Updating the Perioperative Beta-Blocker Guidelines: Absorbing the Impact of POISE

Disclosure:Dr. London: Significant research support from the Anesthesia Patient Safety Foundation. Dr. Levy: None.
Pub Date: Wednesday, November 4, 2009
Author: Martin J. London, MD  and Jerrold H. Levy, MD, FAHA

Fleischmann KE, Beckman JA, Buller CE, et al. 2009 ACCF/AHA focused update on perioperative beta blockade: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009. Published online before print November 2, 2009. 10.1161/CIRCULATIONAHA.109.192689.

In recent years, the growth in worldwide surgical volume has been facilitated by technical advances in surgical and anesthetic management, but it has also been increasingly associated with a societal imperative to maximize patient safety and minimize unnecessary costs. As a result, careful analyses of therapeutic interventions to reduce cardiovascular complications are of paramount importance.[1] With advances in information technology and outcomes reporting we are entering an era where rapid evaluation of treatment effectiveness offers significant potential to alter clinical practice as new data become available.[2] Despite these advances, cardiovascular complications following noncardiac surgery, in particular the continuum of myocardial ischemia to infarction and their resulting adverse consequences (most notably heart failure, pulmonary edema, cardiac arrest, and death), remain a major problem.[3] Given the increasing sensitivity of methods used to detect myocardial damage, this problem is in many ways a "moving target."[4] It is now well demonstrated that ST-segment elevation infarction (STEMI) is a distinctly uncommon presentation in the perioperative period in contrast to non-ST-segment elevation infarction (NSTEMI), the latter now classified as either type 1 (acute coronary syndrome) or type 2 (myocardial oxygen supply-demand mismatch) subtypes.[5] Although perioperative mortality from STEMI is considerably lower than NSTEMI, strong associations of low-grade degrees of troponin release with longer term mortality point toward, but do not definitively prove, a casual relation. Thus, efforts to minimize the occurrence of such damage are of considerable importance.

The ability of beta-blockers to effectively reduce myocardial oxygen demand primarily by heart-rate reduction, increasing left ventricular diastolic time and thus, coronary perfusion, has served as the cornerstone of their therapeutic use in managing stable angina and ischemia during acute coronary syndromes. Concurrent reduction in myocardial contractility can favorably improve the myocardial oxygen supply demand equation as long as other key variables are not adversely affected (e.g. diastolic blood pressure, left ventricular end-diastolic pressure, relaxation, and oxygen carrying capacity).[6] Despite other well documented (e.g., protection of the adrenergic receptor in heart failure) or controversial effects (e.g., possible antiinflammatory, antiatherogenic actions), the former actions are postulated to be the primary mechanisms to offset the adverse increase in oxygen demand induced by perioperative adrenergic activation that can lead to subendocardial ischemia and possible plaque rupture.[7

The saga of perioperative beta blockade has seen twists and turns along its nearly 50-year history since patients first presented for surgery taking these agents for hypertension, stable angina, and other disorders. It became considerably more complicated from physiologic and epidemiologic standpoints when previously naïve patients, either with overt coronary disease, major risk factors, or disease in other arterial distributions, were deliberately started on beta blockers expressly for perioperative prophylaxis against ischemic cardiac complications based on the seminal but controversial studies of Mangano et al. and Poldermans et al. (DECREASE) in the late 1990's.[8,9] These studies reported robust efficacy in either the perioperative (the latter) or only the longer term period after surgery (the former). In the ensuing years more studies of varying quality have supported or disputed efficacy as well as suggested an increased frequency of "clinically significant" hemodynamic events that include beta-blocker induced bradycardia and hypotension.[10] Other reports also suggested their discontinuation in chronic users was associated with substantial risk.[11

Since the first iteration of the ACCF/AHA Perioperative Guidelines on Perioperative Evaluation and Care for Noncardiac Surgery in 1996 these issues have been addressed incrementally as more studies became available. The current 2009 Focused Update on Perioperative Beta Blockade by Fleischmann et al. has been eagerly awaited by clinicians and nonmedical "stakeholders" involved in efforts to monitor and improve health-care outcomes via performance measures, since publication of the controversial PeriOperative Ischemic Evaluation Trial (POISE).[12,13] The results of this trial of over 8,000 relatively high-risk patients (with over 80% having either CAD, PAD, or CVD and 40% undergoing vascular surgery) in which oral beta blockade with sustained release metoprolol was started immediately prior to surgery and continued for 30 days, are by this time well known to most AHA members given widespread "dissection" in opinion pieces (with the majority taking a decidedly negative stance toward further efforts at widespread implementation).[14-16] Absorbing this study's primary findings of significant efficacy in reducing ischemic complications (mostly asymptomatic troponin release) counterbalanced by increased rates of stroke (primarily disabling) and death (primarily from sepsis) with significant hypotension appearing to play a strong etiologic role, posed a substantial challenge to the guideline committee. At the same time, formal publication of the DECREASE-IV study from the Poldermans group (just prior to completion of the guidelines) in a lower risk cohort of 1,066 patients undergoing nonvascular surgery (with approximately half receiving bisoprolol with or without fluvastatin), reporting strong efficacy (even in low risk strata) with no adverse safety outcomes, added an additional dimension of controversy.[17] In contrast to POISE, a slow titration protocol of low dose bisoprolol started gradually prior to surgery over approximately a 30-day period titrated to perioperative heart rates of 50-70 bpm was used and continued for 30 days after surgery. It is notable the starting doses used in recent studies from this group are 50% of those in original DECREASE study, although the upper heart rate range has decreased from 80 to 70 bpm.

Fleischmann et al. have updated the literature review of the guidelines with detailed discussion of these and other less influential reports. As expected, particular emphasis is placed on the serious safety issues raised by the POISE protocol and other studies reporting higher rates of hypotension and bradycardia (without overt sequelae but with sample sizes unlikely to demonstrate them conclusively). The primary changes in the guidelines recommendations would first and foremost be a resounding "nay" to the POISE protocol with it being accorded a Class III (level of evidence B) recommendation stated as "routine administration of high-dose beta blockers in the absence of dose titration is not useful and may be harmful to patients not currently taking beta blockers who are undergoing noncardiac surgery." The wording of this recommendation is open to some degree of debate given use of qualifier "in the absence of dose titration" as well as what qualifies as "high dose." It should be emphasized that sustained release metoprolol results in considerably lower peak concentrations than its tartrate preparation.[18]

The POISE protocol is one that must be considered carefully in the proper historical context coming in the immediate time period following the 1999 DECREASE publication. These Canadian investigators, well known for large scale efficacy and effectiveness studies, including work on secondary prevention, developed and implemented a mega-trial that negotiated through complexities that included the logistics of health-care delivery, ease of drug administration, funding, availability of a pharmaceutical sponsor, and whether possible cardioprotective effects result primarily from heart rate reduction or the beta blocker alone (via "pleiotropic effects"). They ultimately concluded more definitively on the "heart rate" side (ensuring a near maximal dose was used to avoid a neutral finding from under dosage). In fact, the Poldermans group has supported high doses of beta blockers as being most effective in attenuating troponin release.[19] The POISE study was conducted in multiple continents to ensure enrollment of adequate numbers of patients required to tackle the definitive, yet low frequency outcome of mortality. Serial troponin surveillance allowed capture of even subtle degrees of myocardial damage. It is possible that the ultimate longterm outcome of patients in the POISE study may be favorable at the one year analysis point if attenuation of longterm adverse effects of troponin release is observed. If so, this would still be considered an unreasonable approach to improve longterm outcome. Yet, processes of health-care delivery have to be taken into account and clearly these differ substantially between countries. Determination of the optimal means for instituting beta blockade (should it be indicated) remains controversial. Several smaller scale implementation studies have been and continued to be reported, examining aspects such as use of dose titration versus fixed dosing. A recent report comparing either approach in 400 patients demonstrated no difference and reported similar high rates of ischemic events (approximately 6%) suggesting that alternate strategies may be required.[20]

The POISE study has already raised considerable interest in the potentially detrimental role of perioperative anemia given the observed risk of bleeding, clopidogrel use, and hypotension in population attributable risk models for stroke. Mounting evidence suggests a detrimental role for perioperative anemia. If an adverse interaction is confirmed in large scale studies this could be a major contribution to perioperative physiology.[21] It should be noted that the Class III indication accorded this protocol would likely apply to the original atenolol protocol advocated by Mangano et al., which had been previously adopted by some hospitals because of the ease of implementation.[8] The guidelines committee has clearly appropriately sided with safety concerns with the ubiquitous use of the terminology "beta blockers titrated to heart rate and blood pressure" throughout the recommendations. It is hoped that future research will specifically evaluate what constitutes a safe blood pressure and hemoglobin level. Although a lower target range of systolic blood pressure of 100 mm Hg is mentioned in this and other studies, such a pressure in an elderly patient with severe systolic hypertension and other comorbidities may be too low.

The other major changes in the recommendations are the downgrading of a previous Class I recommendation for patients with cardiac ischemia on preoperative testing. This was combined with a previous IIa recommendation considering vascular patients with evidence of coronary artery disease on preoperative assessment. Minor downgrading of levels of evidence from B to C was applied to institution of beta blockade in patients with one or more clinical risk factors (comprising the five nonsurgical risk factors of the revised cardiac risk index). Although reasons for these changes are not explicitly stated, one can speculate the lack of evidence in lower risk populations (excluding the more recent DECREASE-IV study) swayed the committee's opinions. It is notable that use of less sensitive risk criteria (e.g. Framingham factors used in the original Atenolol study), are not part of these treatment algorithms. Finally, it is also notable that the upper intra and postoperative heart rate ranges are higher than in the prior guideline increasing from 60-65 to 60-80 bpm. We applaud this change given the common occurrence of perioperative anemia or hypovolemia where cardiac output may be dependent on higher heart rate.[22]

The committee reaffirms the previous Class I recommendation regarding continuation of beta blockade, but it has revised the wording to indicate they should be continued only "for conditions with Class I indications" over the prior terminology "to treat angina, symptomatic arrhythmias, hypertension or other class I indications." Again the precise rationale is not presented, but may be at least in part due to the growing controversy over beta-blocker therapy for uncomplicated hypertension, a controversy where new physiologic concepts regarding changes in pulse wave propagation and increased afterload present with atenolol but not a calcium channel blocker, are emerging.[23]

This committee has done an admirable job of taking the middle ground between "everyone out of the pool" as one opinion leader has suggested (presumably with tongue in cheek) and "full steam ahead and damn the torpedoes" as others suggest.[14] Despite our best intentions we still don't know if it is "heart rate reduction alone or a little bit of beta blocker" that is (most) cardioprotective. Other pharmacologic interventions such as use of the pure bradycardic agents (e.g. the i(f) inhibitor, ivabradine) or even combined inotrope/beta-blocker therapy require evaluation.[24,25] We look forward to future revisions of this important guideline with an increasing eye toward new concepts in perioperative cardiovascular physiology, pharmacology, and the emerging area of pharmacogenomics.

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-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --