Role of medical therapy in the device era for the treatment of heart failure

The disease entity known as heart failure (HF) has emerged as a malady of rampant proportions over the last three decades. Like a pathologic juggernaut, deaths due to HF have skyrocketed by over 150% in the last 20 years, and it is estimated that the lifetime risk of developing HF at 40 years of age is one in five for both men and women [1]. In addition, sudden cardiac death in HF patients occurs at a rate of nearly eight-times the general population. Given these grim figures, it is of no wonder that the scientific community has been toiling away trying to find alternate methods of halting this downward spiral. Although medical therapy has provided the basis of treatment, recent advances in mechanical therapy have also supplemented the therapeutic options available to the clinician. Given the recent positive results of trials utilizing device therapy in HF, the question now being asked is whether the role of background medical therapy changes, and if so, which direction should be taken with the medications?

Foundation of treatment: pharmacotherapy

Although the prevalence of HF in the community remains high, dramatic advances in medical therapy have also taken place. The current understanding of the pathoetiology of HF involves the concept of the neurohormonal cascade, which represents the potential deleterious effects of an unmitigated systemic inflammatory state. Large-scale, randomized trials have established the survival benefit of certain medications in HF combating this cascade (angiotensin-converting enzyme [ACE] inhibitors/angiotensin receptor blockers [ARBs], β-blockers, aldosterone antagonists) and these agents are now considered the cornerstone of any treatment plan for patients with HF [2–5]. The current understanding of treatment guidelines is to titrate these medications to their maximum therapeutic dose, or to a dose best tolerated by the patient. Although these medications have alleviated the mortality curve of HF somewhat, they have failed to be the ‘silver bullet’ sought by clinicians, either individually or in cocktail form. In addition, patients often have difficulty achieving the higher doses of these medications that are required for the greatest mortality benefit due to untoward side effects, and thus, fall into the gray area of probable, but not maximal, benefit from their use.

Enter the fray: device therapy

Given the aforementioned mildly attenuated mortality rates through medical therapy, alternate forms of remedies have been actively sought after by both researchers and clinicians alike. The growth of device therapy for HF has emerged as one of the areas where a significant amount of clinical success has been particularly noted. Device therapy, namely cardiac resynchronization therapy (CRT) or biventricular pacing, represents the new era of HF management, where the actual mechanical alterations of the heart due to the progression of HF are primarily targeted. Studies utilizing this modality have demonstrated improvements in 6-min walk tests, ejection fraction (EF), New York Heart Association (NYHA) classification and quality-of-life scores [6–8]. The HF patient population primarily enrolled in these trials were NYHA classification III–IV, with a baseline QRS of more than 120 milliseconds, an ejection fraction (EF) of less than 35% and, most importantly, were on optimal medical therapy.

The effect of device therapy on mortality in HF was examined by Bristow and colleagues in the Comparison Of Medical therapy, Pacing And defibrillatioN In chrONic heart failure (COMPANION) trial [9]. This trial enrolled a total of 1520 patients with HF who were NYHA class III or IV, with ischemic or nonischemic cardiomyopathy, and a QRS interval of at least 120 milliseconds. These patients were randomly assigned in a 1:2:2 ratio to receive optimal pharmacologic therapy alone or in combination with CRT or with CRT plus a defibrillator (implantable cardioverter defibrillator [ICD]) with the primary composite end point being time to death from any cause or hospitalization for any cause. The results revealed that CRT decreased the risk of the primary end point (heart rate 0.81; p = 0.014), as did CRT plus a defibrillator (heart rate 0.80; p = 0.01) when compared with medical therapy alone. Additionally, CRT reduced the risk of the secondary end point of death from any cause by 24% (p = 0.059), and CRT plus a defibrillator reduced the risk by 36% (p = 0.003). Although there was a significant trend towards reducing the risk of death with CRT alone, this result left lingering questions regarding the mortality benefit of CRT without an ICD, and necessitated further investigations.

The recently reported results of the CArdiac REsynchronization – Heart Failure (CARE-HF) trial by Cleland and colleagues has provided some clarification on the initial thoughts of CRT’s role in decreasing mortality in patients with HF, irrespective of ICD placement [10]. The study enrolled 813 patients with HF who met guidelines for CRT, as established by prior trials, and randomized them to either medical therapy alone or medical therapy plus CRT. The primary end point was the time to death from any cause or a hospitalization for a major cardiovascular event. The principal secondary end point was death from any cause. The results demonstrated that the primary end point was reached by 159 patients in the CRT group, as compared with 224 patients in the medical therapy group (39 vs. 55%; hazard ratio 0.63; confidence interval 0.51–0.77; p < 0.001). There were 82 deaths in the CRT group, as opposed to 120 in the medical therapy group (20 vs. 30%; hazard ratio 0.64; confidence interval 0.48–0.85; p < 0.002). These results have bolstered the opinion that CRT with optimal medical therapy, even without an ICD, does not only improve the symptoms of HF, but can also reduce their associated risk of death.

Impact on standard treatment

An additional positive effect that the authors have found in patients who have received CRT is the ability to modify their baseline medications. Often, pre-implant, many patients have difficulty attaining the maximal effective doses with β-blockers or ACE-inhibitors/ARBs, due to light-headedness or lethargy, but after CRT implantation, many of these patients can be effectively uptitrated. Also, patients who have had an improvement in functional class and EF from CRT can often have their doses of diuretics and nitrates decreased as symptoms warrant. The improvement in functional class may not be paralleled by a change in EF and vice versa; thus, the authors’ adjustments of aldosterone antagonists and the use of digoxin are based on an individual patient basis.

Additive or alternative treatment?

Although there has been a recent flurry of large-scale trials demonstrating the efficacy of CRT plus/minus ICD usage in patients with HF, it should be understood that all of these device trials were based on the pretense of optimal background medical therapy. To replace this line of therapy with CRT exclusively would be unethical and unsubstantiated. Device therapy is still in its infancy, as revealed by the number of issues that still surround its proper implementation. Questions such as why nearly a third of all CRT recipients are deemed as nonresponders, the role of pacing in atrial fibrillation and the importance of QRS duration as opposed to ventricular dyssynchrony, are all debatable subjects that warrant further examination. To anoint device therapy as a first-line treatment option would be premature; this modality should be viewed as complementary, rather than as a replacement, to the already well established standard of pharmacotherapy that currently exists for the management of patients with HF.