Regarding the drug interactions between sacubitril/valsartan and statins, we identified 3 reports of rhabdomyolysis with high-potency statins. However, it remains unknown whether the combined use of these medications could lead to additive or synergistic effects on rhabdomyolysis. This study aims to assess the disproportionality in reporting rhabdomyolysis for these medications when used alone or in combination. Case reports from the United States Food and Drug Administration’s Adverse Event Reporting System from 1991 to Q4/2020 were used. Queries extracted reports based on exposure to statins alone, sacubitril/valsartan alone, and statin+sacubitril/valsartan each. Proportional reporting ratios (PRR) and 95% confidence intervals (CIs) were calculated, where a lower limit of the 95% CI (Lower 95% CI) value of ≥2.0 was interpreted as a safety signal. Lower 95% CIs for statins other than rosuvastatin alone demonstrated no potential safety signals for rhabdomyolysis, death, or the control event. The PRRs and 95% CI for rhabdomyolysis were 2.39 (2.01 to 2.84) with rosuvastatin alone and 2.06 (2.01 to 2.12) for sacubitril/valsartan alone. For atorvastatin+sacubitril/valsartan, the PRR and 95% CI were 0.95 (0.64 to 1.40). Statin+sacubitril/valsartan was not associated with a safety signal. However, rosuvastatin alone and sacubitril/valsartan alone were associated with rhabdomyolysis.
The common cause of rhabdomyolysis is the administration of drugs such as statins. Recently, the drug interactions between sacubitril/valsartan and high-potency statins have identified 3 reports of rhabdomyolysis. Sacubitril/valsartan decreases the risk of cardiovascular death in patients with congestive heart failure (CHF). However, co-administration of high-potency statins and sacubitril/valsartan is not rare, because patients with CHF commonly experience cardiovascular disease complications. Sacubitril is an inhibitor of the organic anion-transporting polypeptide (OATP) 1B1, and 1B3 and statin are their substrates. Therefore, we consider that health care providers should be careful in prescribing high-potency statins to patients with CHF. However, it remains unknown whether the combined use of these medications could lead to additive or synergistic effects on rhabdomyolysis. The purpose of this study was to assess the disproportionality in reporting rhabdomyolysis for these medications when used alone or in combination.
Methods
Case reports from the United States Food and Drug Administration’s Adverse Event Reporting System (FAERS) from 1991 to Q4/2020 were used. Each report includes suspected medications, outcomes (e.g., death), concomitant medication, adverse events mapped to the Medical Dictionary for Regulatory Activities (MedDRA) terminology, and other patient information. As the Japanese Adverse Drug Event Report includes little data regarding sacubitril/valsartan because of being approved by the Pharmaceuticals and Medical Devices Agency only in August 2020 in Japan, we used the FAERS database that was approved in 2015 in the United States instead of the Japanese Adverse Drug Event Report database. Each FAERS report was identified to be mutually exclusive based on the following observed drug mentions: atorvastatin alone, atorvastatin+sacubitril/valsartan, rosuvastatin alone, rosuvastatin+sacubitril/valsartan, simvastatin alone, simvastatin+sacubitril/valsartan, pravastatin alone, pravastatin+sacubitril/valsartan, lovastatin alone, lovastatin+sacubitril/valsartan, fluvastatin alone, fluvastatin+sacubitril/valsartan, pitavastatin alone, pitavastatin+sacubitril/valsartan, and sacubitril/valsartan alone.
The main adverse events of interest were death and rhabdomyolysis. We used standardized MedDRA queries to capture each adverse drug event. To further increase confidence in the results, the analyses also included standardized MedDRA queries for “dummy” outcomes of depression, as these unrelated medical conditions or events should not be affected by possible drug-drug interaction effects. A structured query captured all FAERS reports that included atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, and sacubitril/valsartan.
We calculated the proportional reporting ratio (PRR) based on binary exposures (yes/no) and binary outcomes (yes/no) using 2 × 2 contingency tables for each drug group ( Figure 1 ). The PRR measures the disproportionality of the outcome in the exposed group compared with the unexposed group. PRRs are interpreted as potentially meaningful in pharmacovigilance based on the lower level of the 95% confidence interval (Lower 95% CI) ≥2.0. Comparative treatment groups were visually inspected for overlap to assess potential biases in reporting. All analyses were conducted using SAS version 9.3 (SAS Institute, Cary, North Carolina).
Results
The frequencies of reported adverse events for each study drug are listed in Table 1 . Lower 95% CIs for atorvastatin alone demonstrated no potential safety signals for rhabdomyolysis, death, or any of the control events ( Table 2 ). For rosuvastatin, there was a significant safety signal detected with a Lower 95% CI of 2.01 for rhabdomyolysis. In addition, for sacubitril/valsartan, a significant safety signal was detected with a Lower 95% CI of 2.01 for rhabdomyolysis. Conversely, the Lower 95% CIs for the atorvastatin+sacubitril/valsartan group (n = 648 total reports) and rosuvastatin+sacubitril/valsartan group (n = 281 total reports) demonstrated no potential safety signals for rhabdomyolysis.
| Drug of interest (No. of reports) | Adverse event of interest | Number of reports with event |
|---|---|---|
| Atorvastatin (N=110,477) | Death | 2344 |
| Rhabdomyolysis | 4325 | |
| Accident/Injuries | 7065 | |
| Depression | 1366 | |
| Atorvastatin+Sacubitril/valsartan (N=648) | Death | 19 |
| Rhabdomyolysis | 24 | |
| Accident/Injuries | 46 | |
| Depression | 6 | |
| Rosuvastatin (N=52,729) | Death | 650 |
| Rhabdomyolysis | 2358 | |
| Accident/Injuries | 3815 | |
| Depression | 741 | |
| Rosuvastatin+Sacubitril/valsartan (N=281) | Death | 3 |
| Rhabdomyolysis | 16 | |
| Accident/Injuries | 23 | |
| Depression | 1 | |
| Simvastatin (N=51,726) | Death | 577 |
| Rhabdomyolysis | 5859 | |
| Accident/Injuries | 4197 | |
| Depression | 955 | |
| Simvastatin+Sacubitril/valsartan (N=87) | Death | 0 |
| Rhabdomyolysis | 1 | |
| Accident/Injuries | 2 | |
| Depression | 0 | |
| Pravastatin (N=17,685) | Death | 237 |
| Rhabdomyolysis | 613 | |
| Accident/Injuries | 889 | |
| Depression | 263 | |
| Pravastatin+Sacubitril/valsartan (N=36) | Death | 0 |
| Rhabdomyolysis | 0 | |
| Accident/Injuries | 0 | |
| Depression | 0 | |
| Lovastatin (N=15,801) | Death | 36 |
| Rhabdomyolysis | 354 | |
| Accident/Injuries | 359 | |
| Depression | 196 | |
| Lovastatin+Sacubitril/valsartan (N=2) | Death | 0 |
| Rhabdomyolysis | 0 | |
| Accident/Injuries | 0 | |
| Depression | 0 | |
| Fluvastatin (N=4,646) | Death | 73 |
| Rhabdomyolysis | 302 | |
| Accident/Injuries | 329 | |
| Depression | 86 | |
| Fluvastatin+Sacubitril/valsartan (N=4) | Death | 0 |
| Rhabdomyolysis | 0 | |
| Accident/Injuries | 0 | |
| Depression | 0 | |
| Pitavastatin (N=1993) | Death | 15 |
| Rhabdomyolysis | 104 | |
| Accident/Injuries | 64 | |
| Depression | 25 | |
| Pitavastatin+Sacubitril/valsartan (N=2) | Death | 0 |
| Rhabdomyolysis | 0 | |
| Accident/Injuries | 0 | |
| Depression | 0 | |
| Sacubitril/valsartan (N=61,847) | Death | 6600 |
| Rhabdomyolysis | 75 | |
| Accident/Injuries | 2573 | |
| Depression | 394 |
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