The Association Between Drospirenone and Hyperkalemia

A Comparative-safety Study

Steven T Bird; Salvatore R Pepe; Mahyar Etminan; Xinyue Liu; James M Brophy; Joseph AC Delaney

Disclosures

BMC Clin Pharmacol. 2011;11(23):1-6. 

In This Article

Discussion

The current study did not find a substantial and meaningful association between drospirenone use and hyperkalemia compared to patients taking levonorgestrel. It is interesting to note that norethindrone and norgestimate are both associated with a higher risk for hyperkalemia compared to levonorgestrel. These however were not a priori hypotheses and may be chance findings due to multiple testing. These results must also be taken into context with the low absolute risk for hyperkalemia in OC users. The increased HR for norethindrone of 1.16 results in a number need to harm (NNH) of 3086 patients, while the HR for norgestimate of 1.27 results in a NNH of 1829 patients.

The null association between drospirenone and hyperkalemia is concordant with the results from previous studies.[13,23] To our knowledge, only one prior cohort study has been conducted with the primary aim to evaluate drospirenone and hyperkalemia.[13] This study had 67,287 OC users, identified 378 cases of hyperkalemia, and found a RR comparing drospirenone to other OCs of 0.9 (95%CI 0.7–1.1). Our study population has approximately seventeen times the OC user population of this prior analysis, allowing greater detection for hyperkalemia and providing increased statistical precision. Another study identified 102 cases of drug-associated hyperkalemia and did not attribute any cases to use of drospirenone.[23] In our study, the comparison among OC users in our analysis minimizes the risk of confounding by indication, and the new user design eliminates the survivor effect that long term OC users are tolerant to the therapy and healthier than short term users. The totality of the evidence suggests that hyperkalemia while on drospirenone is not of clinical importance.

Utilization

We found that drospirenone users are 2.66 times more likely to receive spironolactone compared with levonorgestrel users. An OR of this magnitude suggests that physicians are not avoiding the concomitant use of drospirenone and spironolactone, but prescribing them together. This is a particularly interesting finding because drospirenone is the only OC with a bolded warning for hyperkalemia. These medications have no overlap in labeled indications; however, drospirenone does have an indication for acne vulgaris, while spironolactone has an off-label use for its treatment. Another likely explanation in the recent literature is that drospirenone and spironolactone are both seen as beneficial for treatment of weight gain and bloating experienced by patients with postmenstrual dysphoric disorder and in reducing hirsutism and acne in patients with polycystic ovarian syndrome (PCOS).[24–28]

It was recently reported that, among 11,019 drospirenone users, 17.6% of patients are taking another medication known to induce hyperkalemia.[29] In this study, spironolactone accounted for 11.1% of this concomitant utilization. Our study found that only 6.5% of patients taking drospirenone and spironolactone underwent potassium monitoring. This raises concern that few physicians are following the recommendations for monitoring serum potassium as stated in the package insert.

Although we found a non-significant interaction for hyperkalemia with concomitant use of drospirenone and spironolactone, this does not assure the safe combined use of these two medications. Particularly, patients with PCOS generally express characteristics of metabolic syndrome, are at an increased risk for drug induced liver injury,[30] and warrant careful monitoring.

Limitations

The use of ICD-9-CM codes for the detection of hyperkalemia provides a high specificity for diagnosed cases because this diagnosis is made from an assay of serum potassium. This measurement however lacks sensitivity due to a lack of potassium testing in the general population. Inadequacies in documenting ICD-9-CM codes could also lead to underreporting of hyperkalemia. To determine if this was likely to be problematic, we interrogated the Lifelink™ database to investigate control drugs with known associations to hyperkalemia. Amiloride, a potassium-sparing diuretic, spironolactone, an aldosterone antagonist, and all ACE inhibitors were selected as positive controls. The Lifelink™ database was able to replicate three known positive associations: amiloride HR 7.94 (95%CI 1.96–32.08), spironolactone HR 3.46 (95%CI 2.97–4.02), and ACE inhibitors HR 1.90 (95%CI 1.70–2.11). Negative controls selected were loratadine, a non-drowsy antihistamine, topical hydrocortisone, and all statins. All negative associations were replicated: loratadine HR 0.84 (95%CI 0.60–1.20), topical hydrocortisone HR 1.37 (95%CI 0.92–2.05), and statins HR 1.06 (95%CI 0.92–1.22). A positive association was not found between NSAIDS and hyperkalemia (HR 0.93 (95%CI 0.81–1.06)). The above positive and negative controls are reassuring for the ability of this claims database to detect clinically relevant hyperkalemia and to find a null result when no association is known.

The bolded warning for drospirenone and hyperkalemia also has the potential to introduce a measurement bias. This warning makes potassium monitoring in the drospirenone group more likely, inducing a bias away from the null. This anti-conservative bias provides additional confidence in our null result. If channeling bias is present in our study population, steering patients at high risk for hyperkalemia away from drospirenone would provide a bias toward the null. Another interpretation of the study results is that, based on the regulatory framework, current clinical practice is sufficient to mitigate the risk of hyperkalemia in this population.

Due to the nature of a claims database, residual confounding is always present. Alcohol consumption, ethnicity, and diet are all potential unadjusted confounders in our study. Two covariates in the analysis, smoking and obesity, are reported only to justify treatment (such as bariatric surgery or smoking cessation therapy) and are not completely controlled.

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