The use of preoperative beta-blockade to minimise the cardiovascular risks of noncardiac surgery has remained controversial for some time, and recent studies have suggested that preoperative beta-blockade may be now decreasing as a result. The purpose of this study was to determine whether early preoperative exposure to beta-blockers could influence 30-day postoperative outcomes in patients undergoing noncardiac surgery.

This was a retrospective analysis examining 136,745 patients (1:1 matched on propensity scores) who were given beta-blockers on the day of or following major non cardiac surgery. 104 VA hospitals were involved. The main outcome measure was 30-day mortality and cardiac morbidity (cardiac arrest or Q-wave myocardial infarction).

55,138 (40.3%) of patients were exposed to beta-blockers, with those undergoing vascular surgery most likely to receive beta-blockade (66.7% of all patients undergoing vascular surgery). 1.1% of patients died and cardiac morbidity occurred among 0.9% of patients. After the propensity matching, beta-blocker use was associated with lower mortality (relative risk 0.73, P<0.001). When stratified by cumulative numbers of Revised Cardiac Risk Index factors, beta-blocker exposure was associated with significantly lower mortality in patients with 2,3, and 4 risk factors, however this association was limited to patients undergoing nonvascular surgery. A lower rate of cardiac arrest and nonfatal Q-wave infarction was seen in patients given beta-blockers (P<0.001), but this again was limited to non-vascular surgery only.

Conclusions:

Following propensity matching, preoperative beta-blockade was associated with lower rates of 30-day mortality in patients with 2 or more Revised Cardiac Risk Index Factors undergoing non-cardiac, non-vascular surgery.

• London MJ, Hur K, Schwartz GG et al. Association of Perioperative Beta-Blockade With Mortality and Cardiovascular Morbidity Following Major Noncardiac surgery. JAMA 2013;309:1704-1713.

Familial hypercholesterolaemia is characterised by substantially raised plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and is associated with a risk of coronary heart disease that is five to eight times higher than average. One charity has estimated a saving of £378.7 million from cardiovascular events avoided if all relatives of index cases were identified and treated optimally over 55 years of age.

The disease is inherited in an autosomal-dominant fashion and is thought to be monogenic, however no mutations are detected in about 60% of patients with the clinical phenotype who are tested. A proportion of these cases of familial hypercholesterolaemia could be polygenic, due to the inheritance of a greater than average number of common LDL-C-rasing alleles. Identification of those individuals with polygenic hyperlipidaemia could improve the efficacy of a testing programme.

Talmud et al. assembled patients with familial hypercholesterolaemia from three UK sources and compared them with a control sample from the UK Whitehall II (WHII) study. Patients from a Belgian lipid clinic were also studied for validation analysis. Participants were genotyped for 12 common LDL-C-raising alleles and a weighted LDL-C-raising gene score was constructed.

The mean weighted LDL-C gene score of the control (Whitehall) participants (0.90) was strongly associated with LDL-C concentration. Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1.0) than did WHII controls, as did the mutation negative Belgian patients (0.99). The score was also higher in UK (0.95) and Belgian (0.92) mutation-positive patients when compared to Whitehall study controls.

Conclusions:

A substantial number of patients with familial hypercholesterolaemia have no known mutation, and this study suggests that in these patients the raised LDL-C concentrations have a polygenic cause. This finding may explain the variable penetrance of the disease, and has implications for genetic testing strategies.

• Talmud PJ, Shah S, Whittall R et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet 2013;381:1291-1301.

20-30% of patients taking oral anticoagulants also have ischaemic heart disease that requires treatment by percutaneous coronary intervention (PCI), thereby necessitating dual anti-platelet therapy to prevent stent thrombosis. However, the combination of dual anti-platelet therapy (DAP) and anti-coagulants is associated with a high annual risk of fatal and non-fatal bleeding episodes. This study hypothesised that in patients who must continue with oral anti-coagulants, clopidogrel alone would reduce the risk of bleeding – while not increasing the risk of thrombotic events – compared to clopidogrel and aspirin.

The What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) study was an open-label, randomised, controlled trial carried out at 15 sites in the Netherlands and Belgium between 2008 and 2011. Patients taking oral anti-coagulants and undergoing PCI were assigned to clopidogrel alone, or clopidogrel plus aspirin. The primary outcome measure was any bleeding episode within one year of PCI; analysis was by intention to treat.

Of the 573 patients enrolled in the study, one-year data were available for 279 (98.2%) of patients assigned double therapy (clopidogrel and oral anticoagulant) and for 284 (98.3%) of patients assigned triple therapy (aspirin, clopidogrel, and oral anticoagulant). In patients receiving double therapy, bleeding episodes were noted in only 54 (19.4%) of patients, compared to 126 (44.4%) in patients receiving triple therapy (hazard ration 0.36, p<0.0001). Multiple bleeding episodes were also more common in the triple therapy group (2.2% vs 12.0%), as were blood transfusions (3.9% vs. 9.5%).

Conclusions:

In patients taking oral anticoagulants who underwent PCI, the use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events.

• DeWilde WJM, Oirbans T, Verheugt FWA et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107-1115.

As life expectancy doubled between 1800 and 2000, atherosclerosis replaced infectious diseases as the main cause of death in the developed world. But is atherosclerosis a purely modern phenomenon, precipitated by lifestyle changes and an ageing population, or was it common in ancient societies too?

Thompson et al. performed whole-body CT scans on 137 mummies from four different geographical areas to look for calcification and therefore atherosclerosis. Atherosclerosis was present in the aorta in 28 (20%) mummies, iliac or femoral arteries in 25 (18%), popliteal or tibial arteries in 25 (18%), carotid arteries in 17 (12%), and coronary arteries in six (4%). Of the five vascular beds examined, atherosclerosis was present in one to two beds in 34 (25%) mummies, in three to four beds in 11 (8%), and in all five vascular beds in two (1%). Of note the age at the time of death was positively correlated with atherosclerosis (mean age at death 43 years for mummies with atherosclerosis vs 32 years for those without; p<0·0001) and with the number of arterial beds involved (p<0·0001).

Conclusions:

This unique study performed CT imaging of mummies from different geographical regions and found that atherosclerosis was common in four ancient populations, and therefore challenges the assumption that it is a largely modern disease.

• Thompson RC, Allam AH, Lombardi GP et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet 2013; published online March 10, 2013. http://dx.doi.org/10.1016/ S0140-6736(13)60598-X

Breast cancer remains the commonest cancer in women with approximately 1 million new cases diagnosed annually. However, survival rates have increased year-on-year with 5 year disease free survival as high as 90% in women in whom the tumour is diagnosed early. Large numbers of cancer survivors are therefore present in the population – an estimated three million women in North America alone. While anthracyclines and therapies targeting the HER2 receptor are known to cause cardiac muscle disease, the long term cardiac effects of radiotherapy – a common component of many treatment strategies – is less well explored.

In this population-based case-control study Darby et al. utilised comprehensive registry data from Sweden and Denmark following 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001. The primary end-point was a major coronary event (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease). Individual patient information was obtained from hospital records and the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from radiotherapy charts.

963 women had major coronary events during follow up. Mean dose to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with mean dose by 7.4% per gray (95% CI, 2.9 to 14.5; P<0.001), with no apparent threshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy. The proportional increase in the rate of major coronary events per gray was similar in women with and women without cardiac risk factors at the time of radiotherapy.

Conclusions:

Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease with the risk being proportional to the mean dose to the heart.

• Darby SC, Ewertz M, McGale P et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013 Mar 14;368(11):987-98.

The anatomical SYNTAX score is advocated in both US and European guidelines to help establish the best revascularisation approach in patients with complex coronary artery disease.  The purpose of this study was to improve the SYNTAX score further by including prognostically important clinical variables, as opposed to the anatomical variables that are used for the current score.

The SYNTAX II score was developed by applying a Cox proportional hazards model to the results of the randomised all-comers SYNTAX trial.  In addition to the anatomical SYNTAX score, baseline features with strong associations to four-year mortality in either the CABG or PCI settings, or in both, were added.  Comparisons of 4-year mortality between CABG and PCI were then made for each patient.  External validation was done in the multinational all-comers DELTA registry (n=2891).

The eight predictors of the SYNTAX II score were: anatomical SYNTAX score, age, creatinine clearance, left ventricular ejection fraction (LVEF), presence of unprotected left main coronary artery (ULMCA) disease, peripheral vascular disease, female sex, and chronic obstructive pulmonary disease (COPD).  The SYNTAX II score significantly predicted a difference in 4-year mortality between patients undergoing CABG and those undergoing PCI; of note, the presence of diabetes was not important for decision making between CABG and PCI.  The concordance indices for internal (SYNTAX trial) and external (DELTA registry) validation were substantially higher than for the anatomical SYNTAX score alone.

Conclusions:

By combining clinical and anatomical predictors, the SYNTAX II score can provide accurate prediction of 4-year mortality from complex coronary artery disease, and guide decision making between CABG and PCI better than the original anatomical SYNTAX score.

• Farooq V, van Klaverern D, Steyerberg EW et al.  Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and vvalidation of SYNTAX score II.  Lancet 2013;381:639-50.

It is known that smoking cessation substantially reduces the risk of cardiovascular disease (CVD), but does any subsequent weight gain attenuate the benefits of quitting smoking?  The goal of this study was to answer this question in adults with and without diabetes.  Specifically, the authors tested the hypothesis that quitting smoking decreases CVD risk compared with continuing smoking, regardless of any associated weight gain.

Data collected from the Framingham Offspring Study between 1984 and 2011 were used.  At four-yearly examinations, patients were weighed and also categorised as being smokers, recent quitters (≤4 years), long-term quitters (>4 years), and nonsmokers.  The main outcome measure was the incidence over six years of total CVD events: coronary heart disease, cerebrovascular events, peripheral artery disease, and congestive heart failure.

Over a mean follow-up of 25 years, 631 CVD events occurred among 3251 participants.  Of note, the median four year weight gain was greater for recent quitters without diabetes (2.7kg) and with diabetes (3.6kg), than for long-term quitters (0.9kg and 0.0kg, respectively).  After adjustment for CVD risk factors, compared to ongoing smokers, recent quitters had a greatly reduced hazard ration (HR) for CVD of 0.47, and long-term quitters had an HR of 0.46; after further adjustment for weight change these associations showed only minimal change.

Conclusions:

This study underlines the substantial cardiovascular benefits of quitting smoking in patients without diabetes, which were not attenuated by any subsequent weight gain.

• Clair C, Rigotti NA, Porneala B et al.  Association of Smoking Cessation and Weight Change With Cardiovascular Disease Among Adults With and Without Diabetes.  JAMA 2013;309:1014-1021.

Approximately a third of patients with peripheral arterial disease (PAD) will develop intermittent claudication.  A previous pilot trial found that the angiotensin-converting enzyme inhibitor ramipril is associated with increased pain-free and maximum walking times, contrasting with previous ACE inhibitor studies which may have been limited by issues of small sample size, short intervention duration, and lack of a placebo group.  Therefore this trial was designed to investigate the effect of 24 weeks of ramipril therapy on walking distance and health-related quality of life as compared with placebo in a larger, more general PAD population including patients with diabetes and patients with aortoiliac and infrainguinal disease.

212 patients with peripheral arterial disease were recruited from three Australian hospitals, and randomised to receive 10mg of ramipril daily, or placebo, for 24 weeks.  Maximum and pain-free walking times were recorded during a standard treadmill test.  The Walking Impairment Questionnaire (WIQ) and Short-Form 36 Health Survey (SF-36) were used to assess walking ability and quality of life, respectively.

At six months, patients taking ramipril had a 75-second increase in pain-free walking time compared to those taking placebo (P<.001), and a 255-second increase in maximum walking time (P<.001).  WIQ and SF-36 scores also improved, although ramipril did not affect the overall SF-36 median Mental Component Summary score.

Conclusions:

In patients with intermittent claudication, 24-week treatment with ramipril led to significant improvements in pain-free and maximum treadmill walking times, which was also associated with an increase in the physical functioning component of the SF-36 score.

• Effect of Ramipril on Walking Times and Quality of Life Among Patients With Peripheral Arterial Disease and Intermittent Claudication.  JAMA 2013;309:453-460.

Following cardiac surgical operations, blood transfusions are associated with a host of complications, including nosocomial infections, immunosuppression, transfusion-related acute lung injury, decreased health-related quality of life, and reduced early and long-term survival. A number of guidelines now emphasise the importance of conservative transfusion strategies and in this study, Lapar et al examine the impact of a multi-institutional effort to reduce blood product use after cardiac surgery.

Using data from a total of 14,259 patients (2006-2010) undergoing nonemergency coronary artery bypass grafting (CABG) at 17 different centres in the Virginia Cardiac Surgery Quality Initiative, participants were stratified according to transfusion guideline era: pre-guideline (n = 7059, age = 63.7 ± 10.6 years) versus post-guideline (n = 7200, age = 63.7 ± 10.5 years). Transfusion guidelines implemented in the mid-study period (2008) suggested transfusion only at an intraoperative level of 6.0 g/dL or a post-operative level of 7.0 g/dL, unless there were concerns of end-organ hypoperfusion or persistent bleeding, in which case a more liberal strategy was allowed.

The introduction of the guidelines led to a significant drop in both intra- (7% absolute decrease (24% vs. 17%, P < 0.001)) and post- (6% absolute decrease (39% vs. 33%, P < 0.001)) operative transfusion rates in the post-guideline era. Patients in the post-guideline era also demonstrated reduced morbidity with decreased pneumonia (P = 0.01), prolonged ventilation (P = 0.05), renal failure (P = 0.03), new-onset haemodialysis (P = 0.004), and composite incidence of major complications (P = 0.001). Operative mortality (1.0% vs. 1.8%, P < 0.001) and postoperative ventilation time (22 vs. 26 hours, P < 0.001) were similarly reduced in the post-guideline era. Of note, after mortality risk adjustment, operations performed in the post-guideline era were associated with a 47% reduction in the odds of death (adjusted OR, 0.57; P < 0.001), whereas the risk of major complications and mortality were significantly increased after intraoperative (adjusted OR, 1.86 and 1.25; both P < 0.001) and postoperative (adjusted OR, 4.61 and 4.50, both P < 0.001) transfusion. Adding to these benefits, a reduction in transfusion was also seen to be cost-effective, reducing associated costs by $4408 and $10,479, for intra- and post-operative transfusion respectively.

Conclusions:

Implementation of a conservative blood transfusion strategy significantly improved postoperative morbidity, mortality, and resource utilization whilst reducing health care costs in patients undergoing CABG.

• Lapar DJ, Crosby IK, Ailawadi G, Ad N, Choi E, Spiess BD, Rich JB, Kasirajan V, Fonner E Jr, Kron IL, Speir AM; Investigators for the Virginia Cardiac Surgery Quality Initiative. Blood product conservation is associated with improved outcomes and reduced costs after cardiac surgery. J Thorac Cardiovasc Surg. 2013 Mar;145(3):796-804.

Heart failure with preserved ejection fraction (HF-PEF) accounts for more than 50% of heart failure cases. To date, medical therapy has failed to show improvements in diastolic dysfunction, cardiac remodelling, or cardiovascular outcomes. As mineralocorticoid receptor activation by aldosterone contributes to the pathophysiology of HF through several different mechanisms, the Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial was designed to assess the effects of spironolactone on diastolic dysfunction and exercise capacity in patients with HF-PEF.

Aldo-DHF was a multicenter, prospective, randomised, double-blind, placebo-controlled trial conducted between March 2007 and April 2012. 422 ambulatory patients (mean age 67 years; 52% female) with chronic NYHA class II or III HF, a preserved ejection fraction of 50% or greater, and evidence of diastolic dysfunction, were random assigned to 25mg of spironolactone once daily or matching placebo. The co-primary endpoints were changes in diastolic function (E/e’) on echocardiography and maximal exercise capacity (peak VO2) on cardiopulmonary exercise testing, both measured at 12 months.

While diastolic dysfunction was found to improve in patients taking spironolactone, it worsened in the placebo group (P<.001). In addition, spironolactone induced reverse remodeling (decrease in left ventricular mass) and improved neuroendocrine activation, but did not improve VO2, heart failure symptoms or quality of life.

Conclusions:

Long-term aldosterone receptor blockade with spironolactone improved diastolic function but did not affect clinical symptoms or exercise capacity. Therefore, further investigation into the clinical significance of these echocardiographic findings will be required in larger studies.

• Edelmann F, Wachter R, Schmidt AG et al. Effect of Spironolactone on Diastolic Function and Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction. The Aldo-DHF Randomized Controlled Trial.  JAMA 2013;309:781-91. doi: 10.1001/jama.2013.905.