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INTRODUCTION
There have been considerable advances in the pharmacologic management of chronic heart failure (CHF) over the past 20 years. Both angiotensin-converting enzyme (ACE) inhibitors and b-adrenoceptor blockers have been shown to reduce mortality and improve symptom status in patients with systolic CHF. In patients with mildto-moderate CHF, ACE inhibitors reduce absolute annual mortality by around 1.5%, b-blockers by 3.6%, and the two agents combined by 4.9%.1 Angiotensin receptor blocking agents may confer additional mortality benefit. Nevertheless, mortality remains high in such patients (around 8% annual mortality) despite optimal use of current agents. Mortality remains very high in patients with more advanced disease despite use of ACE inhibitors, b-blockers, and aldosterone receptor antagonists. Furthermore, CHF is a debilitating condition with high morbidity, frequent hospitalization, and poor quality of life. Therefore, the need for new pharmacologic agents in addition to the above therapies continues to be a priority.
Novel therapies have emerged from our improved understanding of the pathophysiology of CHF. The benefits of blocking activated neurohormonal vasoconstrictor systems in CHF are now well-recognized. This has been supported by the success of treatment strategies involving blockade of the renin-angiotensin-aldosterone system (RAAS) (specifically with ACE inhibitors and aldosterone receptor antagonists) and the sympathetic nervous system (SNS) (specifically with b-blockers, angiotensin receptor blockers (ARBs), and aldosterone receptor antagonists). More recently, further understanding of other key systems involved in pathophysiologic responses to myocardial injury (Fig. 13-1) have led to promising new avenues for pharmacologic intervention that may be of therapeutic benefit in this condition.
RECENT TRIALS OF ANCILLARY THERAPIES
In the development of novel agents for the treatment of heart failure, it is important to consider the results of recent trials in the development of promising drug classes for this indication. These recent trials include studies of vasopeptidase inhibitors (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events [OVERTURE]), endothelin receptor antagonists (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure [ENABLE]), and tumor necrosis factor (TNF)-a inhibitory agents (Randomized Etanercept Worldwide Evaluation [RENEWAL]), Anti-TNF Therapy Against Congestive Heart Failure (ATTACH).2–5 These studies were all based on compelling preclinical data and a strong mechanistic rationale. Furthermore there were supportive early phase data that led to these Phase III programs. The results of these study programs are summarized in Table 13-1.
It is therefore worth speculating, in the context of discussion of novel and emerging therapies, to consider why these strategies might have failed.
A number of possibilities exist as to the failure of these agents in heart failure. First, it has been suggested that there may be a threshold for benefit of pharmacological therapy. Next, the patient population studied may have been too broad-based. Specific subgroups within the total heart failure population may have benefited the most. For example, with TNF antagonists, patients with evidence of cardiac cachexia and/or elevated baseline TNF levels may a priori be considered to be those most likely to benefit.
Further, some degree of target system activity may be required for maintenance of normal cardiac function. Therefore, even though the target system may be activated within the failing heart, complete inhibition may have contributed to lack of benefit. There is some evidence to support this from within the TNF literature.
Next, the target for drug therapy may have been too specific to be of benefit in the setting of a broad-based response to myocardial injury. Again, using the example of TNF-a blockade, these biologicals potently inhibit TNF without necessarily acting on other activated proinflammatory cytokines. In this way, only TNF and not other activated cytokines are inhibited and indeed there may be a negative feedback loop operative, which may further activate non-TNF-a proinflammatory cytokines.
Finally, there exists the concept of “regression to the truth” whereby therapies producing false-positive results in the early phase go on to be studied in the late phase with the therapy proving to be nonbeneficial when definitively tested.6
All the above are critical considerations in the planning of trials of novel therapies and will need to be considered in the development of new drugs as outlined in the remainder of this chapter.
ANCILLARY THERAPIES IN CLINICAL DEVELOPMENT
Neurohormonal Blockade
It is well-recognized that blockade of the RAAS and SNS are the cornerstone of therapy for the treatment of heart failure. Therefore, it is not surprising that other, more recently discovered, neurohormonal systems may also be a target for pharmacological intervention in heart failure.
Development of these new therapies has proven more difficult than expected (as outlined above), for example, with regard to the development of endothelin antagonists. However, there are a number of other activated neurohormonal systems recently described that appear to play a role in heart failure disease progression.
Renin Blockade
Renin is the upstream substrate for RAAS activity and agents that block the biological activity of renin have been developed. The most advanced of these is the Novartis compound aliskerin. A highly bioavailable renin activity from Actelion is also soon to enter clinical development.
Despite low bioavailability, studies with the Novartis compound have demonstrated improved hemodynamic parameters and are about to enter an extensive clinical trial program in heart failure.7
The major drug development issue to be considered is whether renin blockade may offer therapeutic benefit over and above that observed with other neurohormonal blocking strategies directed towards the RAAS such as ACE inhibitors, ARBs, and aldosterone receptor antagonists. What can be offered by direct renin inhibitors are the benefits of blocking a system upstream rather than downstream. In this way, there is no reflex activation of renin, angiotensin I, and angiotensin II with the potential for direct adverse effects of activation of these peptides. Against this argument is the increasing recognition that the AT2 receptor subtype of the angiotensin II receptor mediates potentially beneficial actions upon activation and is generally vasodilatory and anti-proliferative.8 With upstream blockade of angiotensin II production by renin inhibitors, those beneficial effects may be diminished or lost. Whether the net effect of these actions translates into overall clinical benefit remains uncertain but is currently being explored.
Vasopressin Receptor Antagonism
The vasopressin system is well known to be activated in heart failure. This system comprises V1A receptors that mediate vasoconstriction primarily, as well as V2 receptors that inhibit aquaresis. Agents have been developed that block either or both receptor subtypes. A number of these agents, for example, tolvaptan and conivaptan, are in clinical development for the treatment of heart failure. These agents are selective V2 receptor antagonists. It is unclear whether blockade of one or both receptor subtypes may confer the greatest clinical benefit.
Much of the initial approach to this development has been focused on patients who are acutely decompensated with evidence of fluid overload. Early trials have shown that these agents are effective at inducing a diuresis with concomitant improvement in clinical status and body weight toward the euvolemic range.9,10 There is also a suggestion of clinical benefit from at least one study, and ongoing studies are currently being conducted for this indication.9
Urotensin II Antagonism
Urotensin II (UII) is an amino acid peptide that, in certain vascular beds, is the most potent vasoconstrictor yet described.11 The peptide appears to have multiple and sometimes opposing vascular actions in various vascular beds, including constriction, dilatation, and no vasoactivity. In the setting of heart failure, increased gene expression of both the ligand and receptor have been observed in failing human myocardium.12 Also observed has been a paradoxical response in heart failure patients whereby skin microcirculation is constricted by UII in heart failure patients in contrast to vasodilation in normal subjects.13 Therefore, UII may be contributory to the increased vascular tone of heart failure. Furthermore, plasma levels of UII have been found to be elevated in some (but not all) studies of CHF patients.14
UII receptor antagonists had been developed that selectively block this system. They have already entered clinical trials for the indication of diabetic nephropathy. CHF is clearly another target.
Neurohormonal Augmentation
A number of vasodilator systems may also be augmented to enhance natriuresis and reduce afterload.
Adrenomedullin is a potential therapy based on its known vasodilatory and antifibrotic actions.15 In this way, adrenomedullin is similar to earlier neutral endopeptidase inhibitors, which augmented natriuretic peptides. These peptides appear to share some of the physiological actions of adrenomedullin. Based on this profile, this is clearly another potentially useful approach to neurohormonal modulation. As with the natriuretic peptides, perhaps a combination of vasoconstrictor inhibitory and vasodilator augmentory approaches may be optimal, although this remains to be formally tested. First time in man studies have demonstrated vasodilatory actions in heart failure.
Modulation of Immune Activation
Despite the disappointment of TNF-a receptor inhibition with etanercept and infliximab, there is still considerable interest in pursuing immune blockade as a therapeutic strategy in CHF. This is based on the pathophysiological consequences of activation of a cascade of proinflammatory cytokines in response to the initial myocardial injury. These activated cytokines include TNF-a, various interleukins (interleukin-1-b, interleukin-2, interleukin-6, interleukin-12, interleukin-17, and interleukin-18), as well as a number of other markers of a proinflammatory state, including c-reactive protein (CRP).16 As mentioned earlier, one hypothesis is that to be effective against this broad-based proinflammatory immune activation in heart failure, broad-based immune inhibition may be necessary.
Intravenous Immunoglobulin Therapy
Intravenous immunoglobulin (IVIG) provides a rich source of buffers against proinflammatory cytokine immune activation. This has been utilized in a number of inflammatory disorders and also studied in heart disease. Data with IVIG from patients with established heart failure are encouraging based on the trial of Gullestad and colleagues.17 In that trial, there was a significant improvement in ejection fraction in IVIG-treated heart failure patients but not in those receiving placebo. However, the study was somewhat underpowered and the between-group difference was not significant. In contrast, a study in patients with recent-onset dilated cardiomyopathy failed to discern differences between IVIG and placebo.18 There were large increases in ejection fraction in the IVIG group but this was also observed in the placebo group, reflecting the spontaneous recovery observed in patients with acute myocarditis manifesting as dilated cardiomyopathy.
Immune Modulation Therapy
This approach involves removal of blood, application of oxidant stress, heat and light, and then reinjection of this autologous blood.19 The ex-vivo processes as described are said to induce an anti-inflammatory cytokine action upon the circulation. A Phase II clinical trial did not meet its primary endpoint of improvement in exercise time.20 However, there was a significant reduction in major clinical endpoint events.20 On this basis, a major outcome trial for registration is currently being undertaken in North America and Europe.
HMG CoA Reductase Inhibitors
Although statins are widely utilized for primary and secondary prevention of cardiovascular disease (primarily in hypercholesterolemic patients), these agents also have potent anti-inflammatory effects. Blockade of TNF-a and interleukin-6 has been demonstrated in man with these agents, both in circulating levels in plasma and in gene expression in mononuclear cells.21
On the basis of this and a number of additional pharmacological properties of these agents, statins have been postulated to be of benefit in patients with heart failure independent of anti-ischemic effects.22
However, there are also theoretical reasons to suggest that statins may not be beneficial in heart failure. Epidemiologically, patients with low-density lipoprotein (LDL) cholesterol levels have the worst outcomes in established heart failure.23 The endotoxin-lipoprotein hypothesis suggests that lipoproteins are required to “mop up” excess endotoxin and thus reduce activation of proinflammatory cytokines such as TNF-a.24 Finally, coenzyme Q is depleted by statins and this may be important in the function of cardiac cells in left ventricular (LV) dysfunction.25
Therefore, like many agents, statins may have positive and negative effects in CHF. The net effect of those actions needs to be definitively elucidated but overall appears to be one of benefit. Several post-hoc analyses of large heart failure databases suggest beneficial effects of statins. However, in none of these were patients prospectively randomized to statins. Preclinical studies support the anti-remodeling benefits of these agents. These findings have recently been supported by a small Japanese study of patients with dilated cardiomyopathy treated with simvastatin for 13 weeks. In that study, potent anti-inflammatory effects of simvastatin were noted, together with anti-remodeling effects as assessed by echocardiography.26
A number of large-scale clinical trials of statin therapy in heart failure are currently being undertaken (CORONA, GISSI HF). Given the large number of patients who are receiving statins by virtue of background ischemic heart disease, the results of these studies are of considerable importance.
Kinase Inhibitors
A number of kinases are involved in mediating the actions of proinflammatory cytokines and inducing downstream cytokine activation. Prominent amongst these are p38 mitogen-activated protein (MAP)-kinase inhibitors. The p38 MAP-kinase inhibitor RWJ-67657 has been demonstrated to reduce remodeling and pathological fibrosis in rats with permanent coronary ligation myocardial infarction (MI).27 These agents have been shown to be potent inhibitors of TNF and other proinflammatory cytokines in man. Indeed, clinical trials are currently underway with these agents for noncardiovascular indications such as rheumatoid arthritis and Crohn’s disease as well as cardiovascular indications such as atherosclerosis.
Other Targets and Agents
Cardiac Metabolic Agents
These agents address defects in cardiac metabolism that occur in the setting of myocardial dysfunction. Metabolism of fatty acids is the major source of adenosine triphosphate (ATP) production in the heart. However, fatty acids require more oxygen than glucose to produce an equivalent amount of ATP. As a result, fatty acids are not as efficient as glucose as a source of energy. In addition, in the setting of myocardial ischemia and dysfunction, products of glycolysis (i.e., lactate and protons) can accumulate and promote an increase in intracellular sodium and calcium, which in turn requires more ATP to reestablish ionic homeostasis.
During LV dysfunction, the oxidation of both fatty acids and carbohydrates is limited by relative myocardial ischemia. Therefore, the ratio of anaerobic glycolysis to ATP production increases, and high concentrations of fatty acid further inhibit, glucose oxidation.
In general, cardiac metabolic agents switch metabolism from fatty acid to that of glucose and this involves more efficient utilization of ATP and thus improved actin-myosin contractility per unit ATP expended.
Agents in this category include ranolazine, a partial fatty acid oxidase inhibitor, perhexiline, a carnitine palmitoyl transferase (CPT1) inhibitor, and trimetazidine, an inhibitor of mitochondrial long chain 3-cetoaryl coenzyme (CoA) thiolase, a fundamental enzyme in cardiac metabolism. Another agent within this group of drugs, etomoxir, has recently yielded disappointing results and is not being further developed for heart failure.
Modulation of Collagen Deposition and Crosslinking
Pathological fibrosis has emerged as a key target for pharmacological intervention in heart failure.28 Renin-angiotensin system blocking agents such as ACE inhibitors, ARBs, and particularly aldosterone receptor antagonists have all been demonstrated to reduce pathological fibrosis, both indirectly via improved hemodynamics but also directly via direct effects on collagen synthesis. Many of these effects are mediated via growth factors and cytokines such as transforming growth factor beta (TGF-b ), p38 MAP-kinase, and protein kinase C. Similarly, b-blockers have also been demonstrated to have antifibrogenic properties.
There are a number of agents where antifibrotic effects are the predominant pharmacological property of the drug. One such agent is tranilast. Tranilast was disappointing in the PRESTO study for post-percutaneous transluminal coronary angioplasty (PTCA) restenosis prevention.25 However, antifibrotic actions have been demonstrated with tranilast in a number of animal models including the Ren-2 diabetic model of cardiomyopathy and the permanent ligation post-MI model.30 Reductions in fibrosis were associated with improvements in the ventricular function in these models.
Other antifibrotic strategies currently being studied including agents that inhibit phosphorylation of TGF-b and blockers of the actions of connective tissue growth factor, the latter a commonly activated factor in the ventricular remodeling process.
Diastolic heart failure is characterized by an increase in advanced glycation end products (AGEs). The biochemical steps of AGE formation are irreversible, leading to accumulation in long-lived proteins such as collagen. Serum concentration of AGEs has been correlated with echocardiographic indices of cardiac stiffness. The AGE cross-link breaker ALT711 has been demonstrated to reduce myocardial stiffness in animal models.31 Clinical trials are ongoing in diastolic heart failure patients, with and without associated diabetes mellitus.
Direct Sinus Node Inhibitors
The IF channel has been identified as a major pathway of sinus node electrical activity, which can be blocked by specific agents, such as ivabradine.
It is unclear whether slowing of heart rate alone results in significant improvements in ventricular function. Preclinical studies do suggest that this is indeed the case with improvements in ventricular function and early clinical evidence of improved cardiac hemodynamics through rate reduction alone.32 Whether this benefit can be observed incremental to background b-blocker therapy in heart failure is currently unclear. Nevertheless, a significant percentage of patients are either ineligible to receive or unable to tolerate b-blockers and these patients may benefit from alternative forms of heart rate reduction. A large-scale clinical trial in patients with ischemic heart disease and systolic LV dysfunction (with and without background b-blockade) is currently underway (BEAUTIFUL study).
Direct Myosin Activators
Cardiac myosin activators directly address the major deficit in myocardial contractile function: defective myosin motor protein activity. Preclinical studies demonstrate increased cardiac contractility without CAMP activation or increasing intracellular calcium. Such agents are about to enter clinical trials.33
Agents Augmenting Renal Function in CHF
Adenosine A1-receptor antagonists decrease different arteriolar pressure, increase urine flow, and enhance sodium excretion in CHF patients. Diuretic actions are achieved via inhibition of sodium reabsorption in tubular sites. The net effect is diuresis with improved or maintained glomerular filtration rate, an attractive pharmacological profile in CHF.34 These agents are currently in clinical development.
SUMMARY
As has been described in this chapter, a number of novel pharmacological approaches have been employed to improve outcomes in patients with heart failure additional to background standard therapies. It is clear that the greatest overall health care gains are to be made in widespread public health campaigns to ensure that all eligible patients are able to receive optimal best practice therapies. However, we should continue to strive to improve outcomes in such patients. This includes not only ancillary drug therapy but also nonpharmacological measures and multidisciplinary supports as described elsewhere in this textbook. More recently, use of devices in selected patients has resulted in improved outcomes. However, for the majority of patients such devices are either clinically inappropriate or unaffordable. For this reason alone we should continue to pursue drug therapies, which are affordable, directed toward appropriate patients, and capable of providing either alternative or complementary benefit to existing therapies. Some have argued that we have reached the limits of clinical benefit that can be obtained from pharmacological therapy in heart failure. It is far from certain, however, that this is the case and we must continue to pursue novel drug therapies for the reasons described above. Clearly, however, these will need to be more carefully targeted to avoid the disappointments with recent trials as described at the beginning of this chapter.
REFERENCES
1. Swedberg K, Cleland J, Dargie H, Task Force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). Eur Heart J. 2005;26:1115–1140.
2. 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;106:920–926.
3. Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Int J Cardiol. 2002;85: 195–197.
4. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized EtanerceptWorldwide Evaluation (RENEWAL). Circulation. 2004;109:1594–1602.
1. Chung ES, Packer M, Lo KH, Anti-TNF therapy against congestive heart failure investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107:3133–3140.
2. Krum H, Tonkin A. Why do phase III trials of promising heart failure drugs often fail? The contribution of “regression to the truth.” J Card Fail. 2003;9:364–367.
3. Stanton A. Therapeutic potential of renin inhibitors in the management of cardiovascular disorders. Am J Cardiovasc Drugs. 2003;3:3 89–394.
4. Matsubara H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ Res. 1998;83: 1182–1189.
5. Gheorghiade M, Gattis WA, O’Connor CM, Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) investigators. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA. 2004;291:1963–1971.
6. Goldsmith SR, Gheorghiade M. Vasopressin antagonism in heart failure. J Am Coll Cardiol. 2005; 46:1785–1791.
7. Gilbert RE, Douglas SA, Krum H. Urotensin-II as a novel therapeutic target in the clinical management of cardiorenal disease. Curr Opin Investig Drugs. 2004;5:276–282.
8. Douglas SA, Tayara L, Ohlstein EH, et al. Congestive heart failure and expression of myocardial urotensin II. Lancet. 2002;359: 1990–1997.
9. Lim M, Honisett S, Sparkes CD, et al. Differential effect of urotensin II on vascular tone in normal subjects and patients with chronic heart failure. Circulation. 2004;109:1212–1214.
10. Richards AM, Nicholls MG, Lainchbury JG, et al. Plasma urotensin II in heart failure. Lancet. 2002;360: 545–546.
11. Rademaker MT, Cameron VA, Charles CJ, et al. Adrenomedullin and heart failure. Regul Pept. 2003;112:51–60.
1. Aukrust P, Gullestad L, Ueland T, et al. Inflammatory and anti-inflammatory cytokines in chronic heart failure: potential therapeutic implications. Ann Med. 2005;37:74–85.
2. Gullestad L, Aass H, Fjeld JG, et al. Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure. Circulation. 2001;103:220–225.
3. McNamara DM, Holubkov R, Starling RC, et all. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation. 2001;103:2254–2259.
4. Torre-Amione G, Sestier F, Radovancevic B, et al. Broad modulation of tissue responses (immune activation) by celacade may favorably influence pathologic processes associated with heart failure progression. Am J Cardiol. 2005; 95:C30–C37.
5. Torre-Amione G, Sestier F, Radovancevic B, et al. Effects of a novel immune modulation therapy in patients with advanced chronic heart failure: results of a randomized, controlled, phase II trial. J Am Coll Cardiol. 2004;44:1181–1186.
6. Marz W, Koenig W. HMG-CoA reductase inhibition: anti-inflammatory effects beyond lipid lowering? J Cardiovasc Risk. 2003;10:169–277.
7. Krum H, McMurray JJ. Statins and chronic heart failure: do we need a large-scale outcome trial? J Am Coll Cardiol. 2002;39:1567–1573.
8. Fonarow GC, Horwich TB. Cholesterol and mortality in heart failure: the bad gone good? J Am Coll Cardiol. 2003;42:1941–1943.
9. Rauchhaus M, Coats AJ, Anker SD. The endotoxinlipoprotein hypothesis. Lancet. 2000;356: 930–933.
10. Hargreaves IP, Duncan AJ, Heales SJ, et al. The effect of HMG-CoA reductase inhibitors on coenzyme Q10: possible biochemical/clinical implications. Drug Saf. 2005;28:659–676.
11. Node K, Fujita M, Kitakaze M, et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy. Circulation. 2003;108:839–843.
12. See F, Thomas W, Way K, et al. p38 mitogenactivated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat. J Am Coll Cardiol. 2004;44:1679–1689.
13. See F, Kompa A, Martin J, et al. Fibrosis as a therapeutic target post-myocardial infarction. Curr Pharm Des. 2005;11:477–487.
14. Savage M, LaBlanche JM, Grip L, et al. Results of Prevention of REStenosis with Tranilast and itsOutcomes (PRESTO) trial. Circulation. 2002;106: 1243–1250. |
