid arthritis. One review included 2 RCTs (N=8734) with a placebo arm (8 weeks) and naproxen arm (9 months).7 The rofecoxib groups (25 mg, 50 mg) had more responders than the placebo group (NNT=8 and 6 respectively). Compared with naproxen (1 g), no difference was seen in efficacy in the OMERACT outcomes (Outcome Measures for Rheumatoid Arthritis Clinical Trials), but all combined GI adverse events (perforation, ulcer, obstruction, bleeding, and all episodes of GI bleeding) were significantly reduced at 9 months (NNH=20). The withdrawals were the same in the 3 groups. Compared with placebo, the rofecoxib groups had similar incidence of elevated blood pressure and edema (NNH=50 and 100, respectively). Compared with the naproxen group, no difference was seen in renal adverse events, but total cardiovascular thrombotic events (NNH=200) and nonfatal MI (NNH=300) increased at 9 months in the 50 mg rofecoxib group.
Similar cardiovascular adverse events were reported in the APPROVE trial.9 In this study, patients taking rofecoxib 25 mg daily for 18 months had increased total thrombotic events (MI, stroke, peripheral arterial and venous thrombosis, and pulmonary embolism) when compared with placebo (NNH=63). A recent study also raised the same concern of increased cardiovascular adverse events with celecoxib.10 This study demonstrated an increase risk of cardiovascular events (combined death, myocardial infarction, stroke, and heart failure) for patients taking celecoxib 200 mg twice a day (NNH=77) or 400 mg twice a day (NNH=42).
Many patients taking low-dose aspirin for cardioprotection also frequently require treatment of pain and inflammation with a NSAID. Even low-dose aspirin (75 mg/d) is known to be associated with increased GI toxicity (ulcers and hemorrhages).11 A recent double-blind, randomized placebo-controlled trial found that 12 weeks of treatment with a combination of low-dose aspirin and a COX-2 selective NSAID (rofecoxib) had more than twice the incidence of endoscopically confirmed gastric and duodenal ulcers, compared with aspirin alone, and no difference with a nonselective NSAID.12 This has raised the safety concern of concomitant use of a COX-2 selective NSAID with low-dose aspirin.
TABLE 1
Prediction of serious gastrointestinal bleeding
| RISK FACTORS PRESENT | RISK OF GI BLEEDING |
|---|---|
| 0 factor | 0.4 % |
| Any 1 factor | 1.0 % |
| All 4 factors | 9.0 % |
| Risk factors include age >75 years, history of peptic ulcer disease, history of gastrointestinal bleeding, history of cardiovascular disease | |
| Source: Silverstein et al, Ann Intern Med 1995.8 | |
Recommendations from others
The American Pain Society recommends that for patients with osteoarthritis, acetaminophen is the drug of choice for mild pain.13 For moderate to severe pain and or inflammation, a COX-2 selective NSAID is the first choice, unless the patient is at significant risk for hypertension or renal disorder. For patients with active rheumatoid arthritis and moderate to severe pain with or without inflammation, a COX-2 selective NSAID should be used concomitantly with a disease-modifying antirheumatic drug (DMARD), unless contraindicated by existing uncontrolled hypertension and renal disease. It further recommends that for a person who is at risk for a cardiovascular event, an aspirin (75–160 mg/d), should be given along with a COX-2 selective NSAID.
The American College of Rheumatology recommends that a COX-2 selective NSAID should be considered for a person with osteoarthritis and pain not relieved by an adequate dose of acetaminophen (not to exceed 4 g/d).14,15 The COX-2 selective NSAID is particularly advantageous for those who have higher risk factors for adverse GI events (TABLE 2). For a person with rheumatoid arthritis, in addition to DMARDs, NSAIDs (salicylates, nonselective NSAID, or COX-2 selective NSAID) should be used to reduce joint pain and swelling and improve joint function. Patients with additional risks for cardiovascular events should be cautioned about use of a COX-2 selective NSAID.
A recent AHRQ report on managing osteoarthritis underscores the importance of physician-patient partnership and patient’s self management of osteoarthritis, and recommends acetaminophen (up to 4 g/day) as the drug of choice.16 It further cautions the injudicious use of NSAIDs because of its greater GI toxicity when compared with acetaminophen, and its higher medical costs.
TABLE 2
Risk factors for upper gastrointestinal adverse events
| Age ≥65 years |
| Comorbid medical conditions |
| Oral glucocorticoids |
| History of peptic ulcer disease |
| History of upper gastrointestinal bleeding |
| Anticoagulants |
| Source: American College of Rheumatology, Arthritis Rheum 2000.12 |
Cyclo-oxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs) are as effective as acetaminophen and nonselective NSAIDs in treating of osteoarthritis, and are equally effective in reducing pain and inflammation and improving of joint function for patients with rheumatoid arthritis, when compared with nonselective NSAIDs. The COX-2 selective NSAIDs also have a better gastrointestinal safety profile in short-term (6–12 month) treatment (strength of recommendation [SOR]: A, based on meta-analysis of randomized controlled trials with patient-oriented outcomes).
However, with recent growing concern of the cardiovascular safety of COX-2 selective NSAIDs, it is imperative to select appropriate patients by considering benefit vs risks, which include serious gastrointestinal bleeding (TABLE 1), history of intolerance to nonselective NSAID, cardiovascular disease or associated risks, renal disease, patient’s preference, and cost.
Nonselective NSAIDs with misoprostol or a PPI instead of COX-2 inhibitor is a reasonable strategy
Joseph Saseen, PharmD, FCCP, BCPS
University of Colorado at Denver and Health Sciences Center, Denver, Colo
Although celecoxib is an effective NSAID, rofecoxib and lumericoxib are the only COX-2 selective inhibitors that definitively reduce gastrointestinal (GI) ulcerations/complications compared with nonselective NSAID therapy.1,2 However, neither of these are on the market. Data from the CLASS study showed no reduced risk of GI ulcerations/complications with celecoxib vs ibuprofen or diclofenac among patients receiving low-dose aspirin.3 Low-dose aspirin reduces cardiovascular events for patients with moderate or high cardiovascular risk (Framingham scores ≥10%). Therefore, using nonselective NSAID therapy in combination with either misoprostol or a proton pump inhibitor (eg, omeprazole) instead of celecoxib, is a reasonable and proven strategy to provide NSAID therapy for patients on low-dose aspirin who are at high risk for NSAID-associated gastropathy.
Evidence summary
A Cochrane review4 (6 randomized controlled trials, N=1689, mean duration 5.8 weeks) assessed the efficacy and safety of acetaminophen in the management of osteoarthritis, comparing it with placebo and NSAIDs. Acetaminophen was superior to placebo in pain reduction and global assessment (number needed to treat [NNT]=2) with a similar safety profile. NSAIDs were better than acetaminophen in pain reduction, patient (NNT=6) and physician global assessment (NNT=17), but no better for functional improvement. Compared with nonselective NSAIDs, acetaminophen led to fewer withdrawals (number needed to harm [NNH]=20) and fewer GI adverse events (NNH=9), but there was no statistical difference when compared with COX-2 selective NSAIDs.
Another Cochrane review5 (26 randomized controlled trials) found that rofecoxib (Vioxx) was more effective than placebo (NNT=5), and equally effective with other NSAIDs in the management of osteoarthritis. They reported fewer GI adverse events (endoscopically observed gastric erosion and ulcers) with rofecoxib than with other NSAIDs—naproxen (Naprosyn), ibuprofen (Motrin), diclofenac (Cataflam), nabumetone (Relafen), diclofenac/misoprostol (Arthrotec), and nimesulide. However, the withdrawal rate due to adverse events and the increase in blood pressure and edema were significantly greater with rofecoxib than placebo at 6 weeks.
Two Cochrane reviews6-7 confirmed the efficacy of celecoxib (Celebrex) and rofecoxib in treating of rheumatoid arthritis. One review included 2 RCTs (N=8734) with a placebo arm (8 weeks) and naproxen arm (9 months).7 The rofecoxib groups (25 mg, 50 mg) had more responders than the placebo group (NNT=8 and 6 respectively). Compared with naproxen (1 g), no difference was seen in efficacy in the OMERACT outcomes (Outcome Measures for Rheumatoid Arthritis Clinical Trials), but all combined GI adverse events (perforation, ulcer, obstruction, bleeding, and all episodes of GI bleeding) were significantly reduced at 9 months (NNH=20). The withdrawals were the same in the 3 groups. Compared with placebo, the rofecoxib groups had similar incidence of elevated blood pressure and edema (NNH=50 and 100, respectively). Compared with the naproxen group, no difference was seen in renal adverse events, but total cardiovascular thrombotic events (NNH=200) and nonfatal MI (NNH=300) increased at 9 months in the 50 mg rofecoxib group.
Similar cardiovascular adverse events were reported in the APPROVE trial.9 In this study, patients taking rofecoxib 25 mg daily for 18 months had increased total thrombotic events (MI, stroke, peripheral arterial and venous thrombosis, and pulmonary embolism) when compared with placebo (NNH=63). A recent study also raised the same concern of increased cardiovascular adverse events with celecoxib.10 This study demonstrated an increase risk of cardiovascular events (combined death, myocardial infarction, stroke, and heart failure) for patients taking celecoxib 200 mg twice a day (NNH=77) or 400 mg twice a day (NNH=42).
Many patients taking low-dose aspirin for cardioprotection also frequently require treatment of pain and inflammation with a NSAID. Even low-dose aspirin (75 mg/d) is known to be associated with increased GI toxicity (ulcers and hemorrhages).11 A recent double-blind, randomized placebo-controlled trial found that 12 weeks of treatment with a combination of low-dose aspirin and a COX-2 selective NSAID (rofecoxib) had more than twice the incidence of endoscopically confirmed gastric and duodenal ulcers, compared with aspirin alone, and no difference with a nonselective NSAID.12 This has raised the safety concern of concomitant use of a COX-2 selective NSAID with low-dose aspirin.
TABLE 1
Prediction of serious gastrointestinal bleeding
| RISK FACTORS PRESENT | RISK OF GI BLEEDING |
|---|---|
| 0 factor | 0.4 % |
| Any 1 factor | 1.0 % |
| All 4 factors | 9.0 % |
| Risk factors include age >75 years, history of peptic ulcer disease, history of gastrointestinal bleeding, history of cardiovascular disease | |
| Source: Silverstein et al, Ann Intern Med 1995.8 | |
Recommendations from others
The American Pain Society recommends that for patients with osteoarthritis, acetaminophen is the drug of choice for mild pain.13 For moderate to severe pain and or inflammation, a COX-2 selective NSAID is the first choice, unless the patient is at significant risk for hypertension or renal disorder. For patients with active rheumatoid arthritis and moderate to severe pain with or without inflammation, a COX-2 selective NSAID should be used concomitantly with a disease-modifying antirheumatic drug (DMARD), unless contraindicated by existing uncontrolled hypertension and renal disease. It further recommends that for a person who is at risk for a cardiovascular event, an aspirin (75–160 mg/d), should be given along with a COX-2 selective NSAID.
The American College of Rheumatology recommends that a COX-2 selective NSAID should be considered for a person with osteoarthritis and pain not relieved by an adequate dose of acetaminophen (not to exceed 4 g/d).14,15 The COX-2 selective NSAID is particularly advantageous for those who have higher risk factors for adverse GI events (TABLE 2). For a person with rheumatoid arthritis, in addition to DMARDs, NSAIDs (salicylates, nonselective NSAID, or COX-2 selective NSAID) should be used to reduce joint pain and swelling and improve joint function. Patients with additional risks for cardiovascular events should be cautioned about use of a COX-2 selective NSAID.
A recent AHRQ report on managing osteoarthritis underscores the importance of physician-patient partnership and patient’s self management of osteoarthritis, and recommends acetaminophen (up to 4 g/day) as the drug of choice.16 It further cautions the injudicious use of NSAIDs because of its greater GI toxicity when compared with acetaminophen, and its higher medical costs.
TABLE 2
Risk factors for upper gastrointestinal adverse events
| Age ≥65 years |
| Comorbid medical conditions |
| Oral glucocorticoids |
| History of peptic ulcer disease |
| History of upper gastrointestinal bleeding |
| Anticoagulants |
| Source: American College of Rheumatology, Arthritis Rheum 2000.12 |
1. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520-1528.
2. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364:665-674.
3. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247-1255.
4. Towheed TE, Judd MG, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2003;(2):CD004257.-
5. Garner SE, Fidan DD, Frankish RR, Maxwell LJ. Rofecoxib for osteoarthritis. Cochrane Database Syst Rev 2005;(1):CD005115.-
6. Garner S, Fidan D, Frankish R, et al. Celecoxib for rheumatoid arthritis. Cochrane Database Syst Rev 2002;(4):CD003831.-
7. Garner SE, Fidan DD, Frankish RR, et al. Rofecoxib for rheumatoid arthritis. Cochrane Database Syst Rev 2005;(1):CD003685.-
8. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduced serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-249.
9. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092-1102.
10. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-1080.
11. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-1187.
12. Laine L, Maller ES, Yu C, Quan H, Simon T. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: A double-blind trial. Gastroenterology 2004;127:395-402.
13. Simon LS, Lipman AG, Jacox AK, et al. Pain in Osteoarthritis, Rheumatoid Arthritis and Juvenile Chronic Arthritis. 2nd ed. Glenview, Ill: American Pain Society; 2002.
14. American College of Rheumatology (ACR) Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;43:1905-1915.
15. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum 2002;46:328-346.
16. Managing Osteoarthritis: Helping the Elderly Maintain Function and Mobility. Issue 4, AHRQ Pub. No 02-0023, May 2002. Agency for Healthcare Research and Quality. Available at: www.ahrq.gov/research/osteoria/osteoria.htm#self-manage.
1. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520-1528.
2. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364:665-674.
3. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247-1255.
4. Towheed TE, Judd MG, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2003;(2):CD004257.-
5. Garner SE, Fidan DD, Frankish RR, Maxwell LJ. Rofecoxib for osteoarthritis. Cochrane Database Syst Rev 2005;(1):CD005115.-
6. Garner S, Fidan D, Frankish R, et al. Celecoxib for rheumatoid arthritis. Cochrane Database Syst Rev 2002;(4):CD003831.-
7. Garner SE, Fidan DD, Frankish RR, et al. Rofecoxib for rheumatoid arthritis. Cochrane Database Syst Rev 2005;(1):CD003685.-
8. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduced serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-249.
9. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092-1102.
10. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-1080.
11. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321:1183-1187.
12. Laine L, Maller ES, Yu C, Quan H, Simon T. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: A double-blind trial. Gastroenterology 2004;127:395-402.
13. Simon LS, Lipman AG, Jacox AK, et al. Pain in Osteoarthritis, Rheumatoid Arthritis and Juvenile Chronic Arthritis. 2nd ed. Glenview, Ill: American Pain Society; 2002.
14. American College of Rheumatology (ACR) Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;43:1905-1915.
15. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum 2002;46:328-346.
16. Managing Osteoarthritis: Helping the Elderly Maintain Function and Mobility. Issue 4, AHRQ Pub. No 02-0023, May 2002. Agency for Healthcare Research and Quality. Available at: www.ahrq.gov/research/osteoria/osteoria.htm#self-manage.
Evidence-based answers from the Family Physicians Inquiries Network