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Departments of
*Anaesthesia,
Cardiovascular Medicine, and
Cardiothoracic Surgery, Sir Charles Gairdner Hospital, Nedlands, Western Australia
Address correspondence and reprint requests to W. M. Weightman, Department of Anaesthesia, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009.
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Abstract |
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Implications: We examined the association between common drug treatments for ischemic heart disease and short-term survival after cardiac surgery using a statistical method to adjust for patients' preoperative medical condition. Death after surgery was more likely after nitrate therapy and less likely after ß-blocker therapy.
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Introduction |
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Cardiac surgical patients may be at increased risk of the adverse effects of drug treatment. Patients requiring coronary artery surgery tend to have more severe cardiac disease, and the perioperative period is characterized by surgical stress, hemodynamic changes, and potential for the interaction with other drugs administered perioperatively. In addition, many regular drug treatments are ceased or interrupted, which exposes the patient to the possibility of drug withdrawal. Moreover, these patients are exposed to myocardial ischemia, myocardial dysfunction, and major changes in thrombotic status.
Although some investigators have suggested digoxin (7), IV inotropes (8), or IV nitrates (8) as markers of patients with reduced left ventricular function and unstable angina, there are little data that systematically examines the influence of preoperative drug therapy on early mortality in coronary artery surgery. One reason for this has been the confounding effects of other risk factors that influence outcome; for example, old age, emergency surgery, previous cardiac surgery, and reduced left ventricular function. However, many studies have delineated the important preoperative patient factors that influence mortality after coronary artery surgery (7–13). Therefore, it is now possible to take these into account when evaluating the effect of preoperative drugs.
The aim of this study was to determine whether there is an association, independent of other known risk factors, between commonly administered preoperative cardiovascular drug therapy and in-patient mortality in patients presenting for coronary artery surgery and, if so, to estimate the strength of that association. Alterations in thrombotic status have also been postulated to mediate some adverse effects of medications, such as calcium antagonists and nitrates; therefore, we have included preoperative antithrombotic drugs in our assessment.
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Methods |
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Typical operative management is described in the following section, although there were variations depending on clinical indications. Therapy with preoperative cardioactive drugs was continued until the morning of surgery. Patients were anesthetized with fentanyl (15–20 µg/kg) and enflurane. Monitoring included computerized ST segment display and a flow-directed pulmonary artery catheter. Cardiopulmonary bypass (CPB) was instituted with a roller pump and membrane oxygenator (Capiox, Terumo, Tokyo) with hypothermia to 28°C, aortic cross-clamping, and intermittent cold blood cardioplegia. A centrifugal pump (Biomedicus; Medtronic, Minneapolis, MN) was used for patients undergoing repeat cardiac surgery and combined valve and graft surgery. Aprotinin was used, in various doses, for some patients with recent exposure to aspirin and many patients scheduled for repeat cardiac surgery. Proximal anastomoses were performed after removal of the cross-clamp. At the completion of surgery, patients were mechanically ventilated in an intensive care unit. Patients undergoing grafting with arterial conduit received a small-dose IV infusion of nitroglycerin until at least the morning after surgery. Postoperative electrocardiogram (ECG) monitoring was continued for a minimum of 3 days. All patients received heparin before surgery, either as an infusion or as subcutaneous injections. Antianginal drug treatment was not routinely restarted after surgery, although antihypertensive treatment was restarted at the discretion of the attending staff.
Data regarding risk factors commonly associated with perioperative mortality were collected (7–13). These were age; gender; preoperative creatinine concentration; preoperative hemoglobin concentration; body mass index; left main coronary artery stenosis; previous peripheral arterial surgery; myocardial infarction within 6 wk before surgery (defined as a diagnostic increase in creatinine kinase MB fraction or diagnostic changes in the ECG; history of cardiac surgery, preoperative use of an intraaortic balloon pump; and preoperative diagnosis of hypertension, diabetes (defined as diagnosis plus use of hypoglycemic medication), cerebrovascular disease (defined as stroke or transient ischemic attack or asymptomatic carotid stenosis), or chronic obstructive pulmonary disease undergoing treatment. The number of coronary vessels grafted was recorded as an indicator of the number of significant coronary vessels diseased. Patients requiring surgery within 24 h and patients who had not been admitted to the hospital specifically for cardiac surgery but who could not be discharged before cardiac surgery, were classified as urgent. Patients who had been admitted to the hospital specifically for cardiac surgery were classified as elective. Left ventricular dysfunction was graded according to wall motion analysis by a cardiologist after either angiography or echocardiography. The overall grade of left ventricular function used was normal, mildly impaired, moderately impaired, or severely impaired. The occurrence of concurrent cardiac or cardiovascular surgery (typically cardiac valve repair, valve replacement, carotid endarterectomy, or left ventricular aneurysmectomy) was recorded. Regular daily patient use of any dose of drugs in the following categories was re- corded: calcium antagonists, ß-blockers, angiotensin converting enzyme (ACE) inhibitors, aspirin (date of last aspirin consumption was also recorded), warfarin, digoxin, and long-acting nitrates (i.e., oral, topical, or iv). Patients receiving sublingual nitroglycerin "as required" were not considered to be taking regular nitrate therapy. Cardioactive or antithrombotic drugs taken by <5% of our surgical population, such as prazosin and dipyridamole, were not included in the model.
In-hospital deaths were defined as deaths before discharge from our institution. Discharge data were collected from hospital records after patient separation from hospital and were checked by one of the authors (WMW). A small proportion of patients, <5%, had missing data in the left ventricular function and preoperative creatinine fields. This was handled by coding these patients as having normal left ventricular function and mean creatinine, respectively.
All of the above drug and nondrug variables were entered as independent variables into a multiple logistic regression model with in-hospital mortality as the dependent variable. Relative risk of mortality and the standard error of the estimate for each variable were calculated from the ß-coefficients and the standard error of the ß-coefficients of the logistic regression equation (14). Stepwise selection of variables was not used. To examine the association of oral nitrates with in-hospital mortality, the analysis was performed again on the subset of patients remaining after exclusion of all patients on IV nitrates.
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Results |
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The mean age was 63.8 yr and 2.8% were >79 yr of age. Of the 125 patients undergoing concurrent cardiac or cardiovascular surgery, 105 underwent valve or aortic root surgery, 15 underwent carotid endarterectomy, and 5 underwent concurrent left ventricular aneurysmectomy. Of the 242 patients with a preoperative diagnosis of cerebrovascular disease, 34 had experienced symptomatic cerebral ischemia and had a proven carotid artery stenosis, 140 had experienced symptomatic cerebral ischemia without proven carotid artery stenosis, 140 had experienced symptomatic cerebral ischemia without proven carotid artery stenosis, and 68 had an asymptomatic carotid stenosis. The mean (range) hemoglobin concentration was 14.1 (7.9–18.9) g/dL, and mean body mass index was 27.1 (16.8–46.7) kg/m2. The mean creatinine concentration was 109 (40–1210) mmol/L, and seven patients were undergoing renal dialysis before surgery. Left main coronary artery stenosis was present in 27.1% of patients, the mean fractional occlusion was 60%. Only one patient was undergoing treatment with an intraaortic balloon pump; this variable was therefore excluded from analysis. There were 38 patients who underwent surgery without CPB. The remainder had a mean bypass time of 94 (19–376) min and a mean aortic cross-clamp time of 60 (0–231) min; 66.6% of patients had cold anterograde and retrograde blood cardioplegia, 33.4% had cold anterograde cardioplegia alone. There was a mean of 3.2 distal anastomoses per patient and at least one internal mammary artery was used in 80% of patients. A mean dose of 1.6 million units of aprotinin was given to 47% of patients. The median postoperative intubation time was 11 h.
The number of patients (mortality rate) taking each class of preoperative drug therapy was as follows: regular daily nitrates 959 (4.8%); ß-blockers 1162 (2.3%); calcium channel antagonists 684, (4.5%); ACE inhibitors 432 (3.7%); warfarin 92 (2.2%); aspirin within 5 days before surgery 936 (3.7%); and digoxin 128, (5.5%). In contrast, among patients not taking regular daily nitrates, the number of patients (mortality rate) was 634, (1.1%); among patients not taking ß-blockers, 431 (6.0%), among patients not taking calcium antagonists, 909 (2.4%); and among patients not taking ACE inhibitors, 1161, (3.2%).
The mortality rates (number of patients) among subgroups of the above classes were: oral nitrates 4.1% (790), topical nitrates 0% (25), IV nitrates 5.3% (56), IV nitrates concurrent with oral or topical nitrates 12.5% (88), metoprolol 2.8% (905), atenolol 0.9% (228) or other ß-blockers 0% (29), nifedipine 3.4% (264), diltiazem 5.4% (261), amlodipine 3.4% (87), other calcium antagonist 6.9% (72), captopril 6.2% (129), enalapril 1.6% (123), lisinopril 6.3% (63), and other ACE inhibitors 3.2% (117). Because of the relatively small numbers of deaths in each group, multivariate analysis by generic subgroup was not attempted.
Severe or moderate impairment of left ventricular function was present in 27% of patients receiving IV nitrates with or without oral or topical nitrates. All patients receiving IV nitrates were scheduled for urgent surgery.
In the intraoperative period, 3.5% of patients were given metoprolol, 11.9% of patients were given esmolol, and 0.6% of patients were given both; the mean dose of metoprolol was 4.2 mg, and the mean dose of esmolol was 95 mg. Nitroglycerin was given in varying doses by infusion to 80% of patients, typically 0.1–0.25 µg · kg-1 · min-1 was used for prophylaxis of mammary artery vasospasm, and doses larger than this were used to control hypertension. The mortality rate of patients receiving intraoperative ß-blockers was 3.8%, and the mortality rate of patients receiving intraoperative nitroglycerin was 3.6%.
Death occurred on the day of surgery in 17 patients, on the first or second postoperative day in 12 patients, within the first postoperative week in another 12 patients, and after the first postoperative week in 12 patients.
The relative risk of in-hospital mortality is shown in Table 1. The model r2 was 0.060 (P < 0.0001). The relative risk of in-hospital mortality in patients taking preoperative nitrate therapy was 3.8, with 95% confidence intervals between 1.5 and 9.6. When the same model was applied to the subset of patients remaining after exclusion of the 144 patients on IV nitrates, the relative risk of each variable was similar to the results in Table 1; in particular, the relative risk of in-hospital mortality in patients taking nitrates was 3.2, with 95% confidence intervals between 1.3 and 6.7.
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Discussion |
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There are several mechanisms that could explain increased mortality with nitrates. First, it has been suggested that continuous therapy with each of the nitrates used in this study may induce tolerance (15–17). This may lead to reduced effectiveness of perioperative nitrates: in particular, reduced vasodilation of internal mammary artery grafts (18), reduced inhibition of platelet aggregation (19), reduced enhancement of ischemic preconditioning (20), and enhanced sensitivity to vasoconstricting drugs (21,22). In addition to concerns about tolerance, the cessation of nitrate therapy may cause rebound coronary vasoconstriction (23) and worsening of myocardial ischemia (5,6). Although most of our patients received nitroglycerin during surgery, there is no reliable means of monitoring the clinical effect of nitroglycerin in each patient, and it is possible that the doses given were inadequate to prevent arterial vasospasm in some patients. Even when patients were given nitroglycerin by infusion, the infusion rate may have been frequently altered, and sometimes stopped; for instance, in response to hypotension.
This article is not the first to raise concerns about the safety of chronic nitrate therapy in patients with ischemic heart disease. Ishikawa et al. (24) performed a randomized study of 1004 postmyocardial infarct patients with an average follow-up of 18 mo; one group received long-acting oral or transdermal nitrates, and a control group received none. Both groups were allowed sublingual or IV nitrates as required. There were a number of methodological problems with the study (not double-blinded, lack of placebo control, significant treatment cross-over between groups); nevertheless, the results suggested a doubling of mortality risk in the nitrate group.
A second important finding of this study is an inverse association between mortality and the preoperative use of ß-blocking drugs. Other investigators have suggested improved survival with the use of ß-blockade in perioperative patients (25) and patients with ischemic heart disease (26,27). However, the relevance of these findings to the present study is not clear, because few of our patients had continuous ß-blocker therapy during the perioperative period. In fact, most would have experienced a period of ß-blocker withdrawal. It is possible that ß-blockers protect during revascularization and that the effects of ß-blocker withdrawal after revascularization are not serious. Regardless of this speculation, we believe that the present study supports the generally accepted practice of continuing treatment with ß-blockade until the morning of surgery in cardiac surgical patients.
The findings for other drugs are less clear. The preoperative use of calcium antagonists was associated with a relative risk of mortality of 1.1, with 95% confidence intervals between 0.6 and 2.1; therefore, our study does not have the power to exclude or confirm a clinically significant association between calcium antagonists and mortality. Similar comments can be made for ACE inhibitors, aspirin, warfarin, and digoxin.
Could nitrate therapy simply be a marker of disease that is not optimal for surgical repair? IV nitrates are generally given to patients with unstable angina, which has repeatedly been shown to be strongly associated with increased operative mortality. Oral nitrates are generally given to patients with anginal symptoms that are not controlled by other medications. It has previously been recognized that the severity of chest pain symptoms, with the exception of unstable angina, is not a strong associate of operative mortality after coronary artery surgery (7). Nevertheless, despite our attempts to control for the confounding effects of the severity of underlying disease using the risk prediction model, it is possible that the association between nitrate therapy and mortality is, in fact, due to differences in underlying disease, not to a deleterious effect of nitrate therapy. Similar considerations affect ß-blockers, which are less likely to be used in diabetics, patients with impaired myocardial function, and patients with chronic lung disease so that it is possible that, in this study, some residual confounding has occurred or that the use of ß-blockers marks disease that is advantageous for surgical repair.
Our initial motivation to study this subject came from the controversy surrounding calcium antagonists. We did not expect to find an association between nitrates or ß-blockers and mortality. Therefore, our results should be viewed as hypothesis-generating, rather than as hypothesis-testing, and they must be confirmed by a hypothesis-testing study. Because few of our patients received topical nitrates, we cannot comment on any association between topical nitrates and mortality. Those patients given oral nitrates received various doses of isosorbide mononitrate and isosorbide dinitrate at the discretion of their cardiologist, and it is possible that the association found in the present study does not apply to all formulations and dose schedules. Finally, as with all epidemiological studies, association does not prove causation.
Our findings support the view that the potential adverse effects of chronic nitrate treatment should be seriously considered, may cause impaired clinical outcome in the setting of cardiac surgery, and are worthy of further investigation. We cannot recommend that nitrate therapy be ceased before coronary artery surgery or that vasodilators, such as sodium nitroprusside, which are not affected by nitrate tolerance, should be chosen for intraoperative use in patients who have been exposed to chronic nitrate therapy. Regardless of whether nitrate therapy is causally associated with postoperative mortality, we think that it is important to recognize that preoperative nitrate therapy seems to be a marker of adverse outcome.
In conclusion, the results of this study suggest that regular daily nitrate therapy before coronary artery surgery is associated with an increased in-hospital mortality rate and that regular daily ß-blocker therapy is associated with reduced in-hospital mortality in patients undergoing coronary artery surgery. Further studies are required to investigate this association and to determine the best way to manage patients receiving nitrate therapy, and patients who are not taking ß-blockers, in the setting of coronary artery surgery.
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