IMPORTANCE Calcium channel blockers, specifically dihydropyridine calcium channel blockers (DH CCBs, eg, amlodipine), may cause lower-extremity edema. Anecdotal reports suggest this may result in a prescribing cascade, where DH CCB-induced edema is treated with loop diuretics. OBJECTIVE To assess the magnitude and characteristics of the DH CCB prescribing cascade. DESIGN, SETTING, AND PARTICIPANTS This cohort study used a prescription sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of DH CCBs among patients aged 20 years or older without heart failure. Data from a private insurance claims database from 2005 to 2017 was analyzed. Use of loop diuretics associated with initiation of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other commonly used medications was used as negative controls. Data were analyzed from March 2019 through October 2019. EXPOSURES Initiation of DH CCB or negative control medications. MAIN OUTCOMES AND MEASURES The temporality of loop diuretic initiation relative to DH CCB or negative control initiation. Secular trend-adjusted sequence ratios (aSRs) with 95% CIs were calculated using data from 360 days before and after initiation of DH CCBs. RESULTS Among 1 206 093 DH CCB initiators, 55 818 patients (4.6%) (33 100 [59.3%] aged <65 years; 32 916 [59.0%] women) had a new loop diuretic prescription 360 days before or after DH CCB initiation, resulting in an aSR of 1.87 (95% CI, 1.84-1.90). An estimated 1.44% of DH CCB initiators experienced the prescribing cascade. The aSR was disproportionately higher among DH CCB initiators who were prescribed high doses (aSR, 2.20; 95% CI, 2.13-2.27), initiated amlodipine (aSR, 1.89; 95% CI, 1.86-1.93), were men (aSR, 1.96; 95% CI, 1.91-2.01), and used fewer antihypertensive classes (aSR, 2.55; 95% CI, 2.47-2.64). The evaluation of ACE inhibitors or ARBs as negative controls suggested hypertension progression may have tempered the incidence of the prescribing cascade (aSR for ACE inhibitors and ARBs, 1.27; 95% CI, 1.24-1.29). CONCLUSIONS AND RELEVANCE This study found an excessive use of loop diuretics following initiation of DH CCBs that cannot be completely explained by secular trends or hypertension progression. The prescribing cascade was more pronounced among those initially prescribed a high dose of DH CCBs.

Medicaid prior authorization (PA) policies for treatment of hepatitis C virus (HCV) with direct‐acting antiviral (DAA) therapy are changing. We aimed to evaluate effects of changes in PA requirements on treatment uptake and to determine the factors associated with DAA treatment among Florida Medicaid beneficiaries with HCV. This is a retrospective cohort analysis of Florida’s Medicaid administrative claims and electronic medical records (2013‐2018). A total of 14,063 newly diagnosed patients with HCV were grouped based on human immunodeficiency virus (HIV) co‐infection and/or a substance use disorder (SUD) (7,735 HCV mono‐infected with a SUD, 5,180 HCV mono‐infected without a SUD, 564 HCV/HIV co‐infected with a SUD, and 584 HCV/HIV co‐infected without a SUD). Although the treatment rate increased three‐fold after June 1, 2016, when a fibrosis‐stage restriction was eliminated, only 8% received DAAs. Compared to HCV mono‐infected without a SUD, HCV mono‐infected with a SUD and HCV/HIV co‐infected with a SUD were 47% (adjusted hazard ratio, 0.53; 95% confidence interval, 0.47‐0.60) and 59% (adjusted hazard ratio, 0.41; 95% confidence interval, 0.28‐0.61) less likely to initiate DAAs. Those with HCV/HIV/SUD did not experience a DAA initiation increase after a fibrosis‐stage restriction was eliminated. Compared with Whites, Blacks were less likely to receive DAAs but were more likely to complete treatment. Use of medication‐assisted therapy was low, despite those on medication‐assisted therapy being 60% more likely to initiate DAA therapy and no more likely to discontinue therapy. Conclusion: Despite changes in Florida’s Medicaid PA requirements for DAA treatment, only 8% received treatment. Disparities in treatment access were found among patients with HIV and a SUD, and who were Black.

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Purpose There is an increased use in the (prescription) sequence symmetry analysis (PSSA); however, limited studies have incorporated a negative control, and no study has formally quantified and controlled for within‐patient time‐varying bias using a negative control. Our aim was to develop a process to incorporate the effect of negative controls into the main analysis of a PSSA. Methods Using a previously assessed dihydropyridine calcium channel blocker (DH‐CCB) and loop diuretic PSSA, we directly compared the adjusted sequence ratios (aSRs) of DH‐CCBs to each of the two negative control index drugs (levothyroxine and angiotensin converting enzyme [ACE] inhibitor/angiotensin‐2 receptor blocker [ARB]) using the ratio of the aSRs to estimate a relative aSR with a Z test. Further, we utilized the relative aSR in stratum‐specific analyses and varying exposure windows. Results The relative aSR of DH‐CCBs decreased from 1.87 to 1.72 (95% CI 1.66–1.78) using levothyroxine as a negative control index drug. ACE inhibitor/ARB negative control index drug resulted in an aSR of 1.27 thus reducing the relative aSR for DH‐CBB from 1.84 to 1.45 (95% CI 1.41–1.49). When restricting the exposure window to 180 and 90 days, the relative aSR of DH‐CCBs increased to 1.68 (95% CI 1.62–1.74) and 1.86 (95% CI 1.78–1.94), respectively, relative to the ACE inhibitor/ARB negative control index drug. Conclusion We illustrated how to incorporate negative control index drugs into a PSSA and generate relative aSRs. Stratum‐specific assessments and varying the exposure windows while using negative control index drugs can yield more informative results.

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Objectives: To evaluate the prescription sequence symmetry analysis assumption regarding balance between marker drug (i.e., medication used to treat a drug-induced adverse event) initiation rates before and after initiation of an index drug (i.e., medication that is potentially associated with the drug-induced adverse event) in the absence of prescribing cascades, we used a well-described example of loop diuretic initiation to treat dihydropyridine calcium channel blockers (DH CCB)induced edema.

BACKGROUND Drug-related adverse events associated with antihypertensive therapy may result in subsequent prescribing of other potentially harmful medications, known as prescribing cascades. The aim of this study was to assess the magnitude and characteristics of a beta-blocker – edema – loop diuretic prescribing cascade. METHODS A prescription sequence symmetry analysis (PSSA) was used to assess loop diuretic initiation before and after initiation of beta-blockers among patients 20 years or older without heart failure, atrial fibrillation, other arrythmias, or use of calcium channel blocker within a US private insurance claims database (2005 to 2018). The temporality of loop diuretic initiation relative to a beta-blocker or negative control (renin-angiotensin system blocker) initiation was tabulated. Secular trend-adjusted sequence ratios (aSRs) with 95% CIs compared the initiation of loop diuretic 90 days before and after initiation of beta-blockers. RESULTS Among 988,675 beta-blocker initiators, 9,489 patients initiated a new loop diuretic prescription 90 days after and 5,245 patients before beta-blocker initiation, resulting in an aSR of 1.78 (95% CI, 1.72-1.84). An estimated 1.72 beta-blocker initiators per 100 patient-years experienced the prescribing cascade in the first 90 days. The aSR was disproportionately higher among older adults (aSR 1.97), men (aSR 2.25), and patients who initiated metoprolol tartrate (aSR 2.48), labetalol (aSR 2.18), or metoprolol succinate (aSR 2.11). Negative control results (aSR 1.09, 95% 1.05-1.13) generally corroborated our findings, but suggested modest within-person time-varying confounding. CONCLUSIONS We observed excess use of loop diuretics following beta-blocker initiation that was only partially explained by secular trends or hypertension progression.

BaCKgRoUND aND aIMS: Our aim was to evaluate the impact of direct-acting antivirals (DAAs) on decompensated cirrhosis (DCC) and HCC in patients with chronic HCV and substance use disorder (SUD) compared with those without an SUD. appRoaCH aND ReSUltS: This retrospective cohort study used the MarketScan database (2013)(2014)(2015)(2016)(2017)(2018) to identify 29,228 patients with chronic HCV, where 22% (n = 6,385) had ≥1 SUD diagnosis. The inverse probability of treatment weighted multivariable Cox proportional hazard models were used to compare the risk of developing DCC and HCC. Among the those who were noncirrhotic, treatment reduced the DCC risk among SUD (adjusted hazard ratio [aHR] 0.13; 95% CI, 0.06-0.30) and non-SUD (aHR 0.11; 95% CI, 0.07-0.18), whereas the risk for HCC was not reduced for the SUD group (aHR 0.91; 95% CI, 0.33-2.48). For those with cirrhosis, compared with patients who were untreated, treatment reduced the HCC risk among SUD (aHR, 0.33; 95% CI, 0.13-0.88) and non-SUD (aHR, 0.40; 95% CI, 0.25-0.65), whereas the risk for DCC was not reduced for the SUD group (aHR, 0.64; 95% CI, 0.37-1.13). Among patients with cirrhosis who were untreated, the SUD group had a higher risk of DCC (aHR, 1.52; 95% CI, 1.03-2.24) and HCC (aHR, 1.69; 95% CI, 1.05-2.72) compared with non-SUD group.CoNClUSIoNS: Among the HCV SUD group, DAA treatment reduced the risk of DCC but not HCC for those who were noncirrhotic, whereas DAA treatment reduced the risk of HCC but not DCC for those with cirrhosis. Among the nontreated, patients with an SUD had a significantly higher risk of DCC and HCC compared with those without an SUD. Thus, DAA treatment should be considered for all patients with HCV and an SUD while also addressing the SUD. (Hepatology 2021;74:566-581). HCV infection is the most common chronic bloodborne infection in the United States and is a substantial cause of morbidity and mortality. In the United States, individuals with a substance use disorder (SUD) are disproportionately affected by HCV. In fact, injection drug use, which is the most common risk factor for contracting HCV, accounts for ~75% of newly acquired cases of HCV and ~50% of cases of chronic HCV infection. (1,2) In addition, the majority of patients infected with HCV also have an alcohol use disorder, which is highly associated with concomitant use of illegal substances, leading to an increased risk for HCV.