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Clonidine and Aspirin Fail to Reduce Peri-operative Myocardial Infarction

29 Jun, 14 | by Alistair Lindsay

Myocardial infarction (MI) is the most common major vascular event that occurs after planned non-cardiac surgery.  Multiple strategies have been assessed to try and reduce the rates of peri-operative MI, but few have consistently demonstrated substantial benefit.  With a pro-thrombotic environment and marked sympathetic activation thought to play etiological roles, in the POISE-2 study, the antiplatelet agent aspirin and the alpha-agonist clonidine, were studied in a 2×2 factorial design.   A total of 10,010 patients were randomized in this multi-center, international study to receive a combination of aspirin and clonidine or corresponding placebo.  The trial results from both arms were reported separately, but both arms of the study were neutral for the primary composite outcome of death or nonfatal myocardial infarction at 30 days. The 30-day event rate was 7.0% in patients treated with aspirin and 7.1% in the placebo group (HR, 0.99; 95% CI, 0.86 to 1.15; P=0.92).   Among patients treated with clonidine, 6.6% suffered an event at 30-days compared with 5.9% in the placebo group (HR, 1.11; 95% CI, 0.95 to 1.30; P=0.18).  Aspirin significantly raised the risk of major bleeding (P=0.04) and clonidine increased the risk of clinically significant hypotension (P<0.001).

Conclusion: This large randomized study of aspirin and clonidine in patients undergoing non-cardiac surgery failed to demonstrate benefit from either intervention in comparison to placebo.  Furthermore, both drugs demonstrated evidence of potentially significant side-effects. The need to further define effective agents to reduce peri-operative myocardial infarction risk remains.

Summarized by Steven M. Bradley and Hussain Contractor

  • Devereaux PJ, Mrkobrada M, Sessler DI, Leslie K, Alonso-Coello P, Kurz A, Villar JC, Sigamani A, Biccard BM, Meyhoff CS, Parlow JL, Guyatt G, Robinson A, Garg AX, Rodseth RN, Botto F, Lurati Buse G, Xavier D, Chan MT, Tiboni M, Cook D, Kumar PA, Forget P, Malaga G, Fleischmann E, Amir M, Eikelboom J, Mizera R, Torres D, Wang CY, VanHelder T, Paniagua P, Berwanger O, Srinathan S, Graham M, Pasin L, Le Manach Y, Gao P, Pogue J, Whitlock R, Lamy A, Kearon C, Baigent C, Chow C, Pettit S, Chrolavicius S and Yusuf S. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014 Apr 17;370(16):1494-503.
  •  Devereaux PJ, Sessler DI, Leslie K, Kurz A, Mrkobrada M, Alonso-Coello P, Villar JC, Sigamani A, Biccard BM, Meyhoff CS, Parlow JL, Guyatt G, Robinson A, Garg AX, Rodseth RN, Botto F, Lurati Buse G, Xavier D, Chan MT, Tiboni M, Cook D, Kumar PA, Forget P, Malaga G, Fleischmann E, Amir M, Eikelboom J, Mizera R, Torres D, Wang CY, Vanhelder T, Paniagua P, Berwanger O, Srinathan S, Graham M, Pasin L, Le Manach Y, Gao P, Pogue J, Whitlock R, Lamy A, Kearon C, Chow C, Pettit S, Chrolavicius S, Yusuf S. Clonidine in patients undergoing noncardiac surgery. N Engl J Med. 2014 Apr 17;370(16):1504-13.

clonidineVSaspirin

Figure: Kaplain-Meier curves for clonidine and aspirin administered in the peri-operative period failed to demonstrate any benefit in reducing myocardial events in comparison with placebo

Vegetarian diet associated with lower blood pressure  

29 Jun, 14 | by Alistair Lindsay

Conflicting evidence exists on the association between a vegetarian diet (involving no or rare meat consumption) and hypertension. In this meta-analysis, the authors included 7 controlled trials and 32 observational studies examining the association between vegetarian diets and hypertension. The 7 trials included 311 individuals with a mean age of 44.5 years.  After pooling of trial results, a vegetarian diet was associated with a mean reduction in systolic blood pressure (SBP) by 4.8mmHg (95% CI 3.1 to 6.6 mmHg reduction; P<.001) and diastolic blood pressure (DBP) by 2.2 mmHg (95% CI 1.0 to 3.5 mmHg reduction; P<.001). The 32 observational studies included 21,604 individuals with a mean age of 46.6 years.  After pooling results of these observational studies, a vegetarian diet was associated with lower SBP by 6.9 mmHg (95% CI 4.7 to 9.1 mmHg lower; P<.001) and lower DBP by 4.7 mmHg (95% CI 3.1 to 6.3 mmHg lower; P<.001). Meta-regression suggested that the association between vegetarian diet and BP was stronger amongst men and those with higher baseline BP.

Conclusion: In this meta-analysis, a vegetarian diet was associated with lower blood pressure compared to omnivorous diet. However, observational studies used for the meta-analysis were all cross-sectional with significant heterogeneity in the patient populations. Additionally, adjustment for other lifestyle factors associated with a vegetarian diet and food composition could not be performed in this analysis.

 Summarized by Steven M. Bradley and Supriya Shore

  •  Yokoyama Y, Nishimura K, Barnard ND, et al. Vegetarian diets and blood pressure: a meta-analysis. JAMA internal medicine. Apr 2014;174(4):577-587.

ACEI reduce mortality whereas ARB did not in diabetic populations  

29 Jun, 14 | by Alistair Lindsay

Where the benefits of renin-angiotensin-aldosterone system blockade for reduction of cardiovascular risk are similar for ACE inhibitors (ACEI) and ARBs are unknown.  The answer to this question is of particular importance among diabetics, given the higher cardiovascular risk in this patient population.  In this meta-analysis, the authors examined effect of ACEI and ARBs on the incidence of mortality and cardiovascular events in diabetics. A total of 23 randomized trials comparing ACEI to placebo/no treatment/ other medications and 13 trials comparing ARBS to placebo/other medications were included. Trials with ACEI enrolled more patients with coronary artery disease than trials of ARBs. Pooled results showed that ACEI reduced the risk of all-cause mortality (relative risk [RR] 0.87; 95% CI 0.78 – 0.98) and cardiovascular events (RR 0.83; 95% CI 0.70 – 0.99). Treatment with ARBs did not influence all-cause mortality (RR 0.94; 95% CI 0.82 – 1.08) or cardiac mortality (RR 0.94; 95% CI 0.85 – 1.01). Meta-regression found the observed effects of ACEI on mortality did not differ by patient baseline characteristics or by ACEI agent.

 Conclusion: This meta-analysis found that ACEI reduced rates of all cause and cardiovascular mortality, while ARB did not.  These findings suggest that ACEI should be considered as first line therapies in diabetics.

 Summarized by Steven M. Bradley and Supriya Shore

  •  Cheng J, Zhang W, Zhang X, et al. Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on All-Cause Mortality, Cardiovascular Deaths, and Cardiovascular Events in Patients With Diabetes Mellitus: A Meta-analysis. JAMA internal medicine. May 1 2014;174(5):773-785.

Epinephrine for Non-Shockable In-hospital Cardiac Arrest — Time is of the Essence

29 Jun, 14 | by Alistair Lindsay

Guidelines recommend epinephrine as the primary medical intervention for cardiac arrest. However, no randomized trial data are available to support this recommendation. In this observational study from the American Heart Association’s Get With The Guidelines – Resuscitation multi-center registry of in-hospital cardiac arrest, the authors sought to determine if timing of epinephrine administration in the setting of non-shockable (i.e. pulseless electrical activity or asystole) in-hospital cardiac arrest is associated with patient outcomes. Among 25,095 patients with non-shockable in-hospital cardiac arrest, the median time to first epinephrine was 3 minutes (IQR 1-5 minutes). When analyzed at 3 minute intervals, there was a stepwise decrease in survival to discharge with increasing time to epinephrine. As compared to 1-3 minutes, the adjusted odds ratios were 0.91 (95% confidence interval [CI] 0.82 – 1.00; p = 0.055) for 4-6 minutes, 0.74 (95% CI 0.63 – 0.88; p < 0.001) for 7-9 minutes, and 0.63 (95% CI 0.52 – 0.76) for > 9 minutes. The authors also performed sensitivity analyses to ensure the primary analysis was not confounded by overall delays in initiation of resuscitation independent of time to epinephrine, by the selection of 3 minute increments for categorization of epinephrine administration, or by missing covariates. The results of the sensitivity analyses were similar to those of the primary analysis.

Conclusion: In this large observational study, increased time to epinephrine for cardiac arrest with non-shockable rhythm was associated with worse patient outcomes. It is important to consider that duration of resuscitation is an important contributor to patient outcomes, and thus later administration of epinephrine may reflect longer resuscitation events with lower likelihood of survival. However, this study reiterates the need for further investigation of epinephrine for cardiac arrest to define its optimal use to improve patient survival.

Summarized by Steven M. Bradley and Preston M. Schneider

Donnino MW, Salciccioli JD, Howell MD, Cocchi MN, Giberson B, Berg K, Gautam S, Callaway C. Time to administration of epinephrine and outcome after in-hospital cardiac arrest with non-shockable rhythms: retrospective analysis of large in-hospital data registry. BMJ. 2014;348.

Figure. Survival to discharge by timing of epinephrine administration among patients with non-shockable in-hospital cardiac arrest.

epinephrine4nonshockable

 

Spironolactone for heart failure with preserved ejection fraction

8 Jun, 14 | by Alistair Lindsay

Nearly half of all patients presenting with heart failure have normal or near normal left ventricular systolic function.  Optimal treatment strategies for this large patient group remain unclear.  Small mechanistic studies have suggested diastolic function may be improved by mineralocorticoid-receptor antagonists.  Whether this mechanistic benefit translates into better patient outcomes is not known.  In the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, 3445 patients with heart failure and an ejection fraction of 45% or more were randomised in a double-blind fashion to either spironolactone (15 to 45 mg daily) or placebo.  The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure with patients.  Over a mean follow-up period of 3.3 years, the primary outcome occurred in 18.6% of the spironolactone group and 20.4% of the placebo group (HR, 0.89; 95% CI, 0.77 to 1.04; P=0.14).  Compared with placebo, spironolactone resulted in a statistically significant reduction in hospitalizations for heart failure (206 patients vs. 245 patients, HR, 0.83; 95% CI, 0.69 to 0.99, P=0.04).  Use of spironolactone came at a cost of increased rates of hyperkaliemia (18.7%, vs. 9.1%), but no differences in serious adverse events.

Conclusions

In this large randomised controlled trial of patients with heart failure and preserved systolic function, the mineralocorticoid receptor antagonist spironolactone failed to result in patient benefit aside from a reduction in heart failure hospitalizations.  Whether the reduction in hospitalizations with spironolactone represents a mechanistic benefit, or just better volume control achieved through diuresis, is unclear.  Therapies that clearly improve outcomes in patients with heart failure and preserved ejection fraction remain elusive.

  • Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O’Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S and McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Apr 10;370(15):1383-92.

Summarized by Steven M. Bradley and Hussain Contractor

 

 

Renal denervation misses the mark in resistant hypertension

8 Jun, 14 | by Alistair Lindsay

The prospect of percutaneous renal-artery denervation to treat hypertension has been widely heralded in response to pilot studies that demonstrated marked reductions in blood pressure after renal denervation.  Despite the rapid adoption of catheter-based renal artery denervation, data from large scale randomised controlled trials remains absent.  A total of  535 patients with severe resistant hypertension were randomized in a 2:1 ratio to renal denervation or a sham procedure consisting of renal angiography alone.  All study patients were receiving a minimum of three antihypertensive medications, including a diuretic, with persistently elevated systolic blood pressures of 160mmHg or more. The primary end point was the change in office systolic blood pressure at 6 months.  The change in mean 24-hour ambulatory systolic pressure at 6 months was used as a secondary end-point.   Compared with the sham procedure, renal-artery denervation resulted in no significant reductions in blood pressure as determined by office measurement of systolic pressure (-14.13±23.93 mm Hg vs -11.74±25.94 mm Hg; difference of -2.39 mm Hg, 95% confidence interval [CI] -6.89 to 2.12; P=0.26) or mean 24-ambulatory pressure (-6.75±15.11 mmHg vs. -4.79±17.25 mmHg; difference of -1.96 mm Hg, 95% CI, -4.97 to 1.06; P=0.98).

Conclusions

In this large-scale, sham-controlled, blinded trial, renal denervation did not result in significant blood pressure reductions.  These findings call into question the utility of renal-denervation as part of current clinical practice.

  • Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL; SYMPLICITY HTN-3 Investigators.  . A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014 Apr 10;370(15):1393-401.

Summarized by Steven M. Bradley and Hussain Contractor

 

Cardiac resynchronization therapy benefit holds up in clinical practice

8 Jun, 14 | by Alistair Lindsay

The benefit of cardiac resynchronization therapy with a defibrillator (CRT-D) relative to implantable cardioverter-defibrillator (ICD) therapy alone has not been evaluated in routine clinical practice.  This study used data from the National Cardiovascular Data Registry’s ICD Registry linked with Medicare claims data to compare outcomes after CRT-D and ICD implantation in community practice.  The analysis included 7090 propensity matched patients who underwent either CRT-D or ICD implantation between 2006 and 2009 at one of 780 U.S. hospitals participating in the NCDR ICD registry.  Patients were over age 65 and met criteria for CRT-D implantation (left ventricular ejection fraction ≤ 35% and QRS duration ≥ 120ms). Over 3 years of follow-up, CRT-D was associated with lower risk of mortality (HR 0.82, 99% CI 0.73-0.93), all-cause readmission (HR 0.86, 99% CI 0.81-0.93), and heart failure readmission (HR 0.78, 99% CI 0.69-0.88) compared with ICD therapy.  However, CRT-D was also associated with a higher risk of device related infection (HR 1.90, 99% CI 1.07–3.37).  In subgroup analyses, the reduced risk of heart failure readmission was most prominent among patients with left bundle branch block or QRS duration of at least 150 ms.

 Conclusions

In routine clinical practice, patients who were eligible for CRT-D therapy according to criteria based on the findings of clinical trials experienced better long-term outcomes than patients treated with ICD alone.  These findings suggest the benefits observed in highly controlled clinical trials of CRT-D have translated into patient benefit in for properly selected patients in routine clinical practice

  • Masoudi FA, Mi X, Curtis LH, Peterson PN, Curtis JP, Fonarow GC, Hammill SC, Heidenreich PA, Al-Khatib SM, Piccini JP, Qualls LG, Hernandez AF. Comparative Effectiveness of Cardiac Resynchronization Therapy With an Implantable Cardioverter-Defibrillator Versus Defibrillator Therapy Alone. A Cohort StudyComparative Effectiveness of Cardiac Resynchronization Therapy. Annals of Internal Medicine. 2014;160:603–611.

Summarized by Steven M. Bradley and Preston M. Schneider

 

β-blockers beneficial in some, but not all, ischemic heart disease patients undergoing non-cardiac surgery

8 Jun, 14 | by Alistair Lindsay

Whether β-blockers reduce adverse events among patients with stable ischemic heart disease (IHD) undergoing non-cardiac surgery remains in debate. In this Danish study, the authors retrospectively identified 28,263 IHD patients who underwent non-cardiac surgeries and examined the association between pre-procedural β-blockers use and a major adverse cardiovascular event (MACE) defined as 30-day cardiac death, myocardial infarction (MI) and stroke. The cohort included 7,990 patients (28.3%) with heart failure and 12,601 (44.6%) with a history of MI.  Overall, 1,374 (4.9%) experienced a MACE. The risk for MACE was lower among patients treated with β-blockers in the setting of a history of heart failure (adjusted hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.66-0.91) but not among patients without heart failure (adjusted HR 1.11; 95% CI 0.92-1.13). Among patients without heart failure, use of β-blockers was associated with lower risk of MACE in patients with an MI in the prior 2 years (HR 0.54; 95% CI 0.37-0.78).

Conclusion: In this retrospective cohort study of patients with IHD, β-blocker use prior to non-cardiac surgery was associated with a lower 30-day risk for major adverse events among patients with heart failure or recent MI. However, lower risk patients without heart failure or recent MI did not appear to benefit from perioperative β-blocker use.  Questions about the optimal IHD risk-threshold for consideration of β-blocker use in the setting of non-cardiac surgery remain.

  •  Andersson C, Merie C, Jorgensen M, et al. Association of beta-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing noncardiac surgery: a Danish nationwide cohort study. JAMA Internal Medicine. Mar 2014;174(3):336-344.

Summarized by Steven M. Bradley and Supriya Shore

 

 

Glycemic measurements are not helpful in CVD risk prediction among non-diabetics

8 Jun, 14 | by Alistair Lindsay

Several clinical guidelines recommend measurement of glycated hemoglobin (HbA1c) to guide cardiovascular risk (CVD) risk assessment. In this study, the authors examined the utility of adding HbA1c measurements to conventional risk factors in prediction of CVD among non-diabetic patients. Data from 73 prospective studies with nearly 300,000 non-diabetic patients without known CVD at enrollment was analyzed. Mean age was 58 years, 49% were women and mean HbA1c was 5.4%. Over a median follow-up duration of nearly 10 years, there were 20,840 fatal and nonfatal incident CVD events. Addition of HbA1c levels to risk prediction models with conventional CVD risk factors of age, sex, smoking, blood pressure, HDL and total cholesterol led to small changes in C-index (0.7434 to 0.7452; change of 0.0018, 95% CI 0.0003-0.0033) and net reclassification 0.42 (-0.63 to 1.48). Use of other glycemic measurements such as fasting glucose, random glucose and postload glucose were no better for CVD risk prediction than HbA1c.

Conclusions

Contrary to existing guidelines, addition of HbA1c levels to traditional CVD risk factors did not lead to meaningful improvement in CVD risk prediction among non-diabetics in this large, multicenter prospective study.

  • Emerging Risk Factors Collaboration,  Di Angelantonio E, Gao P, et al. Glycated hemoglobin measurement and prediction of cardiovascular disease. JAMA. Mar 26 2014;311(12):1225-1233

Summarized by Steven M. Bradley and Supriya Shore

 

Warfarin for atrial fibrillation in patients with chronic kidney disease – does the thromboembolic benefit outweigh the bleeding risk?

8 Jun, 14 | by Alistair Lindsay

Chronic kidney disease (CKD) predisposes to high risks for both thrombo-embolism and bleeding. As a result, understanding the risk-benefit profile for use of anticoagulation therapies among CKD patients with atrial fibrillation is important to optimize patient outcomes. However, clinical trials evaluating efficacy and safety of anti-coagulants for atrial fibrillation generally exclude CKD patients and observational studies have had conflicting results. Accordingly, this prospective cohort study of 24,317 atrial fibrillation patients admitted with myocardial infarction in Sweden examined the association between warfarin therapy and patient outcomes by stage of CKD. Warfarin was prescribed in 21.8% patients and CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m2) was present in 51.7%. Compared with patients not treated with warfarin, the risk-adjusted composite outcome of death, myocardial infarction, or ischemic stroke was lower at 1 year of follow-up among patients treated with warfarin, regardless of CKD class. This reduction in thromboembolic events was not offset by an increased risk of bleeding events.

Conclusions

This study confirms the benefit of warfarin for thromboembolic risk protection in patients with CKD and atrial fibrillation. However, given that warfarin is known to increase bleeding risk, the lack of apparent bleeding risk with warfarin therapy in this study raises concerns that baseline bleeding risk was markedly lower among patients treated with warfarin. Given the increasing prevalence of both CKD and atrial fibrillation, a better understanding of the risk-benefit profile of anticoagulation in these high risk patients is needed.

  • Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA. Mar 5 2014;311(9):919-928.

Summarized by Steven M. Bradley and Supriya Shore

 

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