Assessing Blood Pressure Responses to Noncardiovascular Drugs: The Beneficial Role of Ambulatory Blood Pressure Monitoring

Abstract

It has become apparent that noncardiovascular drugs can affect blood pressure (BP) in an off-target manner, either by raising or lowering pressure or by negating the beneficial hypotensive effect of concomitantly prescribed antihypertensives. This paper presents compelling evidence that ambulatory blood pressure monitoring (ABPM) should be used to detect BP effects during the development of noncardiovascular drugs. The requirements for standardizing ABPM to obtain the most information from the least number of participants and the many advantages of obtaining a 24-hour BP profile are discussed. The use of ABPM in trials of antihypertensive agents, though differing in purpose (the demonstration of BP-lowering efficacy) from the use of ABPM in trials of noncardiovascular drugs (the demonstration of any off-target effect on BP) nonetheless provides methodological similarities that can be applied in both contexts with advantage. The paper also considers whether there are lessons to be learned from a regulatory science approach that is designed to prospectively identify unacceptable off-target cardiac effects of noncardiac drugs and offers some thoughts on how a future paradigm of standardized use of ABPM to assess off-target BP effects during the development of noncardiovascular drugs might benefit patient safety. J Clin Hypertens (Greenwich). 2013; 15:55-62. Ó2012 Wiley Periodicals, Inc.It has become clear that noncardiovascular drugs can raise or lower blood pressure (BP) in an off-target manner. The clinical relevance of small and transient, off-target drug-induced changes in BP to symptomatology, morbidity, or mortality is not known because the subject has not been systematically studied. However, Grossman and Messerli 1 recently observed that ''severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported.'' Off-target BP responses have therefore garnered increasing scientific and regulatory interest in recent years, being addressed at various conferences and in the literature (Table). 14,15Considerable attention is now being paid to designing an appropriately informative assessment strategy that can be employed in noncardiovascular drug development programs to prospectively identify such BP responses.While increases will likely attract more attention, decreases of certain magnitudes are also undesirable, particularly in some patient populations. Additionally, interactions between noncardiovascular drugs and antihypertensives that may either negate or potentiate hypotensive efficacy have received little study to date, but it can be reasonably assumed that many drugs either reduce or potentiate the BP-lowering effect of antihypertensive medication. For example, Grossman and Messerli 1 noted that rifampicin, a bactericidal antibiotic that induces CYP3A4 and P-glycoprotein, considerably reduces the plasma concentrations and the renin-inhibiting effect of aliskiren and some calcium antagonists by decreasing oral bioavailability. Sitagliptin, a dipeptidyl peptidase-IV inhibit...

Usefulness of ambulatory blood pressure monitoring to assess the melanocortin receptor agonist bremelanotide

“…Furthermore, phase 2 is an opportune time to evaluate drug-induced off-target BP increases because these studies typically involve patients with the disease or disorder of interest, have more intensive monitoring of vital signs compared with phase 3, and use a wider dose spectrum [6]. Many classes of drugs – from antidepressants to NSAIDs to oncologic therapies – can increase BP via distinct mechanisms ranging from activation of the sympathetic nervous system, salt and water retention to inhibition of vascular endothelial growth factor [14]. For example, a number of prior studies using ABPM with the NSAIDs demonstrated the ability to provide more precise information on the pressor effects of these agents outside of the clinical research environment along or when combined with antihypertensive therapies [15–17].…”

“…For example, a number of prior studies using ABPM with the NSAIDs demonstrated the ability to provide more precise information on the pressor effects of these agents outside of the clinical research environment along or when combined with antihypertensive therapies [15–17]. These earlier trials have led the way for utilizing out-of-office BP monitoring that has affected regulatory advice in drug development as it relates to BP changes [6,14]. …”

Diagnosis and Treatment of Resistant Hypertension: The Critical Role of Ambulatory Blood Pressure Monitoring

“…Second, as we have noted previously, “While it is essential that appropriate hardware is employed in clinical trials employing ABPM, it is equally (and arguably more) important that appropriately informative software is employed. ABPM monitoring fulfills its full promise when sophisticated software is employed to collate, interpret, analyze, and electronically transmit data for central hosting and analysis.” This allows maximum use of ABPM data for both screening potential trial participants and evaluating the intervention's therapeutic benefit at the end of the trial.…”

Raising the Bar in Renal Sympathetic Denervation Research and Reporting

“…The Joint UK Societies' commentary is well summarized by their statement that they do not recommend “the use of renal denervation for treatment of resistant hypertension in routine clinical practice,” but they remain “committed to supporting research activity in this field.” The ramifications of their observation that “It is remarkable that to date there is no agreement on the precise anatomy of human sympathetic nerves, and in particular the variation in their trajectories relative to the renal arteries”are also addressed by White and colleagues . Importantly, all expert opinions advocated the employment of ambulatory BP monitoring (ABPM) as an informative methodology likely to mitigate the impact of white‐coat hypertension. Interestingly, three of the papers advocated the use of a sham‐control treatment arm, while Mahfoud and colleagues did not, as discussed below.…”