Antihypertensive Drugs, Hypotension, and Ischemic Colitis

Abstract

In this issue of the journal, Hines et al. [1] report incidence rates of ischemic colitis in treated hypertensive adults in the USA, with a focus on aliskiren, a direct renin inhibitor. While these investigators are to be commended for assessing such a large dataset (2,356,226 hypertensive patients), they provide no clear explanation for the focus on aliskiren. The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) trial, which concerned patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, was stopped prematurely because of a slight excess risk of cardiovascular events in patients receiving aliskiren plus an angiotensin receptor blocker (ARB) or angiotensinconverting enzyme inhibitor (ACEI) compared with those receiving placebo plus an ARB or ACEI. This study also demonstrated a significantly higher risk of renal impairment, hypotension, and hyperkalemia in the aliskiren group [2]. Consequently, the US FDA modified the labeling of aliskiren in April 2012 with a new contraindication against the use of aliskiren with ARBs or ACEIs in patients with diabetes, and a warning to avoid the use of aliskiren with ARBs or ACEIs in patients with moderate to severe renal impairment [3] The European Medicines Agency (EMA) contraindicated aliskiren in both situations [4]. One and a half years later, the FDA published a new warning and precaution about symptomatic hypotension that may occur after initiation of aliskiren in patients with marked volume depletion, those with salt depletion, or those receiving other agents acting on the renin–angiotensin–aldosterone system [5]. More recently, in light of two other clinical trials and a meta-analysis [6–8], the EMA recommended against the prescription of dual reninangiotensin system blockade through the combined use of ACEIs, ARBs, or aliskiren [9] because these combinations were associated with an increased risk of hyperkalemia, kidney damage, and hypotension. Furthermore, no significant benefits from dual blockade were seen in patients without heart failure. Benefits were thought to outweigh risks only in a selected group of patients with heart failure in whom other treatments were unsuitable. Hypotension is a risk factor of ischemic colitis, an uncommon, potentially severe, and sometimes fatal disease caused by a lack of blood flow. It is also a diagnosis of exclusion with no identified cause [10, 11]. The ageand sex-adjusted incidence rate was estimated to be 22.9 per 100,000 patient-years (PYs) (95 % confidence interval [CI] 18.6–27.3) for the period 2006–2009 among unselected subjects in a US county [12]. The incidence was twice as frequent for women and increased strongly with age, from 1.1 per 100,000 PYs before the age of 40 years to 107 per 100,000 PYs for subjects aged 80 years or older [10]. In this study, the main risk factor was a hypotensive episode in the previous month (odds ratio [OR] 33.0, 95 % CI 13.3–80.9) [11]. Other independent risk factors identified were collagen vascular disease (OR 8.0, 95 % CI 2.2–28.3), peripheral vascular disease (OR 7.9, 95 % CI 4.7–13.2), congestive heart failure (OR 4.1, 95 % CI 2.6–6.3), psychotropic medications used in the past This comment refers to the article available at doi:10.1007/s40256-014-0101-4.