Nebivolol Versus Metoprolol: Comparative Effects on Fatigue and Quality of Life
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      Beta-blockers are prescribed to millions of people for treatment of hypertension. Fatigue is
      a recognized and common side effect of beta-blockers that can have significant effects on
      quality of life. Worse, many people taking a beta-blocker for years are not even aware of the
      reduction of energy with which they are living.

      A new vasodilating beta-blocker, nebivolol, which is approved by the FDA for treatment of
      hypertension, appears to be far less associated with fatigue than are most currently
      available beta-blockers. The purpose of this study is to compare nebivolol with the current
      best-selling beta-blocker, metoprolol, and determine whether there is a significant
      difference in side effects including fatigue, reduced exertion tolerance, and reduced quality
      of life.

      In this study, 30 subjects will take each of the 2 study drugs for 8 weeks, consisting of 4
      weeks at a lower dose, and 4 weeks at a higher dose. All dosages are FDA-approved for
      treatment of hypertension. Subjects and investigators will not know which drug is being
      administered until completion of the study. Subjects will undergo a treadmill stress test and
      will complete fatigue and quality of life questionnaires after each 4 weeks of treatment. An
      echocardiogram and non-invasive measurement of aortic blood pressure will be performed after
      8 weeks on each drug. Also, blood will be drawn and stored for possible measurement of drug
      levels, after 4 and 8 weeks on each drug. Results on each drug will then be compared. If
      nebivolol is found to cause significantly less fatigue, it would be of substantial importance
      to the many millions of people who are on life-long beta-blocker therapy, and are living with
      reduced energy.
    

Detailed description: 
      -  Hypothesis: the beta-blocker nebivolol is associated with less fatigue than metoprolol,
           the most widely-prescribed beta-blocker

        -  Methods: a double-blinded crossover trial comparing nebivolol with metoprolol.
           Experimental procedures: Subjects will undergo electrocardiogram and routine blood
           testing, unless such tests have been performed within 6 months and are available for
           review. Subjects entered into the study will receive each of the two study drugs for 8
           weeks. Metoprolol succinate will be given at a dose of 50 mg daily for 4 weeks, then 100
           mg daily for 4 weeks. For nebivolol, dosage will be 5 mg daily for 4 weeks and 10mg
           daily for 4 weeks. Identical-appearing pills will be given, and the drugs will be given
           in randomized order without a placebo run-in period.

      At the end of each 4-week treatment period on each drug, subjects will undergo a treadmill
      stress test (using the standard Cornell protocol), complete Quality of Life and fatigue
      questionnaires, and have blood drawn and frozen for later analysis for drug levels.

      At the end of 8 weeks of treatment on each drug, subjects will undergo echocardiography and
      applanation tonometry (non-invasive measurement of aortic blood pressure) to assess heart
      function.

      At the end of the study, the blinded subjects will be asked which of the two study drugs they
      preferred, and the extent to which their energy differed between the two drugs.

      -Rationale: Millions of hypertensive patients are on life-long beta-blocker therapy. In many,
      it reduces cardiac output and increases peripheral resistance to blood flow (1). It is
      well-established that beta-blockers cause fatigue in many patients and reduce exertion
      tolerance. Every physician knows this, and tacitly accepts that many patients are living with
      this unwelcome side effect.

      A new beta-blocker, nebivolol, has the standard beta-blocking effects, but also produces
      blood vessel relaxation (vasodilation), probably through increased secretion of the
      vasodilator nitric oxide. Studies indicate that nebivolol, unlike most beta-blockers, does
      not cause constriction of peripheral blood vessels, and is associated with improved heart
      function (2). Studies suggest that it is also less likely to cause fatigue (3).

      Personal experience is consistent with this, as I have observed marked improvement in energy
      in patients in whom I have prescribed nebivolol in place of a different beta-blocker. The
      possibility of placebo effect of course cannot be excluded. Nevertheless, the known
      hemodynamic differences between nebivolol and other beta-blockers, and the positive clinical
      experience, warrant formal study to determine whether nebivolol is kinder than other
      beta-blockers in terms of the important side effect of fatigue.
    

Intervention name(s): Metoprolol; Nebivolol
Intervention type(s): Drug; Drug
Intervention description(s): Metoprolol 50 mg, Metoprolol 100 mg,; Nebivolol 5 mg, Nebivolol 10 mg.
Other intervention name(s): Lopressor, Toprol-XL; Bystolic
Intervention MeSH terms: Metoprolol; Nebivolol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: hypertension; beta blockers; Metoprolol; blood pressure, high; antihypertensive agents; vascular resistance; adrenergic beta-receptor blockaders; beta-Adrenergic blockers; beta-Adrenergic Blocking Agents; beta-Adrenergic Receptor Blockaders; beta-Blockers, Adrenergic; Bystolic; Nebivolol; Nebivololum; Nebivololum [Latin]; R65,824; Beloc- Zok; H 93/26 succinate; Metoprolol succinate; Seloken ZOC; Selozok; Spesicor Dos; Toprol XL; Toprol-XL; UNII-TH25PD4CCB