Innovations in management of cardiac disease: drugs, treatment strategies and technology.

Within the last generation, the management of patients with heart disease has been transformed by advances in drug treatments, interventions and diagnostic technologies. The management of arterial hypertension saw beta-blockers demoted from first- to third-line treatment. Recent studies suggest that the goal of treatment may have to change to lower systolic blood pressures to prevent long-term organ damage. Today less than 15% of coronary revascularizations are surgical and more than 85% are done by interventional cardiologists inserting coronary stents. Thus, managing patients on dual antiplatelet therapy has become an important issue. With new generations of coronary stents, recommendations are changing fast. In the past, decisions concerning non-cardiac surgery after acute myocardial infarction were based on the delay between infarction and non-cardiac surgery. Today, the main concern is the patient's status in respect of dual antiplatelet therapy after primary percutaneous intervention. There have been advances in the management of heart failure but new drugs (ivabradine, sacubitril/valsartan) and cardiac resynchronization are recommended only in patients with an ejection fraction below 35% on optimal medication. Heart failure remains a major perioperative risk factor. Prospective studies have shown that troponin elevations represent myocardial injury (not necessarily myocardial infarction), are mostly silent and are associated with increased 30-day mortality. Monitoring (troponin assays) for myocardial injury in non-cardiac surgery (MINS) seems increasingly justified. The treatment of MINS needs further research. Technological advances, such as intelligent, portable monitors benefit not only patients with cardiac disease but all patients who have undergone major surgery and are on the wards postoperatively.

Cohort study of preoperative blood pressure and risk of 30-day mortality after elective non-cardiac surgery.

BACKGROUND: Preoperative blood pressure (BP) thresholds associated with increased postoperative mortality remain unclear. We investigated the relationship between preoperative BP and 30-day mortality after elective non-cardiac surgery. METHODS: We performed a cohort study of primary care data from the UK Clinical Practice Research Datalink (2004-13). Parsimonious and fully adjusted multivariable logistic regression models, including restricted cubic splines for numerical systolic and diastolic BP, for 30-day mortality were constructed. The full model included 29 perioperative risk factors, including age, sex, comorbidities, medications, and surgical risk scale. Sensitivity analyses were conducted for age (>65 vs <65 years old) and the timing of BP measurement. RESULTS: A total of 251 567 adults were included, with 589 (0.23%) deaths within 30 days of surgery. After adjustment for all risk factors, preoperative low BP was consistently associated with statistically significant increases in the odds ratio (OR) of postoperative mortality. Statistically significant risk thresholds started at a preoperative systolic pressure of 119 mm Hg (adjusted OR 1.02 [95% confidence interval (CI) 1.01-1.02]) compared with the reference (120 mm Hg) and diastolic pressure of 63 mm Hg [OR 1.24 (95% CI 1.03-1.49)] compared with the reference (80 mm Hg). As BP decreased, the OR of mortality risk increased. Subgroup analysis demonstrated that the risk associated with low BP was confined to the elderly. Adjusted analyses identified that diastolic hypertension was associated with increased postoperative mortality in the whole cohort. CONCLUSIONS: In this large observational study we identified a significant dose-dependent association between low preoperative BP values and increased postoperative mortality in the elderly. In the whole population, elevated diastolic, not systolic, BP was associated with increased mortality.

Use of beta-blockers in non-cardiac surgery: an open debate.

The perioperative use of beta-blockers (BBs) with the aim of decreasing perioperative adverse cardiac events has been strongly supported, especially after the publication of two small trial (McSPI and DECREASE I) that showed major benefits. However, some later trials did not confirm these benefits. The POISE trial, with 8351 patients, showed reduced primary outcomes (cardiac death, non-fatal myocardial infarction, non-fatal cardiac arrest) at the expense of significant harm, increasing all-cause and sepsis-related deaths, and doubling the incidence of stroke. These results led to revised American and European guidelines. The American guideline recommended a substantial narrowing of indication for perioperative BBs, while the European guideline remained far more liberal. Since the publication of the results of POISE, meta-analyses and new studies have been published. In this review the most recent available evidence, the changes in the guidelines and the criticism on POISE results are discussed together with reasons why recent meta-analyses may not have greater certainty. This is explained by the huge numeric influence of the POISE trial and the heterogeneity in the design of the trials on perioperative BBs. Thus all the evidence available must now be taken into consideration to develop more appropriate guidelines to minimise the risks and enhance the benefits of perioperative beta-blockade.

Neuraxial block, death and serious cardiovascular morbidity in the POISE trial.

BACKGROUND: This post hoc analysis aimed to determine whether neuraxial block was associated with a composite of cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal cardiac arrest within 30 days of randomization in POISE trial patients. METHODS: A total of 8351 non-cardiac surgical patients at high risk of cardiovascular complications were randomized to ß-blocker or placebo. Neuraxial block was defined as spinal, lumbar or thoracic epidural anaesthesia. Logistic regression, with weighting using estimated propensity scores, was used to determine the association between neuraxial block and primary and secondary outcomes. RESULTS: Neuraxial block was associated with an increased risk of the primary outcome [287 (7.3%) vs 229 (5.7%); odds ratio (OR), 1.24; 95% confidence interval (CI), 1.02-1.49; P=0.03] and MI [230 (5.9%) vs 177 (4.4%); OR, 1.32; 95% CI, 1.07-1.64; P=0.009] but not stroke [23 (0.6%) vs 32 (0.8%); OR, 0.76; 95% CI, 0.44-1.33; P=0.34], death [96 (2.5%) vs 111 (2.8%); OR, 0.87; 95% CI, 0.65-1.17; P=0.37] or clinically significant hypotension [522 (13.4%) vs 484 (12.1%); OR, 1.13; 95% CI, 0.99-1.30; P=0.08]. Thoracic epidural with general anaesthesia was associated with a worse primary outcome than general anaesthesia alone [86 (12.1%) vs 119 (5.4%); OR, 2.95; 95% CI, 2.00-4.35; P<0.001]. CONCLUSIONS: In patients at high risk of cardiovascular morbidity, neuraxial block was associated with an increased risk of adverse cardiovascular outcomes, which could be causal or because of residual confounding.

Meta-analysis of the effect of heart rate achieved by perioperative beta-adrenergic blockade on cardiovascular outcomes.

BACKGROUND: Acute perioperative beta-adrenergic blockade may be cardioprotective in the high-risk cardiac patient for major non-cardiac surgery. We have investigated the association between the heart rate achieved with perioperative beta-blockade and the incidence of perioperative cardiac complications. METHODS: We identified eight randomized studies (1931 patients) reporting acute perioperative beta-blockade and major perioperative cardiovascular outcomes after non-cardiac surgery. The mean heart rates within the first 72 h after operation were analysed. A meta-analysis of means was conducted using a random effects model. A bivariate correlation analysis was conducted using Spearman's correlation coefficient to assess for an association between the mean postoperative heart rate and the 30 day cardiac outcomes. RESULTS: Acute perioperative beta-blockade did not significantly reduce 30 day cardiac death [odds ratio (OR) 0.35, 95% confidence interval (CI) 0.08-1.52] or non-fatal myocardial infarction (OR 0.90, 95% CI 0.52-1.56) in the studies with adequate methodology. The mean (95% CI) heart rate was 73 (71-74) beats min(-1) in the beta-blockade group, which was significantly lower than the placebo group (mean heart rate 82, P=0.0001). There was no correlation between heart rate and 30 day cardiac complications (P=0.848). The reduction in heart rate was associated with increased drug-associated adverse events (OR 2.53, 95% CI 2.05-3.13, P<0.0001). A major limitation of this analysis may be that postoperative heart rate was not a primary outcome in any of the studies identified and the mean postoperative heart rate achieved may be too high to realize optimal cardioprotection. CONCLUSION: This meta-analysis cannot confirm that heart rate control with beta-adrenergic blockade is cardioprotective. A randomized controlled trial examining the effect of tight perioperative heart rate control with beta-adrenergic blockade on clinically important outcomes and adverse events is warranted.

Coronary artery stents and non-cardiac surgery.

The utility of interventional cardiology has developed significantly over the last two decades with the introduction of coronary angioplasty and stenting, with the associated antiplatelet medications. Acute coronary stent occlusion carries a high morbidity and mortality, and the adoption of therapeutic strategies for prophylaxis against stent thrombosis has major implications for surgeons and anaesthetists involved in the management of these patients in the perioperative period. Currently, there is limited published information to guide the clinician in the optimal care of patients who have had coronary stents inserted when they present for non-cardiac surgery. This review examines the available literature on the perioperative management of these patients. A number of key issues are identified: the role of surgery vs percutaneous coronary intervention for coronary revascularization in the preoperative period; the different types of coronary stents currently available; the emerging issues related to drug-eluting stents; the pathophysiology of coronary stent occlusion; and the recommended antiplatelet regimes that the patient with a coronary stent will be receiving. The role of preoperative platelet function testing is also discussed, and the various available tests are listed. Appropriate management by all the clinicians involved with patients with coronary stents undergoing a variety of non-cardiac surgical procedures is essential to avoid a high incidence of postoperative cardiac mortality and morbidity. The review examines the evidence available for the perioperative strategies aimed at reducing adverse outcomes in a number of different clinical scenarios.

The pharmaco-economics of peri-operative beta-blocker and statin therapy in South Africa.

We conducted a pharmaco-economic analysis of the prospective peri-operative studies of beta-blocker and statin administration for major elective non-cardiac surgery, using the Discovery Health claims costs for 2004. This analysis shows that acute peri-operative beta-blockade and statin therapy could result in a cost saving through a reduction in major perioperative cardiovascular complications in patients with an expected peri-operative major cardiovascular complication rate exceeding 10% following elective major non-cardiac surgery. The validity of these findings is dependent on whether the incidence of cardiovascular complications following major noncardiac surgery reported in the international literature is found to be similar in South Africa.

Methods of detecting atherosclerosis in non-cardiac surgical patients; the role of biochemical markers.

Atherosclerosis is a common condition in both the developed and developing world and is now recognised to be an inflammatory condition leading to the development of ischaemic heart disease, cerebrovascular disease and peripheral vascular disease. Ischaemic heart disease is a major risk factor in the pathogenesis of perioperative adverse cardiovascular events which lead to significant morbidity and mortality within the high risk surgical patient population. Current methods of evaluating the likelihood of postoperative cardiovascular complications depend largely on risk scoring systems, and the preoperative assessment of the functional status of the cardiovascular system. However, the possible role of inflammation in the generation of atherosclerosis has led to the identification of several biochemical markers such as acute phase proteins, cellular adhesion molecules and cytokines. An alternative approach therefore is the measurement of preoperative levels of these biomarkers with the aim of assessing pre-existing disease activity. This review summarises the pathophysiology of atherosclerosis and perioperative myocardial infarction, and discusses the possible future role of biomarkers in the risk stratification of patients undergoing non-cardiac surgery.

Acute peri-operative beta blockade in intermediate-risk patients.

Peri-operative beta-blockade has been shown to reduce the incidence of postoperative cardio- vascular complications including cardiac death in high-risk non-cardiac surgical patients. However, the recent analysis by Lindenauer et al. suggests that it is inappropriate to administer beta-blockers blindly to all surgical patients. In an attempt to determine the appropriateness of peri-operative beta-blocker administration across patients with a spectrum of cardiovascular risks, we have examined studies of intermediate-risk patient groups (that is those undergoing intermediate risk surgery or those with a Lee Revised Cardiac Risk Score of < or =2). We analysed data from randomised prospective studies of the effects of acute peri-operative beta-blockade on the incidence of peri-operative myocardial ischaemia. By examining the demographics and surgical interventions in these patients, we have compared these studies with other studies of peri-operative silent myocardial ischaemia representing patients of similar risk. We thus estimated the expected long-term postoperative cardiovascular complication rate associated with myocardial ischaemia in these patients in terms of number needed to treat for ischaemia prevention and for prevention of major cardiovascular complications. Prevention of peri-operative myocardial ischaemia with acute beta-blockade in non-cardiac surgical patients with 1-2 RCRI clinical risk factors can be achieved with a number needed to treat of 10. It is not associated with a significant increase in drug associated side-effects. However, acute beta-blockade shows no real benefit in the prevention of major cardiovascular complications in intermediate risk non-vascular surgical patients with a number-needed-to-treat of 833. Vascular surgical patients undergoing intermediate-risk surgery may benefit from the protective effects of acute peri-operative beta-blockade, however, with a number-needed-to-treat of 68 it would require a randomised clinical trial of over 24,000 patients to prove their efficacy.

The pharmacoeconomics of peri-operative beta-blocker therapy.

It is widely recommended that beta-blockade be used peri-operatively as it may reduce the incidence of postoperative cardiovascular complications including death. However, there are few data concerning the cost-effectiveness of such strategies. We have analysed the pharmacoeconomics of acute beta-blockade using data from eight prospective peri-operative studies in which patients underwent elective non-cardiac surgery, and in which the incidence of adverse side-effects of treatment, as well as clinical outcomes, have been reported. The costs of treatment were based on the NHS reference costs for 2004. From these data, the number-needed-to-treat (NNT) to prevent a major cardiovascular complication (including cardiovascular death) in high-risk patients was 18.5. This is comparable to the NNT for peri-operative statin therapy. The incremental cost of peri-operative beta-blockade (costs of drug acquisition and of treating associated adverse drug events) was 67.80 pounds sterling per patient. This results in a total cost of 1254.30 pounds sterling per peri-operative cardiovascular complication prevented. However, there is evidence that in patients at lower cardiovascular risk, beta-blockers may be potentially harmful, since their adverse effects (hypotension, bradycardia) may outweigh their potential cardioprotective effects.

The pharmaco-economics of peri-operative statin therapy.

We analysed the pharmaco-economics of the prospective peri-operative studies of statin administration for major elective vascular surgery, using the NHS reference costs for 2004. This analysis suggests that peri-operative statin therapy for patients undergoing vascular surgery may present the most cost-effective use of statin therapy yet described, with a number-needed-to-treat of 15 and almost 60% of the total cost of atorvastatin therapy recovered through a reduction in peri-operative adverse events.