Stephen Hulkower, MD

EVIDENCE SUMMARY

Two recent multicenter, open-label RCTs, 1 in the United States and 1 in Norway, compared monthly XR-NTX with daily BUP-NX.^1,2 Both studies evaluated effectiveness (defined by either the number of people who relapsed or self-reported opioid use), cravings, and safety (defined as the absence of serious adverse events such as medically complex withdrawal or fatal overdose).

The participant populations were similar in both mean age and mean age of onset of opioid use. Duration of opioid use was reported differently (total duration or years of heavy heroin or other opioid use) and couldn’t be compared directly.

Naltrexone and buprenorphine-naloxone are similarly effective

The US study enrolled 570 opioid-dependent participants in a 24-week comparative effectiveness trial.¹ The 8 study sites were community treatment programs, and the participants were recruited during voluntary inpatient detoxification admissions. Some participants were randomized while on methadone or buprenorphine tapers and some after complete detoxification.

The intention-to-treat analysis included 283 patients in the XR-NTX group and 287 in the BUP-NX group. At 24 weeks, the number of participants who’d had a relapse event (self-reported use or positive urine drug test for nonstudy opioids or refusal to provide a urine sample) was 185 (65%) for XR-NTX compared with 163 (57%) for BUP-NX (odds ratio [OR] = 1.44, 95% confidence interval [CI], 1.02 to 2.01; P = .036).

The 12-week Norwegian noninferiority trial enrolled 159 participants.² In contrast to the US study, all participants were required to complete inpatient detoxification before randomization and induction onto the study medication.

Patients on BUP-NX reported 3.6 more days of heroin use within the previous 28 days than patients in the XR-NTX group (95% CI, 1.2 to 6; P = .003). For other illicit opioids, self-reported use was 2.4 days greater in the BUP-NX group (95% CI, −0.1 to 4.9; P = .06). Retention with XR-NTX was noninferior to BUP-NX (mean days in therapy [standard deviation], 69.3 [25.9] and 63.7 [29.9]; P = .33).

Randomizing after complete detox reduces induction failures

Naltrexone, a full opioid antagonist, precipitates withdrawal when a full or partial opioid agonist is engaging the opioid receptor. For this reason, an opioid-free interval of 7 to 10 days is generally recommended before initiating naltrexone, raising the risk for relapse during the induction process.

Continue to: The Norwegian trial...

The Norwegian trial randomized participants after detoxification. The US trial, in which some participants were randomized before completing detoxification, reported 79 (28%) induction failures for XR-NTX and 17 (6%) for BUP-NX.¹ As a result, a per protocol analysis was completed with the 204 patients on XR-NTX and 270 patients on BUP-NX who were successfully inducted onto a study medication. The 24-week relapse rate was 52% (106) for XR-NTX and 56% (150) for BUP-NX (OR = 0.87; 95% CI, 0.60 to 1.25; P = .44).

Cravings, adverse events, and cost considerations

Patients reported cravings using a visual analog scale. At 12 weeks in both studies, the XR-NTX groups reported fewer cravings than the BUP-NX groups, although by the end of the 24-week US trial, no statistically significant difference in cravings was found between the 2 groups.^1,2

The Norwegian trial found a difference between the XR-NTX and the BUP-NX groups in the percentage of nonserious adverse events such as nausea or chills (60.6% in the XR-NTX group vs 30.6% in the BUP-NX group; P < .001), and the US trial found a difference in total number of overdoses (64% of the total overdoses were in the XR-NTX group). Neither trial, however, reported a statistically significant difference in serious adverse events or fatal overdoses between the 2 groups.^1,2

The price for naltrexone is $1665.06 per monthly injection.³ The price for buprenorphine-naloxone varies depending on dose and formulation, with a general range of $527 to $600 per month at 16 mg/d.⁴

Editor’s takeaway

Two higher-quality RCTs show similar but imperfect effectiveness for both XR-NTX and daily sublingual BUP-NX. Injectable naltrexone’s higher cost may influence medication choice.

EVIDENCE SUMMARY

Two recent multicenter, open-label RCTs, 1 in the United States and 1 in Norway, compared monthly XR-NTX with daily BUP-NX.^1,2 Both studies evaluated effectiveness (defined by either the number of people who relapsed or self-reported opioid use), cravings, and safety (defined as the absence of serious adverse events such as medically complex withdrawal or fatal overdose).

The participant populations were similar in both mean age and mean age of onset of opioid use. Duration of opioid use was reported differently (total duration or years of heavy heroin or other opioid use) and couldn’t be compared directly.

Naltrexone and buprenorphine-naloxone are similarly effective

The US study enrolled 570 opioid-dependent participants in a 24-week comparative effectiveness trial.¹ The 8 study sites were community treatment programs, and the participants were recruited during voluntary inpatient detoxification admissions. Some participants were randomized while on methadone or buprenorphine tapers and some after complete detoxification.

The intention-to-treat analysis included 283 patients in the XR-NTX group and 287 in the BUP-NX group. At 24 weeks, the number of participants who’d had a relapse event (self-reported use or positive urine drug test for nonstudy opioids or refusal to provide a urine sample) was 185 (65%) for XR-NTX compared with 163 (57%) for BUP-NX (odds ratio [OR] = 1.44, 95% confidence interval [CI], 1.02 to 2.01; P = .036).

The 12-week Norwegian noninferiority trial enrolled 159 participants.² In contrast to the US study, all participants were required to complete inpatient detoxification before randomization and induction onto the study medication.

Patients on BUP-NX reported 3.6 more days of heroin use within the previous 28 days than patients in the XR-NTX group (95% CI, 1.2 to 6; P = .003). For other illicit opioids, self-reported use was 2.4 days greater in the BUP-NX group (95% CI, −0.1 to 4.9; P = .06). Retention with XR-NTX was noninferior to BUP-NX (mean days in therapy [standard deviation], 69.3 [25.9] and 63.7 [29.9]; P = .33).

Randomizing after complete detox reduces induction failures

Naltrexone, a full opioid antagonist, precipitates withdrawal when a full or partial opioid agonist is engaging the opioid receptor. For this reason, an opioid-free interval of 7 to 10 days is generally recommended before initiating naltrexone, raising the risk for relapse during the induction process.

Continue to: The Norwegian trial...

The Norwegian trial randomized participants after detoxification. The US trial, in which some participants were randomized before completing detoxification, reported 79 (28%) induction failures for XR-NTX and 17 (6%) for BUP-NX.¹ As a result, a per protocol analysis was completed with the 204 patients on XR-NTX and 270 patients on BUP-NX who were successfully inducted onto a study medication. The 24-week relapse rate was 52% (106) for XR-NTX and 56% (150) for BUP-NX (OR = 0.87; 95% CI, 0.60 to 1.25; P = .44).

Cravings, adverse events, and cost considerations

Patients reported cravings using a visual analog scale. At 12 weeks in both studies, the XR-NTX groups reported fewer cravings than the BUP-NX groups, although by the end of the 24-week US trial, no statistically significant difference in cravings was found between the 2 groups.^1,2

The Norwegian trial found a difference between the XR-NTX and the BUP-NX groups in the percentage of nonserious adverse events such as nausea or chills (60.6% in the XR-NTX group vs 30.6% in the BUP-NX group; P < .001), and the US trial found a difference in total number of overdoses (64% of the total overdoses were in the XR-NTX group). Neither trial, however, reported a statistically significant difference in serious adverse events or fatal overdoses between the 2 groups.^1,2

The price for naltrexone is $1665.06 per monthly injection.³ The price for buprenorphine-naloxone varies depending on dose and formulation, with a general range of $527 to $600 per month at 16 mg/d.⁴

Editor’s takeaway

Two higher-quality RCTs show similar but imperfect effectiveness for both XR-NTX and daily sublingual BUP-NX. Injectable naltrexone’s higher cost may influence medication choice.

EVIDENCE SUMMARY

Two recent multicenter, open-label RCTs, 1 in the United States and 1 in Norway, compared monthly XR-NTX with daily BUP-NX.^1,2 Both studies evaluated effectiveness (defined by either the number of people who relapsed or self-reported opioid use), cravings, and safety (defined as the absence of serious adverse events such as medically complex withdrawal or fatal overdose).

The participant populations were similar in both mean age and mean age of onset of opioid use. Duration of opioid use was reported differently (total duration or years of heavy heroin or other opioid use) and couldn’t be compared directly.

Naltrexone and buprenorphine-naloxone are similarly effective

The US study enrolled 570 opioid-dependent participants in a 24-week comparative effectiveness trial.¹ The 8 study sites were community treatment programs, and the participants were recruited during voluntary inpatient detoxification admissions. Some participants were randomized while on methadone or buprenorphine tapers and some after complete detoxification.

The intention-to-treat analysis included 283 patients in the XR-NTX group and 287 in the BUP-NX group. At 24 weeks, the number of participants who’d had a relapse event (self-reported use or positive urine drug test for nonstudy opioids or refusal to provide a urine sample) was 185 (65%) for XR-NTX compared with 163 (57%) for BUP-NX (odds ratio [OR] = 1.44, 95% confidence interval [CI], 1.02 to 2.01; P = .036).

The 12-week Norwegian noninferiority trial enrolled 159 participants.² In contrast to the US study, all participants were required to complete inpatient detoxification before randomization and induction onto the study medication.

Patients on BUP-NX reported 3.6 more days of heroin use within the previous 28 days than patients in the XR-NTX group (95% CI, 1.2 to 6; P = .003). For other illicit opioids, self-reported use was 2.4 days greater in the BUP-NX group (95% CI, −0.1 to 4.9; P = .06). Retention with XR-NTX was noninferior to BUP-NX (mean days in therapy [standard deviation], 69.3 [25.9] and 63.7 [29.9]; P = .33).

Randomizing after complete detox reduces induction failures

Naltrexone, a full opioid antagonist, precipitates withdrawal when a full or partial opioid agonist is engaging the opioid receptor. For this reason, an opioid-free interval of 7 to 10 days is generally recommended before initiating naltrexone, raising the risk for relapse during the induction process.

Continue to: The Norwegian trial...

The Norwegian trial randomized participants after detoxification. The US trial, in which some participants were randomized before completing detoxification, reported 79 (28%) induction failures for XR-NTX and 17 (6%) for BUP-NX.¹ As a result, a per protocol analysis was completed with the 204 patients on XR-NTX and 270 patients on BUP-NX who were successfully inducted onto a study medication. The 24-week relapse rate was 52% (106) for XR-NTX and 56% (150) for BUP-NX (OR = 0.87; 95% CI, 0.60 to 1.25; P = .44).

Cravings, adverse events, and cost considerations

Patients reported cravings using a visual analog scale. At 12 weeks in both studies, the XR-NTX groups reported fewer cravings than the BUP-NX groups, although by the end of the 24-week US trial, no statistically significant difference in cravings was found between the 2 groups.^1,2

The Norwegian trial found a difference between the XR-NTX and the BUP-NX groups in the percentage of nonserious adverse events such as nausea or chills (60.6% in the XR-NTX group vs 30.6% in the BUP-NX group; P < .001), and the US trial found a difference in total number of overdoses (64% of the total overdoses were in the XR-NTX group). Neither trial, however, reported a statistically significant difference in serious adverse events or fatal overdoses between the 2 groups.^1,2

The price for naltrexone is $1665.06 per monthly injection.³ The price for buprenorphine-naloxone varies depending on dose and formulation, with a general range of $527 to $600 per month at 16 mg/d.⁴

Editor’s takeaway

Two higher-quality RCTs show similar but imperfect effectiveness for both XR-NTX and daily sublingual BUP-NX. Injectable naltrexone’s higher cost may influence medication choice.

EVIDENCE SUMMARY

All NSAIDs at maximum clinical doses reduced large joint OA pain more effectively than placebo and acetaminophen based on data from a network meta-analysis of 129 RCTs with 32,129 patients (TABLE 1).¹ When various doses of NSAIDs are ranked for efficacy based on their effect size compared to placebo, diclofenac 150 mg/d had the greatest treatment effect, followed by ibuprofen 2400 mg/d.² Lower doses of NSAIDs—including diclofenac 70 mg/d, naproxen 750 mg/d, and ibuprofen 1200 mg/d—were not statistically superior to placebo (TABLE 2).²

Selective vs nonselective. There was no statistical difference in pain relief between the selective COX-2 inhibitor celecoxib and the nonselective NSAIDs naproxen, diclofenac, and ibuprofen (TABLE 1).¹

Meloxicam. A systematic review of 16 RCTs and 22,886 patients found that meloxicam reduced pain more effectively than placebo (10-point visual analogue scale [VAS] score pain difference of –6.8; 95% CI, –9.3 to –4.2) but was marginally less effective than other NSAIDs (VAS score pain difference of 1.7; 95% CI, 0.8 to 2.7).³

Acetaminophen. Data from 6 RCTs involving 2083 adults with knee OA indicate acetaminophen did not achieve clinical significance compared to placebo (TABLE 1).¹ Another meta-analysis of 5 RCTs involving 1741 patients with hip or knee OA also demonstrated that acetaminophen failed to achieve a clinically significant effect on pain, defined as a reduction of 9 mm on a 0 to 100 mm VAS (–3.7; 95% CI, –5.5 to –1.9).⁴ Another network meta-analysis of 6 RCTs including 58,556 patients with knee or hip OA, with the primary outcome of pain (using a hierarchy of pain scores, with global pain score taking precedence) also found no clinically significant difference between acetaminophen at the highest dose (4000 mg/d) and placebo (–0.17; 95% credible interval [CrI], –0.27 to –0.6).²

RECOMMENDATIONS

In a systematic review of mixed evidence-based and expert opinion recommendations and guidelines on the management of OA, 10 of the 11 guidelines that included pharmacologic management recommended acetaminophen as a first-line agent, followed by topical NSAIDs, and then oral NSAIDs. The exception is the most recent American Academy of Orthopaedic Surgeons guideline, which continues to recommend NSAIDs but is now unable to recommend for or against acetaminophen.⁵

EVIDENCE SUMMARY

All NSAIDs at maximum clinical doses reduced large joint OA pain more effectively than placebo and acetaminophen based on data from a network meta-analysis of 129 RCTs with 32,129 patients (TABLE 1).¹ When various doses of NSAIDs are ranked for efficacy based on their effect size compared to placebo, diclofenac 150 mg/d had the greatest treatment effect, followed by ibuprofen 2400 mg/d.² Lower doses of NSAIDs—including diclofenac 70 mg/d, naproxen 750 mg/d, and ibuprofen 1200 mg/d—were not statistically superior to placebo (TABLE 2).²

Selective vs nonselective. There was no statistical difference in pain relief between the selective COX-2 inhibitor celecoxib and the nonselective NSAIDs naproxen, diclofenac, and ibuprofen (TABLE 1).¹

Meloxicam. A systematic review of 16 RCTs and 22,886 patients found that meloxicam reduced pain more effectively than placebo (10-point visual analogue scale [VAS] score pain difference of –6.8; 95% CI, –9.3 to –4.2) but was marginally less effective than other NSAIDs (VAS score pain difference of 1.7; 95% CI, 0.8 to 2.7).³

Acetaminophen. Data from 6 RCTs involving 2083 adults with knee OA indicate acetaminophen did not achieve clinical significance compared to placebo (TABLE 1).¹ Another meta-analysis of 5 RCTs involving 1741 patients with hip or knee OA also demonstrated that acetaminophen failed to achieve a clinically significant effect on pain, defined as a reduction of 9 mm on a 0 to 100 mm VAS (–3.7; 95% CI, –5.5 to –1.9).⁴ Another network meta-analysis of 6 RCTs including 58,556 patients with knee or hip OA, with the primary outcome of pain (using a hierarchy of pain scores, with global pain score taking precedence) also found no clinically significant difference between acetaminophen at the highest dose (4000 mg/d) and placebo (–0.17; 95% credible interval [CrI], –0.27 to –0.6).²

RECOMMENDATIONS

In a systematic review of mixed evidence-based and expert opinion recommendations and guidelines on the management of OA, 10 of the 11 guidelines that included pharmacologic management recommended acetaminophen as a first-line agent, followed by topical NSAIDs, and then oral NSAIDs. The exception is the most recent American Academy of Orthopaedic Surgeons guideline, which continues to recommend NSAIDs but is now unable to recommend for or against acetaminophen.⁵

EVIDENCE SUMMARY

All NSAIDs at maximum clinical doses reduced large joint OA pain more effectively than placebo and acetaminophen based on data from a network meta-analysis of 129 RCTs with 32,129 patients (TABLE 1).¹ When various doses of NSAIDs are ranked for efficacy based on their effect size compared to placebo, diclofenac 150 mg/d had the greatest treatment effect, followed by ibuprofen 2400 mg/d.² Lower doses of NSAIDs—including diclofenac 70 mg/d, naproxen 750 mg/d, and ibuprofen 1200 mg/d—were not statistically superior to placebo (TABLE 2).²

Selective vs nonselective. There was no statistical difference in pain relief between the selective COX-2 inhibitor celecoxib and the nonselective NSAIDs naproxen, diclofenac, and ibuprofen (TABLE 1).¹

Meloxicam. A systematic review of 16 RCTs and 22,886 patients found that meloxicam reduced pain more effectively than placebo (10-point visual analogue scale [VAS] score pain difference of –6.8; 95% CI, –9.3 to –4.2) but was marginally less effective than other NSAIDs (VAS score pain difference of 1.7; 95% CI, 0.8 to 2.7).³

Acetaminophen. Data from 6 RCTs involving 2083 adults with knee OA indicate acetaminophen did not achieve clinical significance compared to placebo (TABLE 1).¹ Another meta-analysis of 5 RCTs involving 1741 patients with hip or knee OA also demonstrated that acetaminophen failed to achieve a clinically significant effect on pain, defined as a reduction of 9 mm on a 0 to 100 mm VAS (–3.7; 95% CI, –5.5 to –1.9).⁴ Another network meta-analysis of 6 RCTs including 58,556 patients with knee or hip OA, with the primary outcome of pain (using a hierarchy of pain scores, with global pain score taking precedence) also found no clinically significant difference between acetaminophen at the highest dose (4000 mg/d) and placebo (–0.17; 95% credible interval [CrI], –0.27 to –0.6).²

RECOMMENDATIONS

In a systematic review of mixed evidence-based and expert opinion recommendations and guidelines on the management of OA, 10 of the 11 guidelines that included pharmacologic management recommended acetaminophen as a first-line agent, followed by topical NSAIDs, and then oral NSAIDs. The exception is the most recent American Academy of Orthopaedic Surgeons guideline, which continues to recommend NSAIDs but is now unable to recommend for or against acetaminophen.⁵

EVIDENCE SUMMARY

A systematic review and meta-analysis of observational studies examined the risk of hypomagnesemia, defined in various studies as serum magnesium levels of 1.6, 1.7, or 1.8 mg/dL.¹ Two cohort studies, one case-control study, and 6 cross-sectional studies met inclusion criteria; 115,455 patients were enrolled. The studies were significantly heterogeneous (I²=89.1%), because of varying study designs, population sizes, and population characteristics.

PPI use increased the risk of hypomagnesemia (pooled odds ratio [OR]=1.5; 95% confidence interval [CI], 1.1-2.0) after adjustment for possible confounders such as use of diuretics.

Risk rises with long-term use, but severe hypomagnesemia is rare

Two more recent cohort studies produced conflicting results. Of 414 patients in a managed care cohort who received long-term PPIs, only 8 had mild hypomagnesemia (1.2-1.5 mg/dL) on nearly 14% of their combined 289 measurements. At final measurement, all patients had normal serum magnesium levels.²

A cross-sectional analysis of data from a retrospective cohort analysis of 9818 patients in the Netherlands found that any PPI use during the previous year was associated with an increased risk of hypomagnesemia (serum magnesium <1.73 mg/dL) compared with no use (adjusted OR=2; 95% CI, 1.4-2.9).³ The risk was greatest with use longer than 182 days (OR=3.0; 95% CI, 1.7-5.2). As with studies included in the meta-analysis, this study examined laboratory values exclusively. Only 3 of 724 PPI users had a serum magnesium level below 1.2 mg/dL, the point at which symptoms usually occur.

Case-control studies produce conflicting results

Two recent case-control studies also produced conflicting results. The first compared 154 outpatients who used PPIs for at least 6 months (mean, 27.5 months) with 84 nonusers.⁴ No association was found with hypomagnesemia (2.17 mg/dL vs 2.19 mg/dL), and none of the patients had a serum magnesium level below 1.7 mg/dL. The control group was poorly defined, however, and the study excluded patients taking diuretics.

Conversely, a study that compared 366 patients hospitalized with a primary or secondary diagnosis of hypomagnesemia (determined from an insurance claims database and defined as the presence of ICD-10 codes for hypomagnesemia or magnesium deficiency) with 1464 matched controls found that hospitalized patients with hypomagnesemia were more likely than controls to be current PPI users (adjusted OR=1.4; 95% CI, 1.1-1.9).⁵ Whether hypomagnesemia was the cause of the hospitalizations or an incidental finding wasn’t clear.

Concurrent use of diuretics and loop diuretics can increase risk

In a subgroup analysis of the second case-control study, PPI users who also used diuretics had an increased risk of hypomagnesemia (adjusted OR=1.7; 95% CI, 1.1-2.7) compared with patients who weren’t taking diuretics (adjusted OR=1.3; 95% CI, 0.8-1.9).⁵

Continue to: A comparison of the use of loop diuretics and...

A comparison of the use of loop diuretics and thiazides by patients taking PPIs found that concurrent use of loop diuretics increased serum magnesium reduction (−0.08 mg/dL; 95% CI, −0.14 to −0.02), but thiazides didn’t. Numbers were small: Of the 45 participants taking both a PPI and a loop diuretic, only 5 had hypomagnesemia (OR=7.2; 95% CI, 1.7-30.8).³

RECOMMENDATIONS

In 2011, the US Food and Drug Administration (FDA) warned of a possible increased risk of hypomagnesemia in patients taking PPIs long-term. The FDA advisory panel recommended evaluating serum magnesium before beginning long-term PPI therapy and in patients concurrently taking diuretics, digoxin, or other medications associated with hypomagnesemia.⁶

EVIDENCE SUMMARY

A systematic review and meta-analysis of observational studies examined the risk of hypomagnesemia, defined in various studies as serum magnesium levels of 1.6, 1.7, or 1.8 mg/dL.¹ Two cohort studies, one case-control study, and 6 cross-sectional studies met inclusion criteria; 115,455 patients were enrolled. The studies were significantly heterogeneous (I²=89.1%), because of varying study designs, population sizes, and population characteristics.

PPI use increased the risk of hypomagnesemia (pooled odds ratio [OR]=1.5; 95% confidence interval [CI], 1.1-2.0) after adjustment for possible confounders such as use of diuretics.

Risk rises with long-term use, but severe hypomagnesemia is rare

Two more recent cohort studies produced conflicting results. Of 414 patients in a managed care cohort who received long-term PPIs, only 8 had mild hypomagnesemia (1.2-1.5 mg/dL) on nearly 14% of their combined 289 measurements. At final measurement, all patients had normal serum magnesium levels.²

A cross-sectional analysis of data from a retrospective cohort analysis of 9818 patients in the Netherlands found that any PPI use during the previous year was associated with an increased risk of hypomagnesemia (serum magnesium <1.73 mg/dL) compared with no use (adjusted OR=2; 95% CI, 1.4-2.9).³ The risk was greatest with use longer than 182 days (OR=3.0; 95% CI, 1.7-5.2). As with studies included in the meta-analysis, this study examined laboratory values exclusively. Only 3 of 724 PPI users had a serum magnesium level below 1.2 mg/dL, the point at which symptoms usually occur.

Case-control studies produce conflicting results

Two recent case-control studies also produced conflicting results. The first compared 154 outpatients who used PPIs for at least 6 months (mean, 27.5 months) with 84 nonusers.⁴ No association was found with hypomagnesemia (2.17 mg/dL vs 2.19 mg/dL), and none of the patients had a serum magnesium level below 1.7 mg/dL. The control group was poorly defined, however, and the study excluded patients taking diuretics.

Conversely, a study that compared 366 patients hospitalized with a primary or secondary diagnosis of hypomagnesemia (determined from an insurance claims database and defined as the presence of ICD-10 codes for hypomagnesemia or magnesium deficiency) with 1464 matched controls found that hospitalized patients with hypomagnesemia were more likely than controls to be current PPI users (adjusted OR=1.4; 95% CI, 1.1-1.9).⁵ Whether hypomagnesemia was the cause of the hospitalizations or an incidental finding wasn’t clear.

Concurrent use of diuretics and loop diuretics can increase risk

In a subgroup analysis of the second case-control study, PPI users who also used diuretics had an increased risk of hypomagnesemia (adjusted OR=1.7; 95% CI, 1.1-2.7) compared with patients who weren’t taking diuretics (adjusted OR=1.3; 95% CI, 0.8-1.9).⁵

Continue to: A comparison of the use of loop diuretics and...

A comparison of the use of loop diuretics and thiazides by patients taking PPIs found that concurrent use of loop diuretics increased serum magnesium reduction (−0.08 mg/dL; 95% CI, −0.14 to −0.02), but thiazides didn’t. Numbers were small: Of the 45 participants taking both a PPI and a loop diuretic, only 5 had hypomagnesemia (OR=7.2; 95% CI, 1.7-30.8).³

RECOMMENDATIONS

In 2011, the US Food and Drug Administration (FDA) warned of a possible increased risk of hypomagnesemia in patients taking PPIs long-term. The FDA advisory panel recommended evaluating serum magnesium before beginning long-term PPI therapy and in patients concurrently taking diuretics, digoxin, or other medications associated with hypomagnesemia.⁶

EVIDENCE SUMMARY

A systematic review and meta-analysis of observational studies examined the risk of hypomagnesemia, defined in various studies as serum magnesium levels of 1.6, 1.7, or 1.8 mg/dL.¹ Two cohort studies, one case-control study, and 6 cross-sectional studies met inclusion criteria; 115,455 patients were enrolled. The studies were significantly heterogeneous (I²=89.1%), because of varying study designs, population sizes, and population characteristics.

PPI use increased the risk of hypomagnesemia (pooled odds ratio [OR]=1.5; 95% confidence interval [CI], 1.1-2.0) after adjustment for possible confounders such as use of diuretics.

Risk rises with long-term use, but severe hypomagnesemia is rare

Two more recent cohort studies produced conflicting results. Of 414 patients in a managed care cohort who received long-term PPIs, only 8 had mild hypomagnesemia (1.2-1.5 mg/dL) on nearly 14% of their combined 289 measurements. At final measurement, all patients had normal serum magnesium levels.²

A cross-sectional analysis of data from a retrospective cohort analysis of 9818 patients in the Netherlands found that any PPI use during the previous year was associated with an increased risk of hypomagnesemia (serum magnesium <1.73 mg/dL) compared with no use (adjusted OR=2; 95% CI, 1.4-2.9).³ The risk was greatest with use longer than 182 days (OR=3.0; 95% CI, 1.7-5.2). As with studies included in the meta-analysis, this study examined laboratory values exclusively. Only 3 of 724 PPI users had a serum magnesium level below 1.2 mg/dL, the point at which symptoms usually occur.

Case-control studies produce conflicting results

Two recent case-control studies also produced conflicting results. The first compared 154 outpatients who used PPIs for at least 6 months (mean, 27.5 months) with 84 nonusers.⁴ No association was found with hypomagnesemia (2.17 mg/dL vs 2.19 mg/dL), and none of the patients had a serum magnesium level below 1.7 mg/dL. The control group was poorly defined, however, and the study excluded patients taking diuretics.

Conversely, a study that compared 366 patients hospitalized with a primary or secondary diagnosis of hypomagnesemia (determined from an insurance claims database and defined as the presence of ICD-10 codes for hypomagnesemia or magnesium deficiency) with 1464 matched controls found that hospitalized patients with hypomagnesemia were more likely than controls to be current PPI users (adjusted OR=1.4; 95% CI, 1.1-1.9).⁵ Whether hypomagnesemia was the cause of the hospitalizations or an incidental finding wasn’t clear.

Concurrent use of diuretics and loop diuretics can increase risk

In a subgroup analysis of the second case-control study, PPI users who also used diuretics had an increased risk of hypomagnesemia (adjusted OR=1.7; 95% CI, 1.1-2.7) compared with patients who weren’t taking diuretics (adjusted OR=1.3; 95% CI, 0.8-1.9).⁵

Continue to: A comparison of the use of loop diuretics and...

A comparison of the use of loop diuretics and thiazides by patients taking PPIs found that concurrent use of loop diuretics increased serum magnesium reduction (−0.08 mg/dL; 95% CI, −0.14 to −0.02), but thiazides didn’t. Numbers were small: Of the 45 participants taking both a PPI and a loop diuretic, only 5 had hypomagnesemia (OR=7.2; 95% CI, 1.7-30.8).³

RECOMMENDATIONS

In 2011, the US Food and Drug Administration (FDA) warned of a possible increased risk of hypomagnesemia in patients taking PPIs long-term. The FDA advisory panel recommended evaluating serum magnesium before beginning long-term PPI therapy and in patients concurrently taking diuretics, digoxin, or other medications associated with hypomagnesemia.⁶

EVIDENCE SUMMARY

A 2013 systematic review of RCTs, systematic reviews, and meta-analyses examined the prophylactic use of low-dose aspirin for the primary prevention of cardiovascular disease (CVD) among adults 18 years and older.¹ Twenty-seven papers met inclusion criteria; the total number of patients wasn’t reported.

A composite finding of nonfatal MI, nonfatal stroke, and CVD death indicated a number needed to treat (NNT) of 138 over 10 years of therapy (relative risk [RR]=0.90; 95% confidence interval [CI], 0.85-0.96). CVD death wasn’t disaggregated from this composite, but an analysis of all-cause mortality didn’t reach statistical significance (RR=0.94; 95% CI, 0.88-1.00). RR for nonfatal stroke alone also wasn’t disaggregated.

Risk of gastrointestinal (GI) bleeding was found to be a number needed to harm (NNH) of 108 over 10 years (RR=1.37; 95% CI, 1.15-1.62) whereas risk of hemorrhagic stroke didn’t reach statistical significance (RR=1.32; 95% CI, 1.00-1.74). This population-level review didn’t report disaggregated findings by age or baseline atherosclerotic cardiovascular disease (ASCVD) risk.

Another review finds benefit only for prevention of nonfatal MI

A 2016 systematic review included 2 good-quality and 9 fair-quality RCTs evaluating the benefits of low-dose aspirin compared with placebo or no treatment for primary prevention of CVD events in 118,445 patients ages 40 years and older.² The review found benefit only for nonfatal MI, with an NNT of 126 over 10 years (RR=0.78; 95% CI, 0.71-0.87). There was no change in RR for nonfatal stroke (RR=0.95; 95% CI, 0.85-1.06); negligible impact on all-cause mortality (RR=0.95; 95% CI, 0.89-0.99); and no statistically significant benefit for CVD-specific mortality (RR=0.94; 95% CI, 0.86-1.03).

A companion 2016 systematic review of 16 RCTs, cohort studies, and meta-analyses evaluated the risk of serious bleeding in patients using low-dose aspirin for primary prevention of either CVD or cancer.³ The review (number of patients not reported) found that estimated excess bleeding events differed substantially depending on varying sources for baseline bleeding rates in aspirin nonusers.

The most conservative comparison yielded an NNH of 72 over 10 years of therapy (1.39 excess major GI bleeding events per 1000 person-years, 95% CI, 0.70-2.28). Comparison with other baseline bleeding rates in trial data yielded less risk of harm, with an NNH of 357 over 10 years (0.28 excess major GI bleeding events per 1000 person-years; 95% CI, 0.14-0.46). Excess risk for hemorrhagic stroke was not statistically significant (0.32 excess events per 1000 person-years; 95% CI, −0.05 to 0.82).

RECOMMENDATIONS

The US Preventive Services Task Force gives a Grade B recommendation (recommended, based on moderate to substantial benefit) to the use of aspirin to prevent CVD among adults ages 50 to 59 years with an ASCVD risk ≥10% who don’t have increased bleeding risk and are capable of 10 years of pharmacologic adherence with a similar expected longevity.⁴ The Task Force assigns a Grade C recommendation (individual and professional choice) to patients 60 to 69 years of age with the same constellation of risk factors and health status. Insufficient evidence was available to make recommendations for other age cohorts.

The American College of Chest Physicians recommends 75 to 100 mg of aspirin daily for adults 50 years or older who have moderate to high CV risk, defined as ≥10%.⁵

A working group of the European Society of Cardiology (ESC) released a statement in 2014 recommending aspirin for primary prevention in adults with a CV risk ≥20% and no risk factors for bleeding. For patients with a CVD risk between 10% and 20%, the ESC recommends deferring to patient preference.⁶

EVIDENCE SUMMARY

A 2013 systematic review of RCTs, systematic reviews, and meta-analyses examined the prophylactic use of low-dose aspirin for the primary prevention of cardiovascular disease (CVD) among adults 18 years and older.¹ Twenty-seven papers met inclusion criteria; the total number of patients wasn’t reported.

A composite finding of nonfatal MI, nonfatal stroke, and CVD death indicated a number needed to treat (NNT) of 138 over 10 years of therapy (relative risk [RR]=0.90; 95% confidence interval [CI], 0.85-0.96). CVD death wasn’t disaggregated from this composite, but an analysis of all-cause mortality didn’t reach statistical significance (RR=0.94; 95% CI, 0.88-1.00). RR for nonfatal stroke alone also wasn’t disaggregated.

Risk of gastrointestinal (GI) bleeding was found to be a number needed to harm (NNH) of 108 over 10 years (RR=1.37; 95% CI, 1.15-1.62) whereas risk of hemorrhagic stroke didn’t reach statistical significance (RR=1.32; 95% CI, 1.00-1.74). This population-level review didn’t report disaggregated findings by age or baseline atherosclerotic cardiovascular disease (ASCVD) risk.

Another review finds benefit only for prevention of nonfatal MI

A 2016 systematic review included 2 good-quality and 9 fair-quality RCTs evaluating the benefits of low-dose aspirin compared with placebo or no treatment for primary prevention of CVD events in 118,445 patients ages 40 years and older.² The review found benefit only for nonfatal MI, with an NNT of 126 over 10 years (RR=0.78; 95% CI, 0.71-0.87). There was no change in RR for nonfatal stroke (RR=0.95; 95% CI, 0.85-1.06); negligible impact on all-cause mortality (RR=0.95; 95% CI, 0.89-0.99); and no statistically significant benefit for CVD-specific mortality (RR=0.94; 95% CI, 0.86-1.03).

A companion 2016 systematic review of 16 RCTs, cohort studies, and meta-analyses evaluated the risk of serious bleeding in patients using low-dose aspirin for primary prevention of either CVD or cancer.³ The review (number of patients not reported) found that estimated excess bleeding events differed substantially depending on varying sources for baseline bleeding rates in aspirin nonusers.

The most conservative comparison yielded an NNH of 72 over 10 years of therapy (1.39 excess major GI bleeding events per 1000 person-years, 95% CI, 0.70-2.28). Comparison with other baseline bleeding rates in trial data yielded less risk of harm, with an NNH of 357 over 10 years (0.28 excess major GI bleeding events per 1000 person-years; 95% CI, 0.14-0.46). Excess risk for hemorrhagic stroke was not statistically significant (0.32 excess events per 1000 person-years; 95% CI, −0.05 to 0.82).

RECOMMENDATIONS

The US Preventive Services Task Force gives a Grade B recommendation (recommended, based on moderate to substantial benefit) to the use of aspirin to prevent CVD among adults ages 50 to 59 years with an ASCVD risk ≥10% who don’t have increased bleeding risk and are capable of 10 years of pharmacologic adherence with a similar expected longevity.⁴ The Task Force assigns a Grade C recommendation (individual and professional choice) to patients 60 to 69 years of age with the same constellation of risk factors and health status. Insufficient evidence was available to make recommendations for other age cohorts.

The American College of Chest Physicians recommends 75 to 100 mg of aspirin daily for adults 50 years or older who have moderate to high CV risk, defined as ≥10%.⁵

A working group of the European Society of Cardiology (ESC) released a statement in 2014 recommending aspirin for primary prevention in adults with a CV risk ≥20% and no risk factors for bleeding. For patients with a CVD risk between 10% and 20%, the ESC recommends deferring to patient preference.⁶

EVIDENCE SUMMARY

A 2013 systematic review of RCTs, systematic reviews, and meta-analyses examined the prophylactic use of low-dose aspirin for the primary prevention of cardiovascular disease (CVD) among adults 18 years and older.¹ Twenty-seven papers met inclusion criteria; the total number of patients wasn’t reported.

A composite finding of nonfatal MI, nonfatal stroke, and CVD death indicated a number needed to treat (NNT) of 138 over 10 years of therapy (relative risk [RR]=0.90; 95% confidence interval [CI], 0.85-0.96). CVD death wasn’t disaggregated from this composite, but an analysis of all-cause mortality didn’t reach statistical significance (RR=0.94; 95% CI, 0.88-1.00). RR for nonfatal stroke alone also wasn’t disaggregated.

Risk of gastrointestinal (GI) bleeding was found to be a number needed to harm (NNH) of 108 over 10 years (RR=1.37; 95% CI, 1.15-1.62) whereas risk of hemorrhagic stroke didn’t reach statistical significance (RR=1.32; 95% CI, 1.00-1.74). This population-level review didn’t report disaggregated findings by age or baseline atherosclerotic cardiovascular disease (ASCVD) risk.

Another review finds benefit only for prevention of nonfatal MI

A 2016 systematic review included 2 good-quality and 9 fair-quality RCTs evaluating the benefits of low-dose aspirin compared with placebo or no treatment for primary prevention of CVD events in 118,445 patients ages 40 years and older.² The review found benefit only for nonfatal MI, with an NNT of 126 over 10 years (RR=0.78; 95% CI, 0.71-0.87). There was no change in RR for nonfatal stroke (RR=0.95; 95% CI, 0.85-1.06); negligible impact on all-cause mortality (RR=0.95; 95% CI, 0.89-0.99); and no statistically significant benefit for CVD-specific mortality (RR=0.94; 95% CI, 0.86-1.03).

A companion 2016 systematic review of 16 RCTs, cohort studies, and meta-analyses evaluated the risk of serious bleeding in patients using low-dose aspirin for primary prevention of either CVD or cancer.³ The review (number of patients not reported) found that estimated excess bleeding events differed substantially depending on varying sources for baseline bleeding rates in aspirin nonusers.

The most conservative comparison yielded an NNH of 72 over 10 years of therapy (1.39 excess major GI bleeding events per 1000 person-years, 95% CI, 0.70-2.28). Comparison with other baseline bleeding rates in trial data yielded less risk of harm, with an NNH of 357 over 10 years (0.28 excess major GI bleeding events per 1000 person-years; 95% CI, 0.14-0.46). Excess risk for hemorrhagic stroke was not statistically significant (0.32 excess events per 1000 person-years; 95% CI, −0.05 to 0.82).

RECOMMENDATIONS

The US Preventive Services Task Force gives a Grade B recommendation (recommended, based on moderate to substantial benefit) to the use of aspirin to prevent CVD among adults ages 50 to 59 years with an ASCVD risk ≥10% who don’t have increased bleeding risk and are capable of 10 years of pharmacologic adherence with a similar expected longevity.⁴ The Task Force assigns a Grade C recommendation (individual and professional choice) to patients 60 to 69 years of age with the same constellation of risk factors and health status. Insufficient evidence was available to make recommendations for other age cohorts.

The American College of Chest Physicians recommends 75 to 100 mg of aspirin daily for adults 50 years or older who have moderate to high CV risk, defined as ≥10%.⁵

A working group of the European Society of Cardiology (ESC) released a statement in 2014 recommending aspirin for primary prevention in adults with a CV risk ≥20% and no risk factors for bleeding. For patients with a CVD risk between 10% and 20%, the ESC recommends deferring to patient preference.⁶

EVIDENCE SUMMARY

A 2013 network meta-analysis compared beta-blockers with placebo or standard treatment by analyzing 21 randomized trials with a total of 23,122 patients.¹ Investigators found that beta-blockers as a class significantly reduced mortality after a median of 12 months (odds ratio=0.71, 95% confidence interval [CI], 0.64-0.80; number needed to treat [NNT]=23). 

They also compared atenolol, bisoprolol, bucindolol, carvedilol, metoprolol, and nebivolol with each other and found no significant difference in risk of death, sudden cardiac death, death resulting from pump failure, or tolerability.

Three drugs are more effective and tolerable than others

A 2013 stratified subset meta-analysis used data from landmark randomized controlled trials (RCTs) that evaluated beta-blockers vs placebo in patients with systolic heart failure to compare metoprolol succinate (MERIT-HF) vs placebo with bisoprolol (CIBIS-II), carvedilol (COPERNICUS), and nebivolol (SENIORS-SHF) vs placebo (TABLE).²

Three of the drugs—bisoprolol, carvedilol, and metoprolol succinate—showed similar reductions relative to placebo in all-cause mortality, hospitalization for heart failure, and tolerability. Investigators concluded that the 3 drugs have comparable efficacy and tolerability, whereas nebivolol is less effective and tolerable.

Carvedilol vs beta-1-selective beta-blockers

Carvedilol, metoprolol succinate, and bisoprolol all reduce mortality by about 30% over one year in patients with Class III or IV systolic heart failure.Another 2013 meta-analysis of 8 RCTs with 4563 adult patients 18 years or older with systolic heart failure compared carvedilol with the beta-1-selective beta-blockers atenolol, bisoprolol, nebivolol, and metoprolol.³ Investigators found that carvedilol significantly reduced all-cause mortality (relative risk=0.85; 95% CI, 0.78-0.93; NNT=23) compared with beta-1-selective beta-blockers.

However, 4 trials (including COMET, N=3029) compared carvedilol with short-acting metoprolol tartrate, which may have skewed results in favor of carvedilol. Moreover, 2 trials comparing carvedilol with bisoprolol and 2 trials comparing carvedilol with nebivolol found no significant difference in all-cause mortality.³

RECOMMENDATIONS

The 2010 Heart Failure Society of America Comprehensive Heart Failure Practice Guideline notes that the marked beneficial effects of beta blockade with carvedilol, bisoprolol, and controlled- or extended-release metoprolol have been well-demonstrated in large-scale clinical trials of symptomatic patients with Class II to IV heart failure and reduced left ventricular ejection fraction.⁴

The 2013 American College of Cardiology Foundation/American Heart Association heart failure guideline recommends the use of one of the 3 beta-blockers proven to reduce mortality (bisoprolol, carvedilol, or sustained-release metoprolol succinate) for all patients with current or previous symptoms of heart failure with reduced ejection fraction, unless contraindicated, to reduce morbidity and mortality.⁵

EVIDENCE SUMMARY

A 2013 network meta-analysis compared beta-blockers with placebo or standard treatment by analyzing 21 randomized trials with a total of 23,122 patients.¹ Investigators found that beta-blockers as a class significantly reduced mortality after a median of 12 months (odds ratio=0.71, 95% confidence interval [CI], 0.64-0.80; number needed to treat [NNT]=23). 

They also compared atenolol, bisoprolol, bucindolol, carvedilol, metoprolol, and nebivolol with each other and found no significant difference in risk of death, sudden cardiac death, death resulting from pump failure, or tolerability.

Three drugs are more effective and tolerable than others

A 2013 stratified subset meta-analysis used data from landmark randomized controlled trials (RCTs) that evaluated beta-blockers vs placebo in patients with systolic heart failure to compare metoprolol succinate (MERIT-HF) vs placebo with bisoprolol (CIBIS-II), carvedilol (COPERNICUS), and nebivolol (SENIORS-SHF) vs placebo (TABLE).²

Three of the drugs—bisoprolol, carvedilol, and metoprolol succinate—showed similar reductions relative to placebo in all-cause mortality, hospitalization for heart failure, and tolerability. Investigators concluded that the 3 drugs have comparable efficacy and tolerability, whereas nebivolol is less effective and tolerable.

Carvedilol vs beta-1-selective beta-blockers

Carvedilol, metoprolol succinate, and bisoprolol all reduce mortality by about 30% over one year in patients with Class III or IV systolic heart failure.Another 2013 meta-analysis of 8 RCTs with 4563 adult patients 18 years or older with systolic heart failure compared carvedilol with the beta-1-selective beta-blockers atenolol, bisoprolol, nebivolol, and metoprolol.³ Investigators found that carvedilol significantly reduced all-cause mortality (relative risk=0.85; 95% CI, 0.78-0.93; NNT=23) compared with beta-1-selective beta-blockers.

However, 4 trials (including COMET, N=3029) compared carvedilol with short-acting metoprolol tartrate, which may have skewed results in favor of carvedilol. Moreover, 2 trials comparing carvedilol with bisoprolol and 2 trials comparing carvedilol with nebivolol found no significant difference in all-cause mortality.³

RECOMMENDATIONS

The 2010 Heart Failure Society of America Comprehensive Heart Failure Practice Guideline notes that the marked beneficial effects of beta blockade with carvedilol, bisoprolol, and controlled- or extended-release metoprolol have been well-demonstrated in large-scale clinical trials of symptomatic patients with Class II to IV heart failure and reduced left ventricular ejection fraction.⁴

The 2013 American College of Cardiology Foundation/American Heart Association heart failure guideline recommends the use of one of the 3 beta-blockers proven to reduce mortality (bisoprolol, carvedilol, or sustained-release metoprolol succinate) for all patients with current or previous symptoms of heart failure with reduced ejection fraction, unless contraindicated, to reduce morbidity and mortality.⁵

EVIDENCE SUMMARY

A 2013 network meta-analysis compared beta-blockers with placebo or standard treatment by analyzing 21 randomized trials with a total of 23,122 patients.¹ Investigators found that beta-blockers as a class significantly reduced mortality after a median of 12 months (odds ratio=0.71, 95% confidence interval [CI], 0.64-0.80; number needed to treat [NNT]=23). 

They also compared atenolol, bisoprolol, bucindolol, carvedilol, metoprolol, and nebivolol with each other and found no significant difference in risk of death, sudden cardiac death, death resulting from pump failure, or tolerability.

Three drugs are more effective and tolerable than others

A 2013 stratified subset meta-analysis used data from landmark randomized controlled trials (RCTs) that evaluated beta-blockers vs placebo in patients with systolic heart failure to compare metoprolol succinate (MERIT-HF) vs placebo with bisoprolol (CIBIS-II), carvedilol (COPERNICUS), and nebivolol (SENIORS-SHF) vs placebo (TABLE).²

Three of the drugs—bisoprolol, carvedilol, and metoprolol succinate—showed similar reductions relative to placebo in all-cause mortality, hospitalization for heart failure, and tolerability. Investigators concluded that the 3 drugs have comparable efficacy and tolerability, whereas nebivolol is less effective and tolerable.

Carvedilol vs beta-1-selective beta-blockers

Carvedilol, metoprolol succinate, and bisoprolol all reduce mortality by about 30% over one year in patients with Class III or IV systolic heart failure.Another 2013 meta-analysis of 8 RCTs with 4563 adult patients 18 years or older with systolic heart failure compared carvedilol with the beta-1-selective beta-blockers atenolol, bisoprolol, nebivolol, and metoprolol.³ Investigators found that carvedilol significantly reduced all-cause mortality (relative risk=0.85; 95% CI, 0.78-0.93; NNT=23) compared with beta-1-selective beta-blockers.

However, 4 trials (including COMET, N=3029) compared carvedilol with short-acting metoprolol tartrate, which may have skewed results in favor of carvedilol. Moreover, 2 trials comparing carvedilol with bisoprolol and 2 trials comparing carvedilol with nebivolol found no significant difference in all-cause mortality.³

RECOMMENDATIONS

The 2010 Heart Failure Society of America Comprehensive Heart Failure Practice Guideline notes that the marked beneficial effects of beta blockade with carvedilol, bisoprolol, and controlled- or extended-release metoprolol have been well-demonstrated in large-scale clinical trials of symptomatic patients with Class II to IV heart failure and reduced left ventricular ejection fraction.⁴

The 2013 American College of Cardiology Foundation/American Heart Association heart failure guideline recommends the use of one of the 3 beta-blockers proven to reduce mortality (bisoprolol, carvedilol, or sustained-release metoprolol succinate) for all patients with current or previous symptoms of heart failure with reduced ejection fraction, unless contraindicated, to reduce morbidity and mortality.⁵