August 29th, 2010
Downshifting Heart Rate in HF Found Beneficial
Larry Husten, PHD
In the SHIFT trial, Karl Swedberg and colleagues tested the effects of ivabradine, a selective sinus-node inhibitor, in 6558 patients with heart failure who had a heart rate ≥70 bpm. After a median 23 months of follow-up, the rate of cardiovascular death or hospital admission for worsening heart failure was 24% in the ivabradine group and 29% in the placebo group (hazard ratio, 0.82; 95% CI 0.75–0.90, P<0.0001). The results were presented at the ESC in Stockholm and published simultaneously in the Lancet.
In an accompanying comment in the Lancet, John Teerlink noted that many patients in SHIFT did not receive optimal medical therapy, especially high-dose beta-blockers. Therefore, he writes: “Whether ivabradine can improve outcomes in addition to optimally managed heart failure therapies or its benefits relative to other therapies, especially beta blockers, remains unknown.”
In a second paper published in the Lancet, Michael Böhm and colleagues analyzed data from SHIFT and found that in the placebo group, patients with heart rates in the highest quintile at baseline had double the risk of patients in the lowest quintile. In the placebo group, the investigators observed a direct correlation between heart rate at 28 days and subsequent outcome, and concluded that “the effect of ivabradine is accounted for by heart-rate reduction.”
9 Responses to “Downshifting Heart Rate in HF Found Beneficial”
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This caused a lot of buzz today at the conference. The adequacy vs inadequacy of background beta-blockade remains hotly debated — and this wasn’t directly addressed during the presentation (interestingly, ESC members were emailed beforehand an invitation to pose questions to the presenters). At the very least, it seems to me interesing as a proof of concept study regarding the importance of heart rate control…
Susan, regarding beta-blockade: only about a quarter of the population were receiving optimal, high dose beta blockade.
Right, agree, though 89-90% were on at least some b-blockade in each arm. I guess the question is just how much more the suboptimally b-blocked folks could have been uptitrated before needed another bradycardic agent added… probably a lot more for most, which is the opinion I’m hearing from at least some HF docs, though there will always be those few who can’t get there due to hypotension, COPD, etc.
What is the use of studies like this one?
If the SHIFT trial had been designed as to assess just two arms – one with full-dose betablockade and the other one with betablockade plus ivabradine, only then could one tell the difference between the two arms. One could also see the proportion of patients not able to achieve full-dosee betablockade and analyze the reasons. Thus the results with this poor background favour only commercial interest – in Europe (US not approved)let the docs try to add ivabradine and forget uptitrating betablockers. The problem is in the study design and conflict of interests. Should there be an independent body of clinicians to assess and influence the design of the study, I believe we would not comment these dilemmas. As for ivabradine, the BEAUTIFUL trial proved to be UGLY in its primary endpoint and the SHIFT trial indicates the SHIFT AWAY from decision-making based on this poor background. (An interesting piece of reading EMEA EPAR = European Public Assessment Report on how this drug was approved in Europe).
As a heart failure physician, this data tells me only that I would potentially use ivabdradine if I had a patient who could not, for other reasons, tolerate a B-blocker.
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Beware ! – betablocker intolerance !! The real world has not shown this from my experience with regard to the big proportion of intolerance claimed by those proposing ivabradine.
I agree in that some patients cannot tolerate betablockers. Yet what is the true intolerance? For instance the reason of hypotension as an obstacle of uptitrating betablocker can be nulled with trying to discard some unnecessary drugs (e.g. nitrates)or adjust the dosage of diuretic if at excessive dose or prefer higher dose of betablockers at the expense of lower dose of ACE inhibitor or ARB in view of larger benefit of betablocker compared with ACE-i or ARB, especially in the setting of HF post MI. Another modality is to discard Ca channel blocker like amlodipine or felodipine if already taken by the HF patient (no benefit proved).
It seems that, IF ivabradine will not have some significant side effects, it could be used as a rythm reduction drug in a very small population of heart failure patients who can’t tolerate beta-blockers.
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Ivabradine has some side effects not precluding its use in clinical pratice. The problem lies in its limitation to patients with STABLE sinus rhythm. Thus at least one third of patients with CHF (congestive heart failure)is excluded for they present with atrial fibrillation (AF), this proportion probably being much higher in the hospital setting with elderly pts with CHF and its acute decompensation. CHF pts have also paroxysmal AF or other arrhytmias which preclude the use of ivabradine, i.e. STABLE sinus rhythm.
Returning to the issue of hypotension, I think, the patient would need an “overhaul” besides looking at the spectrum of other drugs used (see above). Just two addtional factors of hypotension might be considered. Significant valuvlar disease (e.g. aortic stenosis, esp. the one with low gradient and low cardiac output=CO) and multi-vessel disease (decreased CO). Both conditions reguire assessment and the appropriate treatment. In the former case, there is no consideration of betablocker, but surgery when indicated. In the latter case, revascularisation of viable myocardium might prove beneficial.
What about patients with gene mutations that might make them less responsive to beta-blocker therapy such as Gly389 variant beta1-adrenergic receptors? Would they benefit from ivabradine? As we know mutations such as these are more common in African American patients and can indicate less of a response to beta-blocker therapy.