Drug therapies in older adults (part 2)

Omar Mukhtar and Stephen HD Jackson
Download PDF
DOI: https://doi.org/10.7861/clinmedicine.15-2-155
Clin Med April 2015

ABSTRACT

In this, the second of two articles, we continue our evaluation of drug therapies in older adults. Having previously described the pharmacokinetic and pharmacodynamic consequences of physiological ageing, along with the challenge of appropriate prescribing, we proposed four key questions which should be considered when prescribing for this cohort of the population. Does this agent reflect the priorities of the patient? Are there alternatives – with greater efficacy, effectiveness or tolerability – that might be considered? Are the dose, frequency and formulation appropriate? How does this prescription relate to concurrent medication? We also highlighted the reliance on subgroup analysis to demonstrate the efficacy of drug therapies for older adults in osteoporosis and the underutilisation of appropriate treatments for patients with Alzheimer's disease as a result of flawed guidelines. Here we describe current drug therapies in systolic heart failure, noting the limited inclusion of older adults in key trials, while also reviewing the pharmacological treatment of orthostatic hypotension. In doing so, we advocate the intermittent use of midodrine as a first-line treatment for orthostasis in older adults, counter to the generic guidelines produced by various learned societies, but in keeping with the scant trial data available.

KEYWORDS 

Introduction

Diseases of the heart and circulatory system are the commonest cause of morbidity and mortality in the UK.1 While ischaemic heart disease (IHD) continues to represent the single largest disease entity within this, cardiac failure, particularly left ventricular systolic dysfunction, is often a consequence in the long term.1 Over two decades, antagonists of the renin–angiotensin–aldosterone system, along with those targeting β-adrenoceptors, have revolutionised outcomes for such patients. However, despite the incidence and prevalence data, landmark trials in this field have disproportionately overlooked the cohort most frequently affected – older adults. This is equally true of the newer agents, ivabradine and LCZ696.

The treatment of orthostatic hypotension (OH) among older adults is equally problematic. Notwithstanding issues relating to the challenge of consistent diagnosis and the prognostic significance of the disease, treatment options are poorly evidenced, particularly for adults aged over 65 years. Here we discuss drug therapies in both disease states, with a particular focus on older adults.

Orthostatic hypotension

OH is currently defined as ‘a sustained reduction in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of 10 mmHg within 3 minutes of standing or head-up tilt to at least 60∞ on a tilt table’.2 It is common among older adults with a prevalence of 6–30% in those aged 65 years and over.3,4 This variability highlights a significant issue which must be considered prior to treatment: the challenge of diagnosis. When completing four distinct assessments for OH in new nursing home residents, 50% of subjects had no readings suggestive of OH, 20% had one reading consistent with the diagnosis, 20% had two or three ‘positive’ readings and only 10% had four readings consistent with OH.5 A second issue is the variability of symptoms experienced; in 205 patients with a systolic BP drop of at least 60 mmHg, 43% had typical symptoms, 24% had atypical symptoms (eg backache or headache) and 33% were asymptomatic.6 Third, is the issue of prognostic importance. In 1998, the Honolulu Heart Program reported that OH was a significant independent predictor of 4-year all-cause mortality in elderly ambulatory men – a paper cited over 300 times.7 Two years later, many of the same authors reported that there was no significant correlation with morbidity or subsequent mortality, again as part of the Honolulu Heart Program – this paper has been cited twice.8

A number of age-related physiological changes increase the likelihood of OH, especially in the presence of related pathology.9–11 The compliance of the arterial tree diminishes with age, diastolic filling may be impaired and the tortuosity of the venous system increases.9,10 The renal conservation of sodium declines, as do renin, angiotensin and aldosterone levels.9,10 Similarly, the circulating concentration of arginine vasopressin falls, while cerebral blood flow is reduced.9,10 Although these changes may account for some of the increased burden of OH among older adults, it is also associated with a multitude of causes, which can be broadly categorised into primary autonomic failure (eg pure autonomic failure), secondary autonomic failure (eg diabetes mellitus), drug-related disease (eg antihypertensive use), volume depletion (eg haemorrhage) and idiopathic OH.9–11

Asymptomatic OH does not require treatment and only rarely is a treatable cause identified eg vitamin B12 deficiency.12 In other instances a number of non-pharmacological methods have been employed, including dietary changes, abdominal compression, lower limb bandaging and drinking increased volumes of water.9 Most of the pharmacological agents which have been trialled in this setting, including dihydroergotamine, midodrine, fludrocortisone, octreotide, yohimbine, domperidone and Korodin, have been limited in their application by studies which are methodologically flawed.11–13 Only two are currently recommended in the 2009 European Society of Cardiology (ESC) guidelines: fludrocortisone and midodrine.14 The 2006 guidelines produced by the European Federation of Neurological Societies (EFNS) make similar recommendations, while also recommending dihydroxyphenylserine and octreotide for the treatment of dopamine β-hydroxylase deficiency and post-prandial OH, respectively.15

Fludrocortisone

Fludrocortisone is a synthetic (0.1–0.3 mg, once daily) mineralocorticoid, devoid of almost all glucocorticoid activity. It is thought to raise blood pressure by promoting the renal retention of sodium and increasing plasma volume.16 However, persistent exposure may lead to the normalisation of both the plasma volume and the degree of sodium retention; despite this, a sustained increase in blood pressure is observed.17 This suggests that fludrocortisone may sensitise the α-adrenergic receptors of blood vessels, leading to an indiscriminate increase in peripheral vascular resistance and a risk of supine hypertension,17 in addition to the more frequent adverse effects of dependent oedema, hypokalemia, headaches and congestive heart failure (HF).12,18

Although guidelines from the ESC and EFNS suggest that fludrocortisone be considered first-line therapy for OH, the trial data supporting these recommendations are weak.14,15 The first double-blind crossover study of fludrocortisone and placebo was reported in six patients with diabetes (mean age: 52 years; range: 33–64 years); symptomatic improvement was observed in four subjects.19 Subsequent studies, published in the English language, adopted an observational approach, whereby fludrocortisone was utilised in combination with head-up sleeping. In the first instance, six patients were studied (mean age: 52 years; range: 23–65 years), in the second, eight (mean age: 50 years; range: 23–65 years).20,21 While both studies suggest that fludrocortisone may help some younger patients with OH, the absence of older adults is notable.20,21 Whether such a bias exists in the double-blind trial published in German is unclear (n = 60); the study also reported haemodynamic benefits and improved symptom control among those receiving fludrocortisone.22

Midodrine

Midodrine (5–20 mg, three times daily) is currently the only drug approved for the treatment of OH in both the US and Europe, although not in the UK.11 A prodrug, it is converted by enzymatic cleavage to its active metabolite, deglymidodrine; a selective α1-adrenoceptor agonist that does not cross the blood–brain barrier.23 It is thought to increase peripheral vascular resistance and venous return by promoting the vasoconstriction of arterioles and venous capacitance vessels.23 Intermittent use is likely to be more effective than regular use as this avoids tachyphylaxis;10 the drug is variably contraindicated if patients have significant IHD, acute kidney injury, an underlying phaeochromocytoma, thyrotoxicosis or problems with urinary retention (a particular issue for older males).9

Although four double-blind, placebo-controlled trials and a number of smaller studies have demonstrated the apparent effectiveness of midodrine in OH, a number of systematic reviews have highlighted key issues with the evidence.12 Criticisms include a failure to conclusively demonstrate symptomatic improvement and an exaggeration of supine blood pressure.12,13 In keeping with studies of fludrocortisone, the trials are also notable for the mean age of participants (60–65 years), although the range extends from 22 to 86 years.

In light of the evidence, it is difficult to concur with the guidelines generated by the ESC and EFNS, particularly when treating older adults experiencing OH.14,15 The intermittent use of midodrine, as a first-line treatment, as opposed to fludrocortisone, would follow the limited evidence more closely in this cohort.

Heart failure

HF is largely a disease of older adults, characterised by objective evidence of cardiac dysfunction and a triad of symptoms: dyspnoea, fatigue and fluid retention.24 The median age at diagnosis is 76 years;25 the British Heart Foundation recently estimated the prevalence to be approximately 3% among adults between the ages of 25 and 74 years and 12.5% in those aged over 75 years.26 Incidence data follows a similar pattern; in the UK, the annual incidence of HF is 102.5 cases per 100,000 person years among those aged between 55 and 64 years and 327.3 cases per 100,000 person years in those aged over 85 years.26 With an ageing population, improved survival from associated cardiovascular diseases, eg IHD, and advances in the treatment of HF itself, both the prevalence and incidence of chronic HF are set to increase.24

However, prior to treatment, the underlying cause must be established, as the condition may be reversible, may provide some indication of prognosis and may have consequences for family members.24 While there are significant variations in the causes of HF between the industrialised and non-industrialised worlds, IHD with associated left ventricular systolic impairment remains the primary cause of HF worldwide, particularly among older adults,27 despite the recent interest in diastolic dysfunction, which frequently co-exists with systolic dysfunction.24

The key aims of therapy for systolic HF secondary to underlying IHD are to relieve symptoms and prolong survival. Integral to this approach are a series of lifestyle measures, which include a graded exercise programme, salt and alcohol restriction, along with weight loss in overweight patients. However, it is antagonists of the renin–angiotensin–aldosterone system and β-adrenoreceptors that have revolutionised outcomes for this cohort of patients – a product of large, randomised controlled trials. More recently, ivabradine, an inhibitor of electrical pacemaker activity in the sinoatrial node, has proved promising, as has LCZ696: a neprilysin inhibitor coupled with valsartan.

ACE inhibitors and angiotensin II receptor antagonists

A number of landmark trials have demonstrated the efficacy of angiotensin-converting-enzyme inhibitors (ACEi) in both symptomatic and asymptomatic HF.28–30 However, these trials primarily recruited younger adults; the mean age of trial subjects in the SOLVD study was 60 years, while the mean age of participants in the ‘Heart Outcomes Prevention Evaluation’ (HOPE) trial was 66 years.28,30 Nonetheless, subgroup analysis of HOPE demonstrated a greater risk reduction among older adults (>65 years old) as compared with the wider trial population;30 results from subgroup analyses of the SOLVD studies were broadly comparable.28

Angiotensin II receptor antagonists (ARBs) are considered an effective alternative for those who are intolerant of ACEi, although the mortality benefit may not be as large as that observed with ACEi.31,32 While the CHARM-Alternative trial, confirms the mortality and morbidity benefits of candesartan in patients with a left ventricular ejection fraction (LVEF) of 40% or less, only 23.3% of the trial population were aged ≥75 years, leaving the authors reliant upon subgroup analyses to demonstrate that the benefits among older adults were broadly akin to those reported for ACEi.33,34 When combined with ACEi and β-adrenoreceptor antagonists, the ARBs, valsartan and candesartan have demonstrated additional mortality and morbidity benefits in patients with HF.32,35 However, caution must be exercised when considering application of this trial data in older adults, as the physiological decline in renal and musculoskeletal function may increase the likelihood of adverse effects, particularly as the target doses for most ACEi and ARBs are independent of age.36 Despite this, sub-maximal dosing is likely to be beneficial in patients with severe left ventricular systolic dysfunction, albeit not as effective as maximal doses.37

β-adrenoreceptors antagonists (β-blockers)

There is now unequivocal evidence that bisoprolol, carvedilol, nebivolol and sustained-release metoprolol, also provide mortality and morbidity benefits for patients with HF, regardless of its severity.38–41 Many consider these results to have been fully validated among older adults, where a meta-analysis of 12,719 patients found no difference in benefit between those defined as ‘elderly’ in the constituent trials and their younger counterparts.42 However, the oldest patient in the individual trials analysed was 71 years old.

While β-blocker therapy should only be initiated when patients are euvolaemic, practical concerns relating to those agents with a known vasodilatory effect (eg carvedilol and nebivolol) may be overstated.43 Data from the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, suggests that carvedilol is extremely well tolerated, even among patients with a baseline systolic blood pressure of 85 mmHg.44 Similarly, β-blockers are not contraindicated among those with chronic obstructive pulmonary disease; the association with broncho-constriction is only observed with reversible airways disease, which may be excluded by performing spirometry pre- and post-bronchodilator therapy.43

Aldosterone antagonists

The aldosterone antagonists, spironolactone and eplerenone, reduce mortality and morbidity in patients with moderate to severe HF (New York Heart Association classes III and IV).45,46 However, the landmark trials in this field again failed to target the population most frequently affected by HF: the median age of patients in the Randomized Aldactone Evaluation Study (RALES) trial was 67 years, while the mean age at enrolment was 64 years among those recruited to the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study.45,46

However, when used in older adults, renal chemistry should be monitored closely, as there is a tendency for aldosterone antagonists to cause renal impairment, thereby exaggerating age-associated changes. Concurrent use of these agents with high-dose ACEi or ARBs also increases the risk of hyperkalemia in patients with a creatinine clearance of <50 ml/min.47 Similarly, the age-associated decline in serum testosterone levels predisposes older men to an increased risk of spironolactone-related gynaecomastia.48

Ivabradine

Ivabradine is a selective inhibitor of the hyperpolarisation-activated, cyclic-nucleotide-gated, funny current I(f) expressed at the sinus node. It does not affect atrioventricular or intraventricular conduction times, myocardial contractility or ventricular repolarization.49 Current guidance from the National Institute for Health and Care Excellence (NICE), recommends that ivabradine be used in the treatment of adults with ‘stable’ HF, who are in sinus rhythm, have a heart rate of ≥75 beats per minute and a LVEF <35%.50 The landmark study demonstrating the efficacy of ivabradine, received the acronym SHIFT – systolic HF treatment with the I(f) inhibitor ivabradine trial.51 This demonstrated an 18% reduction in the primary endpoint of cardiovascular death or hospital admission with progressive HF among those treated with ivabradine, when compared with patients receiving placebo.51 Significant improvements were observed throughout all pre-specified subgroups, including patients below and above 65 years of age. However, the average age of patients recruited to the trial was 60.4 years (standard deviation 11.4) and only 722 (11%) patients were aged ≥75 years.51 Again it was a post hoc, subgroup analysis that led the authors to conclude that the safety and efficacy of ivabradine was comparable across all age groups.52

Neprilysin inhibitors

Neprilysin is a neutral endopeptidase which degrades a variety of vasoactive peptides, including natriuretic peptides, bradykinin and adrenomedullin.53–55 Inhibition of neprilysin increases the circulating concentration of such peptides, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention and maladaptive attempts at physiological remodeling.56,57 Neutral endopeptidase inhibition was evaluated as a possible antihypertensive mechanism, but proved ineffective; trials were never conducted on its efficacy in cardiac failure.58 In preclinical studies, the combined inhibition of neprilysin and the renin–angiotensin system had effects that were superior to either approach in isolation;59,60 however, in clinical trials, such agents were associated with serious angioedema.61,62

LCZ696, which consists of the neprilysin inhibitor, sacubitril (AHU377), and the ARB, valsartan, produced morbidity and mortality benefits superior to those observed with enalapril, in patients with chronic HF and a reduced ejection fraction.63 However, in keeping with many of the previous landmark trials, older adults were underrepresented in the study. Of the 8,399 patients randomised to either treatment arm, only 1,563 were aged 75 years and above (18.7%).62 Among this cohort neither the primary outcome (a composite of death from cardiovascular causes or hospitalisation for HF) nor death from cardiovascular causes alone, achieved statistical significance. By contrast, in those under 75 years old, statistical significance was noted.62 Whether this is a function of the trial design or LCZ696 has yet to be determined.

Concluding thoughts

The utilisation of drug therapies is increasingly evidence based; however, this process is at its most tenuous at the extremes of age. As with osteoporosis, there is often a reliance on subgroup analysis to demonstrate the efficacy of pharmacological treatments for older adults experiencing systolic HF, despite incidence and prevalence data demonstrating the propensity of these disease states for this growing cohort of the population. While Alzheimer's disease highlights the issue of underutilisation of appropriate treatments, for this oft-neglected group, the current guidelines for the management of OH highlight a failure on the part of researchers and clinicians to undertake meaningful trials of treatment for diseases which predominantly afflict older adults.

References

  1. 1 .↵
    1. Capewell S
    , Allender C, Critchley J. Modelling the UK burden of cardiovascular disease to 2020: A research report for the Cardio & Vascular Coalition and the British Heart Foundation. London: BHF, 2008.
  2. 2 .↵
    1. Freeman R
    , Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Auton Neurosc 2011;161:46–8.
    OpenUrlCrossRef
  3. 3 .↵
    1. Mader SL
    . Orthostatic hypotension in older patients. Aging Health 2006;2:54–61.
    OpenUrl
  4. 4 .↵
    1. Tilvis RS
    , Hakala SM, Valvanne J, Erkinjuntti T. Postural hypotension and dizziness in a general aged population: a four-year follow-up of the Helsinki Aging Study. J Am Geriatr Soc 1996;44:809–14.
    OpenUrlPubMed
  5. 5 .↵
    1. Ooi WL
    , Barrett S, Hossain M, et al. Patterns of orthostatic BP change and their clinical correlates in a frail elderly population. JAMA 1997;277:1299–304.
    OpenUrlCrossRefPubMed
  6. 6 .↵
    1. Arbogast SD
    , Alshekhlee A, Hussain Z, et al. Hypotension un-awareness in profound orthostatic hypotension. Am J Med 2009;122:574–80.
    OpenUrlCrossRefPubMed
  7. 7 .↵
    1. Masaki KH
    , Schatz IJ, Burchfiel CM, et al. Orthostatic hypotension predicts mortality in elderly men: the Honolulu Heart Program. Circulation 1998;98:2290–5.
    OpenUrlAbstract/FREE Full Text
  8. 8 .↵
    1. Alagiakrishnan K
    , Masaki K, Schatz I, et al. Postural hypertension in elderly men – the Honolulu Heart Program. Hawaii Med J 2000;59:48–50.
    OpenUrlPubMed
  9. 9 .↵
    1. Perlmuter LC
    , Sarda G, Casavant V, et al. A review of the etiology, associated comorbidities, and treatment of orthostatic hypotension. Am J Ther 2013;20:279–91.
    OpenUrlPubMed
  10. 10 .↵
    1. Mader SL
    . Identification and management of orthostatic hypotension in older and medically complex patients. Expert Rev Cardiovasc Ther 2012;10:387–95.
    OpenUrlPubMed
  11. 11 .↵
    1. Ong AC
    , Myint PK, Shepstone L, et al. A systematic review of the pharmacological management of orthostatic hypotension. Int J Clin Pract 2013;67:633–46.
    OpenUrlPubMed
  12. 12 .↵
    1. Schroeder C
    , Jordan J, Kaufmann H. Management of neurogenic orthostatic hypotension in patients with autonomic failure. Drugs 2013;73:1267–79.
    OpenUrlPubMed
  13. 13 .↵
    1. Logan IC
    , Witham MD. Efficacy of treatments for orthostatic hypotension: a systematic review. Age Ageing 2012;41:587–94.
    OpenUrlAbstract/FREE Full Text
  14. 14 .↵
    1. European Society of Cardiology. Guidelines for the diagnosis and management of syncope
    (2009): the Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC). Eur Heart J 2009;30:2631–71.
    OpenUrlFREE Full Text
  15. 15 .↵
    1. Lahrmann H
    , Cortelli P, Hilz M, et al. EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur J Neurol 2006;13:930–6.
    OpenUrlCrossRefPubMed
  16. 16 .↵
    1. van Lieshout JJ
    , ten Harkel AD, Wieling W. Fludrocortisone and sleeping in the head-up position limit the postural decrease in CO in autonomic failure. Clin Auton Res 2000;10:35–42.
    OpenUrlCrossRefPubMed
  17. 17 .↵
    1. Chobanian AV
    , Volicer L, Tifft CP, et al. Mineralocorticoid-induced hypertension in patients with orthostatic hypotension. N Engl J Med 1979;301:68–73.
    OpenUrlPubMed
  18. 18 .↵
    1. Weber KT
    , Brilla CG. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83:1849–65.
    OpenUrlAbstract/FREE Full Text
  19. 19 .↵
    1. Campbell IW
    , Ewing DJ, Clarke BF. 9-Alpha-fluorohydrocortisone in the treatment of postural hypotension in diabetic autonomic neuropathy. Diabetes 1975;24:381–4.
    OpenUrlAbstract/FREE Full Text
  20. 20 .↵
    1. van Lieshout JJ
    , ten Harkel AD, Wieling W. Fludrocortisone and sleeping in the head-up position limit the postural decrease in cardiac output in autonomic failure. Clin Auton Res 2000;10:35–42.
    OpenUrlCrossRefPubMed
  21. 21 .↵
    1. ten Harkel AD
    , van Lieshout JJ, Wieling W. Treatment of orthostatic hypotension with sleeping in the head-up tilt position, alone and in combination with fludrocortisones. J Intern Med 1992;232:139–45.
    OpenUrlCrossRefPubMed
  22. 22 .↵
    1. Finke J
    , Sagemuller I. Fludrocortisone in the treatment of orthostatic hypotension: ophthalmodynamography during standing. Dtsch Med Wochenschr 1975;100:1790–2.
    OpenUrlPubMed
  23. 23 .↵
    1. Cruz DN
    . Midodrine: a selective alpha-adrenergic agonist for orthostatic hypotension and dialysis hypotension. Expert Opin Pharmacother 2000;1:835–40.
    OpenUrlCrossRefPubMed
  24. 24 .↵
    1. Gardner RS
    , McDonagh TA. Heart failure: epidemiology, investigation and management. Medicine 2010;38:473–8.
    OpenUrl
  25. 25 .↵
    1. Cowie MR
    , Wood DA, Coats A, et al. Incidence and aetiology of heart failure: a population-based study. Eur Heart J 1999;20:421–8.
    OpenUrlAbstract/FREE Full Text
  26. 26 .↵
    1. Townsend N
    , Wickramasinghe K, Bhatnagar P et al. Coronary heart disease statistics 2012. London: British Heart Foundation, 2012.
  27. 27 .↵
    1. McMurray JJ
    , Stewart S. Epidemiology, aetiology, and prognosis of heart failure. Heart 2000;83:596–602.
    OpenUrlFREE Full Text
  28. 28 .↵
    1. The SOLVD Investigators
    . Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302.
    OpenUrlCrossRefPubMed
  29. 29 .↵
    1. The SOLVD Investigators
    . Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685–91.
    OpenUrlCrossRefPubMed
  30. 30 .↵
    1. Yusuf S
    , Sleight P, Pogue J, et al. Effects of an angiotensin converting enzyme inhibitor, ramipril, on cardiovascular events in high risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145–53.
    OpenUrlCrossRefPubMed
  31. 31 .↵
    1. Young JB
    , Dunlap ME, Pfeffer MA, et al. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation 2004;110:2618–26.
    OpenUrlAbstract/FREE Full Text
  32. 32 .↵
    1. Cohn JN
    , Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2000;345:1667–75.
    OpenUrl
  33. 33 .↵
    1. Granger CB
    , McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772–6.
    OpenUrlCrossRefPubMed
  34. 34 .↵
    1. Cohen-Solal A
    , McMurray JJ, Swedberg K, et al. Benefits and safety of candesartan treatment in heart failure are independent of age: insights from the Candesartan in Heart failure–Assessment of Reduction in Mortality and morbidity programme. Eur Heart J 2008;29:3022–8.
    OpenUrlAbstract/FREE Full Text
  35. 35 .↵
    1. McMurray JJ
    , Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767–71.
    OpenUrlCrossRefPubMed
  36. 36 .↵
    1. Massie BM
    , Armtrong PW, Cleland JG, et al. Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: results from the ATLAS trial. The Assessment of Treatment with Lisinopril and Survival. Arch Intern Med 2001;161:165–71.
    OpenUrlCrossRefPubMed
  37. 37 .↵
    1. Packer M
    , Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin- converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999;100:2312–8.
    OpenUrl
  38. 38 .↵
    1. Packer M
    , Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. US Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349–55.
    OpenUrlCrossRefPubMed
  39. 39 .↵
    1. CIBIS-II Investigators and Committees
    . The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13.
    OpenUrlCrossRefPubMed
  40. 40 .↵
    1. MERIT-HF Study Group
    . Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–7.
    OpenUrlCrossRefPubMed
  41. 41 .↵
    1. Flather MD
    , Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215–25.
    OpenUrlAbstract/FREE Full Text
  42. 42 .↵
    1. Dulin BR
    , Haas SJ, Abraham WT, et al. Do elderly systolic heart failure patients benefit from beta blockers to the same extent as the non-elderly? Meta-analysis of >12,000 patients in large-scale clinical trials. Am J Cardiol 2005;95:896–8.
    OpenUrlCrossRefPubMed
  43. 43 .↵
    1. Krum H
    , Driscoll A. Management of heart failure. Med J Aust 2013;199:334–9.
    OpenUrlPubMed
  44. 44 .↵
    1. Packer M
    , Coats AJ, Fowler MB, et al. Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–8.
    OpenUrlCrossRefPubMed
  45. 45 .↵
    1. Pitt B
    , Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–17.
    OpenUrlCrossRefPubMed
  46. 46 .↵
    1. Pitt B
    , Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Eng J Med 2003;348:1309–21.
    OpenUrlCrossRefPubMed
  47. 47 .↵
    1. Juurlink DN
    , Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med 2004;351:543–51.
    OpenUrlCrossRefPubMed
  48. 48 .↵
    1. Braunstein GD
    . Gynecomastia. N Engl J Med 2007;357:1229–37.
    OpenUrlCrossRefPubMed
  49. 49 .↵
    1. DiFrancesco D
    , Camm AJ. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine. A new therapeutic perspective in cardiovascular disease. Drugs 2004;64:1757–65.
    OpenUrlCrossRefPubMed
  50. 50 .↵
    1. Edwards SJ
    , Barton S, Nherera L et al. Ivabradine for the treatment of chronic heart failure: A Single Technology Appraisal. London: BMJ-TAG, 2012.
  51. 51 .↵
    1. Swedberg K
    , Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled trial. Lancet 2010;376:875–85.
    OpenUrlCrossRefPubMed
  52. 52 .↵
    1. Tavazzi L
    , Swedberg K, Komajda M, et al. (SHIFT Investigators). Efficacy and safety of ivabradine in chronic heart failure across the age spectrum: insights from the SHIFT study. Eur J Heart Fail 2013;15:1296–303.
    OpenUrlCrossRefPubMed
  53. 53 .↵
    1. Cruden NL
    , Fox KA, Ludlam CA, et al. Neutral endo-peptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition. Hypertension 2004;44:913–8.
    OpenUrl
  54. 54 .↵
    1. Rademaker MT
    , Charles CJ, Espiner EA, et al. Neutral endopeptidase inhibition: augmented atrial and brain natriuretic peptide, haemodynamic and natriuretic responses in ovine heart failure. Clin Sci (Lond) 1996;91:283–91.
    OpenUrlPubMed
  55. 55 .↵
    1. Wilkinson IB
    , McEniery CM, Bongaerts KH, et al. Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal 20 peptide (PAMP). Br J Clin Pharmacol 2001;52:159–64.
    OpenUrlCrossRefPubMed
  56. 56 .↵
    1. Maric C
    , Zheng W, Walther T. Interactions between angiotensin ll and atrial natriuretic peptide in renomedullary interstitial cells: the role of neutral endopeptidase. Nephron Physiol 2006;103:149–56.
    OpenUrl
  57. 57 .↵
    1. Kuhn M
    . Molecular physiology of natriuretic peptide signalling. Basic Res Cardiol 2004;99:76–82.
    OpenUrlCrossRefPubMed
  58. 58 .↵
    1. Bevan EG
    , Connell JM, Doyle J, et al. Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension. J Hypertens 1992;10:607–13.
    OpenUrlPubMed
  59. 59 .↵
    1. Rademaker MT
    , Charles CJ, Espiner EA, et al. Combined neutral endopeptidase and angiotensin-converting enzyme inhibition in heart failure: role of natriuretic peptides and angiotensin II. J Cardiovasc Pharmacol 1998;31:116–25.
    OpenUrlCrossRefPubMed
  60. 60 .↵
    1. Trippodo NC
    , Fox M, Monticello TM, et al. Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril. J Cardiovasc Pharmacol 1999;34:782–90.
    OpenUrlCrossRefPubMed
  61. 61 .↵
    1. Kostis JB
    , Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 2004;17:103–11.
    OpenUrlAbstract/FREE Full Text
  62. 62 .↵
    1. Packer M
    , Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002;106:920–6.
    OpenUrlAbstract/FREE Full Text
  63. 63 .↵
    1. McMurray JJ
    , Packer M, Desai AS, et al. (PARADIGM-HF Investigators and Committees). Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.
    OpenUrlCrossRefPubMed
Back to top

Article Tools

Download PDF
Article Alerts
Citation Tools
Drug therapies in older adults (part 2)
Omar Mukhtar, Stephen HD Jackson
Clinical Medicine Apr 2015, 15 (2) 155-159; DOI: 10.7861/clinmedicine.15-2-155
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section