Testing for Primary Aldosteronism and Mineralocorticoid Receptor Antagonist Use Among U.S. Veterans: A Retrospective Cohort Study

“Hypertension affects 46% of the adult population in the United States and is a leading risk factor for disability, cardiovascular morbidity, and mortality. Although treatment reduces morbidity and mortality, approximately 17% to 20% of patients using antihypertensive medications have apparent treatment-resistant hypertension, defined as inadequately controlled blood pressure (BP) with 3 antihypertensive medications, including a diuretic, or a requirement for at least 4 antihypertensive medications to achieve adequate control. Compared with patients who require fewer antihypertensive agents, those with apparent treatment-resistant hypertension are at increased risk for cardiovascular and all-cause mortality, independent of BP control. High-quality evidence supports the use of mineralocorticoid receptor antagonist (MRA) therapy for management of treatment-resistant hypertension.

[..] Studies of health systems in California, Illinois, and New York found that testing rates for primary aldosteronism were less than 3% among patients for whom it is recommended. However, no similar study has been performed on a large scale, and whether testing rates are low in a large, highly integrated health care system is unknown. We aimed to evaluate the frequency of testing for primary aldosteronism in U.S. veterans with incident apparent treatment-resistant hypertension and factors associated with testing.

[..] The primary end point was testing for primary aldosteronism, defined as concomitant measurement of blood aldosterone concentration and either plasma renin activity or plasma renin concentration. Secondary end points were initiation of MRA treatment and change in SBP over time.

[..] After a median follow-up of 3.3 years (IQR, 1.0 to 6.7 years) after meeting criteria for apparent treatment-resistant hypertension, 4277 (1.6%) patients had testing for primary aldosteronism.

[..] We performed mixed-effects modeling to evaluate factors associated with primary aldosteronism testing, accounting for differences in testing patterns across providers and centers. At the patient level, several factors, including hypokalemia (standardized hazard ratio [HR], 1.93 [95% CI, 1.80 to 2.07]) and higher SBP (standardized HR, 1.43 [CI, 1.37 to 1.49]), were associated with a higher likelihood of undergoing testing. At the provider level, index visits with a nephrologist (HR, 2.05 [CI, 1.66 to 2.52]) or an endocrinologist (HR, 2.48 [CI, 1.69 to 3.63]), but not a cardiologist, were associated with a higher likelihood of testing compared with primary care. At the center level, rural location was associated with a lower likelihood of testing than nonrural location (HR, 0.53 [CI, 0.31 to 0.91]). The number of patients with treatment-resistant hypertension seen by a provider or center, overall center volume, and center academic affiliation were not meaningfully associated with testing.

[..] In analyses adjusted for patient-, provider-, and center-level covariates (including baseline BP), compared with no testing, testing for primary aldosteronism was associated with an average 1.47–mm Hg (CI, −1.64 to −1.29 mm Hg) lower SBP over time. The results were similar after adjustment for MRA use.

[..] We observed that fewer than 2% of patients with incident apparent treatment-resistant hypertension underwent guideline-recommended testing for primary aldosteronism. Testing rates ranged from 0% to 6% across medical centers and did not correlate to population size of patients with apparent treatment-resistant hypertension. Testing rates also did not change meaningfully over nearly 2 decades of follow-up despite an increasing number of guidelines recommending testing for primary aldosteronism in this population. Our finding of infrequent testing among patients with apparent treatment-resistant hypertension accords with prior studies in smaller health systems. We also found that consultation with a nephrologist or an endocrinologist and nonrural center location were independently associated with a higher likelihood of testing. In addition, we observed that testing for primary aldosteronism was associated with a substantially higher likelihood of initiation of evidence-based MRA therapy for management of apparent treatment-resistant hypertension (even in the absence of biochemical evidence of primary aldosteronism) and with greater improvement in BP over time.

[..] Various barriers to testing for primary aldosteronism have been identified via focus group from the perspective of German primary care clinicians. For example, some clinicians preferred an empirical trial of spironolactone without making a diagnosis, and others noted that stopping β-blockers before testing was impractical. However, we observed relatively low rates of MRA therapy initiation after patients met criteria for apparent treatment-resistant hypertension, particularly among those who were not tested for primary aldosteronism. Only 13% of patients with incident apparent treatment-resistant hypertension ultimately started MRA therapy, even though MRAs are recommended in approximately 70% of patients with treatment-resistant hypertension. Our results show that empirical MRA therapy in patients with apparent treatment-resistant hypertension is widely underused, particularly among those who are not tested for primary aldosteronism. In addition, testing for primary aldosteronism can proceed without stopping medication use under most circumstances.

Generally, failure to test patients with apparent treatment-resistant hypertension for primary aldosteronism may reflect a lack of familiarity with this common and treatable condition or a broader propensity for treatment inertia in this patient population. We found no relationship between center or provider volume of patients with apparent treatment-resistant hypertension and likelihood of testing for primary aldosteronism. Nonetheless, we did see substantial variation in testing practices across centers and providers. We observed higher rates of testing among patients seen by endocrinologists and nephrologists (who typically perform confirmatory testing for and oversee management of primary aldosteronism) compared with those seen by primary care providers or cardiologists. We also saw higher rates of evidence-based MRA treatment and better BP control over time among those who had testing, despite higher baseline BPs. These findings support the hypothesis that testing coincides with familiarity with primary aldosteronism and complex hypertension management. Further investigation is needed into barriers to testing for primary aldosteronism and ways to better implement best practices and guidelines among providers and medical centers that care for patients with treatment-resistant hypertension.

Testing for primary aldosteronism in patients with apparent treatment-resistant hypertension is cost-effective and may substantially improve long-term outcomes. In patients with positive results who undergo adrenalectomy for an aldosterone-secreting adenoma, compared with usual care, adrenalectomy is associated with lower risk for all-cause mortality (HR, 0.23 [CI, 0.13 to 0.26]), atrial fibrillation (HR, 0.55 [CI, 0.32 to 0.93]), and chronic kidney disease (difference in cumulative incidence, 6.5 [CI, 2.7 to 10.4]) and an improvement in quality-adjusted life-years. In addition to detecting primary aldosteronism, testing can identify patients with suppressed renin and normal aldosterone levels who may particularly benefit from treatment with an MRA or another potassium-sparing diuretic. Testing can also help to identify apparent mineralocorticoid excess syndrome and Liddle syndrome (in which patients tend to have low renin and aldosterone levels).”

Full article, Cohen JB, Cohen DL, Herman DS et al. Annals of Internal Medicine, 2020.12.29