Randomized, Placebo-Controlled, Double-Blind, Crossover Study With Tolterodine And Darifenacin In Healthy Participants > Or = 50 Years

Main Category: Urology / Nephrology
Also Included In: Cardiovascular / Cardiology;  Infectious Diseases / Bacteria / Viruses;  Clinical Trials / Drug Trials
Article Date: 23 Feb 2009 - 1:00 PST

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UroToday.com - The measurement of heart rate is increasingly being recognized as an important prognostic indictor^{1, 2}. Higher heart rates are associated with greater risk of myocardial infarction and total mortality. Large long-term follow-up studies have been performed in healthy males, females, hypertensive patients, those with structural heart disease and other populations^3-7. All the data are consistent - higher heart rates are associated with a poorer prognosis. The mechanism by which higher heart rates are associated with adverse outcomes remains uncertain. Several possibilities exist including the following:

1. There may be a direct effect of heart rate itself,
2. Heart rate may be a marker of cardiac parasympathetic tone⁸,
3. Heart rate may reflect sympathetic activation.

It is likely that reduced parasympathetic tone at least in part is an important contributor. Higher vagal tone has been consistently documented as a marker of improved survival. Whatever may be the mechanism, even small increments in heart rate (as low as 3 beat/minute increments) is associated with a poorer prognosis9. Move than just that, changes in heart rate over time are associated with outcomes and small changes upward and downward with the same magnitude is related to outcomes.

The best marker for heart rate changes is uncertain. This may be one of the reasons only recently that this issue has been carefully evaluated and yet now it is being considered a low tech predictor of coronary events⁶. A resting pulse can be challenging as a predictor since it reflects only one point in time and that point can be influenced by many extraneous variables. Alternatively it may be time to redefine what we consider to be tachycardia even from a resting heart rate measurement¹⁰.

In our study¹¹, we performed a carefully controlled assessment of heart rate evaluating it over a 24-hour period. There was a significant difference between tolterodine and darifenacin when compared to placebo. Tolterodine was associated with an increase in heart rate versus darifenacin and versus placebo. Darifenacin was not associated with any increase in heart rate versus placebo. This was true considering the mean heart rate and the increase in heart rate greater than 5 beats/minute using a categorical analysis.

These data are consistent with the present knowledge of the drugs - tolterodine is a relatively nonselective antimuscarinic and darifenacin is relatively selective for the M3 receptors. Since M2 receptor activation is responsible for sinus node slowing but M3 receptor activation does not have any substantial effect on the sinus node, blockade of this receptor selectively should not affect heart rate by blocking the effects of vagal activation of the sinus node.

The implications of this study are that there are differences in cardiovascular effects of antimuscarinics when treating patients with overactive bladder. Vagal tone can be in part abolished by antimuscarinics that are relatively non-selective. While no cardiovascular outcomes data yet support the use of one antimuscarinic over another, based on data in many populations indicating that an increased heart rate indicates increased risk of mortality and other concerning endpoints, these data should warrant careful consideration about the use of non-selective antimuscarinic to treat overactive bladder.

1. Greenland P, Daviglus ML, Dyer AR, Liu K, Huang CF, Goldberger JJ, Stamler J. Resting heart rate is a risk factor for cardiovascular and noncardiovascular mortality: the Chicago Heart Association Detection Project in Industry. Am J Epidemiol. 1999;149(9):853-862.
2. Mensink GB, Hoffmeister H. The relationship between resting heart rate and all-cause, cardiovascular and cancer mortality. Eur Heart J. 1997;18(9):1404-1410.
3. Jouven X, Empana JP, Schwartz PJ, Desnos M, Courbon D, Ducimetiere P. Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med. 2005;352(19):1951-1958.
4. Fox K, Borer JS, Camm AJ, Danchin N, Ferrari R, Lopez Sendon JL, Steg PG, Tardif JC, Tavazzi L, Tendera M. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50(9):823-830.
5. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372(9641):817-821.
6. Hsia J, Larson JC, Ockene JK, Sarto GE, Allison MA, Hendrix SL, Robinson JG, LaCroix AZ, Manson JE. Resting heart rate as a low tech predictor of coronary events in women: prospective cohort study. Bmj. 2009;338:b219.
7. Okin PM, Wachtell K, Kjeldsen SE, Julius S, Lindholm LH, Dahlof B, Hille DA, Nieminen MS, Edelman JM, Devereux RB. Incidence of Atrial Fibrillation in Relation to Changing Heart Rate over Time in Hypertensive Patients: The LIFE Study. Circ Arrhythmia Electrophysiol. 2008;1:337-343.
8. Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation. 2008;118(8):863-871.
9. Jouven X, Empana JP, Escolano S, Buyck JF, Tafflet M, Desnos M, Ducimetiere P. Relation of heart rate at rest and long-term (>20 years) death rate in initially healthy middle-aged men. Am J Cardiol. 2009;103(2):279-283.
10. Gopinathannair R, Sullivan RM, Olshansky B. Slower Heart Rates for Healthy Hearts: Time to Redefine Tachycardia? Circ Arrhythmia Electrophysiol. 2008;1(1):321-322.
11. Olshansky B, Ebinger U, Brum J, Egermark M, Viegas A, Rekeda L. Differential pharmacological effects of antimuscarinic drugs on heart rate: a randomized, placebo-controlled, double-blind, crossover study with tolterodine and darifenacin in healthy participants > or = 50 years. J Cardiovasc Pharmacol Ther. 2008;13(4):241-251.

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