Calcium channel blockers, beta-blockers, and perioperative cardiovascular stability
It is contentious whether calcium channel blockers as a group offer any cardioprotection in the perioperative period for patients undergoing non-cardiac surgery. Meta-analyses of the cardioprotective efficacy of calcium channel blockers have resulted in conflicting results, with one meta-analysis having a sample size too small to draw any conclusions,1 and the other showing significantly reduced myocardial ischaemia and a significantly reduced composite of death, myocardial infarction, or congestive heart failure.2 However, of all the studies identified, only a single study of 50 patients specifically examined dihydropyridines.3Dihydropyridines have properties which are theoretically hazardous in the perioperative period for patients undergoing major non-cardiac surgery. Of particular concern in the perioperative period is that the vasodilation produced by dihydropyridines causes reflex adrenergic activation producing an increase in heart rate, which may be associated with myocardial ischaemia.4 As a result, it is suggested that in patients with unstable angina, dihydropyridines are contraindicated in the absence of beta-blockade.4 Unfortunately, approximately half of the perioperative cardiac events are related to myocardial oxygen supply-demand imbalances and half to rupture of vulnerable atherosclerotic plaque.5 6 Thus, the presence of dihydropyridines may adversely effect both these processes in the perioperative period.
The paper by Kertai and colleagues7 in this issue of the British Journal of Anaesthesia is important because they have specifically examined the effect of dihydropyridines on the outcome after aortic surgery. In a retrospective analysis of a large database, they identified treatment with dihydropyridines as an independent predictor of perioperative mortality [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.6–4]. However, at best observational data present an association but do not prove causation.
In order to adjust for potential confounding by the co-morbidities that lead to patients being prescribed calcium channel blockers, propensity scoring was used in this study.7 However, propensity scoring will not control for the bias of unmeasured variables.8 9 These may be variables which are either associated with treatment assignment or the outcome being investigated.10
There is increasing evidence in the perioperative literature that physiological data such as heart rate and arterial pressure are important in modifying the cardioprotective efficacy of medical therapy. For example, Lindenauer and colleagues conducted a large propensity-matched perioperative cohort study to examine the impact of perioperative beta-blockade (119, 632 beta-blocked patients matched with either one or two patients). Administration of beta-blockers in the early hospital admission was not associated with increased all-cause mortality (OR 0.99, 95% CI 0.95–1.04, P=0.68).11 However, the recently published randomized, placebo controlled PeriOperative Ischemic Evaluation trial (POISE) found all-cause mortality to be increased with perioperative beta-blockade (HR 1.33, 95% CI 1.03–1.74).12
Failure to include physiological data in the study11 may explain the difference in mortality reported between these two studies, as the propensity analysis excluded patients with secondary diagnoses considered to be contraindications to beta-blockade, which included bradycardia and hypotension. Indeed, it is possible some of the excluded patients may have had these secondary diagnoses as a result of beta-blocker therapy. Unfortunately, therefore, even with the best intentions, the ‘bad apples’ may have been removed. The POISE trial results strongly suggest that the haemodynamic changes brought about by drugs acting on the cardiovascular system may be associated with major morbidity in the perioperative period.12 13 In the POISE trial, clinically significant hypotension and bradycardia were associated with increased all-cause mortality (adjusted OR 4.97, 95% CI 3.62–6.81 and adjusted OR 2.13, 95% CI 1.37–3.32, respectively).12 If causality could be shown, these two haemodynamic changes could explain a population attributable risk (PAR) for perioperative mortality of 37%, 95% CI 30–46% and a PAR of 8%, 95% CI 4–15% for beta-blocker-associated hypotension and bradycardia, respectively.12 Similarly, a meta-analysis of the heart rate associated with perioperative beta-blockers suggests that patients who have a maximum heart rate >100 beats min–1 obviates any potential cardioprotective efficacy on postoperative myocardial infarction (OR 1.17, 95% CI 0.79–1.80, P=0.43).14
The influence of physiological variables on outcome, in the presence of cardiovascular medication, has been investigated in medical patients in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA).15 In this study, patients were randomized to either amlodipine and perindopril as required, or atenolol and bendroflumethiazide and potassium as required. The following physiological variables were all found to be independent predictors of coronary and stroke events: arterial pressure, heart rate, body weight, serum potassium, serum creatinine, triglycerides, and blood glucose. Adjustment for differences in these variables between the two arms of the study, established that approximately 50% of the coronary risk reduction and 40% of stroke risk reduction seen in the amlodipine arm of the study, could be explained by these physiological variables.15 A lower heart rate was associated with an improved outcome.15 As none of these physiological variables were controlled for in the propensity score of Kertai and colleagues,7 it may be too bold to suggest that ‘dihydropyridine use should not be considered for patients undergoing aortic surgery’.7
Clearly, physiological data are an important consideration in understanding the outcomes associated with dihydropyridines and beta-blockers in the perioperative period. In particular, the interaction between heart rate, dihydropyridine, and beta-blocker administration is potentially important and may have resulted in bias in this paper.7 However, haemodynamic data are often ignored in the propensity analyses of surgical outcomes, and this may be an important source of bias in studies examining perioperative outcomes associated with cardiac medications. A Medline search conducted on June 25, 2008 using the keywords ‘propensity’, ‘surgery’, and ‘heart rate’ did not reveal a single non-cardiac surgical study which controlled for heart rate.
Although aortic surgical patients receiving dihydropyridines should raise an important warning flag,7 there are unresolved issues to consider. First, readers may be tempted to withdraw dihydropyridines in the perioperative period. This may be desirable, especially if the patient has potentially vulnerable atherosclerotic plaque, as dihydropyridines may result in a reflex tachycardia,4 and an increased heart rate has been associated with plaque disruption.16 However, there are two further issues which this paper unfortunately does not address. First, although withdrawal of amlodipine has not been associated with adverse outcomes in medical patients with stable angina pectoris,17 18 this has not been investigated in the perioperative period. Secondly, in some patients, it will not be possible to withdraw the drug, due to the emergency presentation of the patient. Indeed, 12% of the patients had an acute presentation.7 Withdrawal of dihydropyridines may therefore be impossible. This fact re-emphasizes the importance of identifying perioperative physiological variables which may either improve or adversely affect outcome associated with preoperative dihydropyridine therapy. It is possible that tighter heart rate control may result in less adverse effects associated with dihydropyridines in the perioperative period. A study of medical patients receiving both beta-blockers and calcium antagonists has shown that the time to onset of exercise-induced myocardial ischaemia is significantly increased if the calcium antagonist is associated with a negative chronotropic effect.19
The analyses of the ASCOT-BPLA study discussed above illustrate the consideration accorded to haemodynamic data in medical studies.15 Patients undergoing surgery face potentially greater haemodynamic challenges than medical patients. There is increasing evidence that physiological variables such as perioperative heart rate are independent predictors of outcome in major non-cardiac surgery.20 There are few prospective randomized,12 14 prospective non-randomized,21 and retrospective data22 which specifically examine hard outcomes associated with perioperative cardiovascular medications and perioperative haemodynamics. Analyses of perioperative physiological data should be an integral part of studies of perioperative outcomes associated with cardiac medications, especially as it is possible patients with different haemodynamic profiles may display different outcomes.14 23
1 Department of Anaesthetics
Nelson R. Mandela School of Medicine
Private Bag 7
Congella
Kwazulu-Natal 4013
South Africa
2 University of Leeds
Leeds General Infirmary
Great George Street
Leeds LS1 3EX
UK
* E-mail: bruce.biccard{at}nda.ox.ac.uk
References
1 Stevens RD, Burri H, Tramer MR. Pharmacologic myocardial protection in patients undergoing noncardiac surgery: a quantitative systematic review. Anesth Analg (2003) 97:623–33.
2 Wijeysundera DN, Beattie WS. Calcium channel blockers for reducing cardiac morbidity after noncardiac surgery: a meta-analysis. Anesth Analg (2003) 97:634–41.
3 du Toit HJ, Weich HF, Weymar HW, Przybojewski JZ. Effects of nifedipine on the peri-operative ECG, as determined by continuous Holter monitoring. A double-blind study. S Afr Med J (1986) 69:427–31.[Web of Science][Medline]
4 Opie L, Gersh BJ. Drugs for the Heart (2005) 6th Edn. Philadelphia: Elsevier Saunders.
5 Dawood MM, Gutpa DK, Southern J, Walia A, Atkinson JB, Eagle KA. Pathology of fatal perioperative myocardial infarction: implications regarding pathophysiology and prevention. Int J Cardiol (1996) 57:37–44.[CrossRef][Web of Science][Medline]
6 Cohen MC, Aretz TH. Histological analysis of coronary artery lesions in fatal postoperative myocardial infarction. Cardiovasc Pathol (1999) 8:133–9.[CrossRef][Web of Science][Medline]
7 Kertai MD, Westerhout CM, Varga KS, Acsady G, Gal J. Dihydropyridine calcium-channel blockers and perioperative mortality in aortic aneurysm surgery. Br J Anaesth (2008) 101:458–65.
8 Nuttall GA, Houle TT. Liars, damn liars, and propensity scores. Anesthesiology (2008) 108:3–4.[Web of Science][Medline]
9 Glynn RJ, Schneeweiss S, Sturmer T. Indications for propensity scores and review of their use in pharmacoepidemiology. Basic Clin Pharmacol Toxicol (2006) 98:253–9.[CrossRef][Web of Science][Medline]
10 Austin PC, Grootendorst P, Anderson GM. A comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: a Monte Carlo study. Stat Med (2007) 26:734–53.[CrossRef][Web of Science][Medline]
11 Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez B, Benjamin EM. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med (2005) 353:349–61.
12 Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet (2008) 371:1839–47.[CrossRef][Web of Science][Medline]
13 Sear JW, Giles JW, Howard-Alpe G, Foex P. Perioperative beta-blockade, 2008: what does POISE tell us, and was our earlier caution justified? Br J Anaesth (2008) 101:135–8.
14 Beattie WS, Wijeysundera DN, Karkouti K, McCluskey S, Tait G. Does tight heart rate control improve beta-blocker efficacy? An updated analysis of the noncardiac surgical randomized trials. Anesth Analg (2008) 106:1039–48.
15 Poulter NR, Wedel H, Dahlof B, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet (2005) 366:907–13.[CrossRef][Web of Science][Medline]
16 Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation (2001) 104:1477–82.
17 Gorwit J, Haidet GC, Russell DC, Tonkon M, Deedwania PC, Borer JS. Randomized placebo-controlled withdrawal study of amlodipine in agina pectoris. Am J Ther (1995) 2:34–42.[Medline]
18 Mehta JL, Lopez LM. A double-blind evaluation of amlodipine in patients with chronic, stable angina: sustained efficacy and lack of ‘withdrawal phenomenon’ upon abrupt discontinuation. Clin Cardiol (1994) 17:III17–22.[Medline]
19 Cleophas TJ, van der Sluijs J, van der Vring JA, et al. Combination of calcium channel blockers and beta-blockers for patients with exercise-induced angina pectoris: beneficial effect of calcium channel blockers largely determined by their effect on heart rate. J Clin Pharmacol (1999) 39:738–46.[Abstract]
20 Biccard BM. Heart rate and outcome in patients with cardiovascular disease undergoing major noncardiac surgery. Anaesth Intensive Care (2008) 36:489–501.[Web of Science][Medline]
21 Poldermans D, Bax JJ, Schouten O, et al. Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate-risk patients receiving beta-blocker therapy with tight heart rate control? J Am Coll Cardiol (2006) 48:964–9.
22 Feringa HH, Bax JJ, Boersma E, et al. High-dose beta-blockers and tight heart rate control reduce myocardial ischemia and troponin T release in vascular surgery patients. Circulation (2006) 114:I344–9.[Web of Science][Medline]
23 Biccard BM, Sear JW, Foex P. Meta-analysis of the effect of heart rate achieved by perioperative beta-adrenergic blockade on cardiovascular outcomes. Br J Anaesth (2008) 100:23–8.
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