By Santosh Vardhana
Faculty Peer Reviewed
Please review Part 1 of this article here.
Mr. M is a 63-year old man with a history of coronary artery disease and systolic congestive heart failure (ejection fraction 32%) on lisinopril, metoprolol, and spironolactone who presents to the Adult Primary Care Center complaining of persistent dyspnea with exertion, two-pillow orthopnea, and severely limited exercise tolerance. His vital signs on presentation are T 98.0˚F, P 84, BP 122/76. What are his therapeutic options?
A randomized, placebo controlled study of ivabradine in patients with chronic heart failure (the SHIFT trial)
Encouraged by data from observational human studies and animal models, investigators at the University of Gothenburg in Sweden designed the SHIFT study to evaluate the role of ivabradine in reducing adverse cardiovascular events in medically-optimized patients with systolic congestive heart failure (CHF) and an elevated resting heart rate. The study included 6558 patients in 37 countries. Criteria for inclusion included stable, chronic, symptomatic CHF of greater than 4 weeks duration with a hospital admission for symptomatic CHF in the past 12 months, an ejection fraction (EF) of less than 35%, and an electrocardiogram showing a resting heart rate of at least 70 beats per minute (bpm) but otherwise normal sinus rhythm. Patients with congenital heart disease, primary valvular disease, a myocardial infarction in the past 2 months, ventricular pacing for greater than 40% of each day, atrial fibrillation or flutter, or symptomatic hypotension were excluded. Patients were randomized to either placebo or ivabradine 5 mg twice daily, which was titrated during 4-month follow-up visits over 2 years to a target heart rate of 50-60 bpm. The minimum acceptable dose of ivabradine was 2.5 mg daily and the maximum dose was 7.5 mg twice daily. Patients with symptomatic bradycardia on 2.5 mg daily were withdrawn from the study but included in the intention-to-treat analysis. The primary endpoint was a composite of cardiovascular death and hospital admission for worsening CHF. Secondary endpoints included an analysis of the primary endpoint in a predetermined subset of patients receiving at least 50% of their target dose of beta-blocker as well as all-cause death and all-cause hospital admission. Follow-up was comprehensive, with only 3 out of 6505 patients lost to follow-up. Patients who withdrew from the study were followed up and included in the analysis. The population was 75% male, 90% white, with an average age of 60. The average heart rate of the population was 80 bpm, with an average BP of 122/76 and EF of 29%. Functional class was New York Heart Association (NYHA) class II in 49%, class III in 50%, and class IV in 2%. Approximately two thirds of the patients had CHF from ischemic causes. Two thirds of the patients had hypertension, 30% had diabetes, and 17% were smokers. Over 90% of the patients were on both beta-blockers and renin-angiotensin system inhibitors; however, it is important to note that only 56% of patients achieved greater than 50% of their target dose of beta-blockers as defined by European Society of Cardiology guidelines, and only 26% achieved the target dose. The authors cited obstructive pulmonary disease, hypotension, fatigue, dyspnea, dizziness, and bradycardia as reasons for failure to achieve target dose.
Two pertinent features of the study population should be noted. First, patients were optimized on medical therapy, including beta-blockers, before being treated with ivabradine. The authors were investigating the utility of ivabradine in addition to current medical therapy and not as a replacement for beta-blockers. Second, the average GFR of the patient population was 75 mL/min; this suggests that this patient population was not already undergoing end-organ hypoperfusion as indicated by renal insufficiency. It may well be that CHF patients with evidence of hypoperfusion would not be able to tolerate the addition of ivabradine; those patients were not addressed in the study.
Intention-to-treat analysis of the entire study population showed a reduction of 8 bpm in heart rate over 2 years with administration of ivabradine. This resulted in significant symptomatic improvement in the treatment group. Ivabradine also reduced the primary endpoint from 29% to 24%, a relative risk reduction of 18% and an absolute risk reduction of 5%, with a number needed to treat of 26. This reduction was primarily due to a reduction in hospital admissions for CHF; death from cardiovascular causes was not reduced by treatment with ivabradine. However, deaths due specifically to CHF were reduced in the treatment group, with a relative risk reduction of 26%. In the subgroup of patients who were at greater than 50% of target beta-blocker therapy, the effect of ivabradine was less dramatic: only a 19% relative risk reduction in hospital admissions and a non-significant reduction in the composite primary endpoint. The authors claim that this was due to insufficient powering for the reduced event rate in this subgroup. Not surprisingly, the effect of ivabradine was most pronounced in patients with resting heart rates greater than 77 bpm. Ivabradine was generally well tolerated in this study; symptomatic bradycardia was present in 10% of the treatment group, but led to study withdrawal in only 1%. This is impressive, given that almost three quarters of the same study population could not tolerate the target dose of beta-blockers, and suggests that ivabradine-induced bradycardia is tolerated significantly better than beta-blocker-induced hypotension and bradycardia. Of note, 3% of patients taking ivabradine experienced phosphenes (transient enhanced brightness in a restricted area of the visual field).
A companion paper released in the same issue of The Lancet performed subgroup analyses stratifying the patient population of SHIFT by heart rate quintiles. The patients in the highest quintile of heart rates (greater than 87 bpm) were much more likely at baseline to have more advanced CHF with a lower ejection fraction. As in prior studies, baseline heart rate in both the placebo and treatment groups was linearly associated with both cardiovascular death and hospitalization for CHF. The risk reduction was greatest in patients whose heart rate was reduced to less than 70 bpm, an endpoint that was achieved in three quarters of patients treated with ivabradine but less than one third of patients receiving placebo. Thus, reduction of cardiovascular morbidity and mortality by ivabradine is dependent on the extent of heart rate reduction; this finding is similar to findings demonstrated for beta-blockers and emphasizes the importance of controlling heart rate in CHF.
In a subsequent study, 60 patients with NYHA class II and III CHF with EFs less than 40% were randomized to either ivabradine or placebo therapy. Over the following 6 months, patients receiving ivabradine reported improved quality of life and improvement in NYHA functional class; objectively, they were found to have improved exercise capacity, improved peak oxygen consumption, and a significant reduction in baseline N-terminal probrain natriuretic peptide levels. Furthermore, a substudy of the BEAUTIFUL trial that performed two-dimensional echocardiography on patients with stable coronary artery disease and left ventricular systolic dysfunction found that treatment with ivabradine improved left ventricular EF in a manner that was proportional to the reduction in heart rate, further supporting a role for ivabradine in preventing pathological remodeling in CHF by achieving optimal heart rate reduction.
Don’t you forget about me: beta-blockers and digoxin
This study brings to light many important considerations in the management of chronic CHF. First, it reintroduces resting heart rate as an important target in the management of CHF and demonstrates for the first time that reduction of heart rate to a target goal of less than 70 bpm in the absence of other modifications results in statistically significant improvements in cardiovascular morbidity and, in some cases, mortality. Second, it introduces a new class of drug, inhibitors of the so-called funny current, as a new potential therapeutic option for patients with chronic CHF. Finally, it suggests that this drug class may be of particular efficacy in patients who cannot achieve target doses of beta-blockers for any reason.
In an editorial in the same issue of The Lancet, Teerlink noted that the majority of patients did not achieve target beta-blocker doses and that ivabradine was most efficacious in these patients. Introduction of ivabradine as an alternative to beta-blockers might diminish the use of beta-blockers, which are often discontinued by patients or physicians despite little evidence that they cause adverse effects such as depression or impotence, or worsen comorbidities such as reactive airway disease.[7,8] Substitution of ivabradine for beta-blockers (which was not endorsed by the authors of SHIFT) would compromise not only patient outcomes, given the broadly demonstrated mortality benefit of beta-blockers, but would also raise the cost of treatment, given the relative cost of less than $5000 per quality-adjusted life year (QALY) for beta blocker administration. This fiscal consideration is particularly important, given that more Medicare dollars are spent on treatment of CHF than on any other disease.
The particular efficacy of ivabradine in patients who were not able to achieve optimal beta-blockade is consistent with a report in 2009 that used multivariable linear regression analysis to determine how carvedilol improves ejection fraction in patients with CHF in the presence of both ACE inhibition and digoxin. The study found that heart rate reduction was responsible for 60% of the improvement in ejection fraction seen with carvedilol, with 30% of improvement being due to increased contractility and less than 20% due to reduction of afterload secondary to alpha-blockade. Patients should be optimized on the maximum tolerable dose of beta-blocker with a target heart rate of less than 70 bpm before considering addition of a funny current inhibitor such as ivabradine.
Similar questions have been asked about the mechanism of digoxin, a drug that has many functional effects similar to ivabradine. Digoxin, via its inhibitory effect on the sodium-potassium ATPase pump and activating effect on parasympathetic vagal tone, has a positive inotropic and negative chronotropic effect, and it appears to decrease hospitalizations without a robust reduction in mortality.[14,15] These are similar effects to those seen with ivabradine, but at a fraction of the cost. It is worth noting that fewer than 25% of the patients enrolled in SHIFT were taking digoxin.
The bottom line
The SHIFT study reopens the debate on mechanisms of myocardial damage in CHF and reintroduces heart rate as a legitimate target in CHF management. The question of whether target heart rates should be achieved by dose optimization of beta-blockers, judicious use of digoxin, or implementation of novel therapies such as the I(f) inhibitor ivabradine remains an interesting and exciting topic for future research.
Santosh Vardhana is a 4th year medical student at NYU Langone Medical Center
Peer reviewed by Robert Donnino, MD, section editor, clinical correlations
Image courtesy of Wikimedia Commons
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