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Bivalirudin in contemporary STEMI treatment

29 Dec, 13 | by Alistair Lindsay

The novel direct thrombin inhibitor bivalirudin is now widely used as an adjunctive therapy in patients undergoing primary PCI for ST elevation myocardial infarction (STEMI). This stems from trial data demonstrating bivalirudin results in lower bleeding rates and better long term survival as compared with the combination of heparin and a GP IIb/IIIa inhibitor. However, clinical practice has subsequently changed, including greater use of radial access with resultant lower bleeding risk and expanded use of newer generation P2Y­12 inhibitors.  The EUROMAX trial sought to understand whether use of bivalirudin benefits patients in light of these changes in clinical practices.

This trial prospectively randomized 2218 patients in an open-label fashion to treatment with bivalirudin or heparin with optional use GP IIb/IIIa (decision left to provider preference) inhibitor by paramedic teams during ambulance transfer to a PCI center.  Approximately 50% of procedures were completed radially with 60% of patients being loaded with one of the novel P2Y12 antagonists.  Nearly 70% of patients in the heparin group received a GP IIb/IIIa inhibitor compared to just over 10% in the bivalirudin treated group.  The primary endpoint was the composite of death and major bleeding at 30-days.  Bivalirudin resulted a lower event rate (5.1% vs. 8.5%; relative risk [RR], 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) due to lower bleeding events, but not mortality benefit (2.9% vs. 3.1%).  Furthermore, bivalirudin therapy resulted in a significant increase in the rate of acute stent thrombosis (1.1% vs. 0.2%; RR, 6.11; 95% CI, 1.37 to 27.24; P=0.007).


In this large contemporary practice trial with frequent use of radial access and novel P2Y12 inhibitors, early use of bivalirudin use in STEMI patients led to reduced bleeding events, but increased rates of acute stent thrombosis.  This investigation is timely, given the impact of radial access on baseline bleeding risk and newer P2Y12 inhibitors on thrombotic risk.  However, as procedural technique and antiplatelet therapies continuing to evolve, the relative benefit of bivalirudin may continue to warrant investigation with changes in practice.

  •  Steg PG, van ‘t Hof A, Hamm CW, Clemmensen P, Lapostolle F, Coste P, Berg JT, Van Grunsven P, Eggink GJ, Nibbe L, Zeymer U, Orto MC, Nef H, Steinmetz J, Soulat L, Huber K, Deliargyris EN, Bernstein D, Schuette D, Prats J, Clayton T, Pocock S, Hamon M and Goldstein P. Bivalirudin Started during Emergency Transport for Primary PCI. N Engl J Med. 2013 Oct 30. [Epub ahead of print]


Joint Replacement in Moderate-Severe Osteoarthritis is Associated with Improved Cardiovascular Outcomes

28 Nov, 13 | by Alistair Lindsay

Physical inactivity and non-steroidal anti-inflammatory drug (NSAID) use are established risks for serious cardiovascular events.  Osteoarthritis can contribute to these risk factors by reducing patient mobility and NSAID use for symptom relief.  Using data from a registry of patients with moderate-severe osteoarthritis, Ravi and colleagues evaluated the relationship between total joint arthroplasty of the hip and knee and subsequent risk for serious cardiovascular events.

Using a propensity score matched landmark analysis design with a median follow-up of seven years, the authors compared outcomes among patients that underwent total joint arthroplasty with those who did not.  The primary outcome of serious cardiovascular event included acute myocardial infarction, stroke or transient ischemic attack, congestive heart failure, coronary revascularization, or in-hospital cardiac death.  The authors found patients that underwent total joint arthroplasty were at a significantly reduced risk for serious cardiovascular events (hazard ratio 0.56; 95% CI 0.43 to 0.74; P < 0.001).  This corresponded to an absolute risk reduction of 12.4% (95% CI 1.7% to 23.1%) and a number needed to treat of 8 (95% CI 4 to 57).  Given the observational nature of the study, the investigators evaluated the potential impact of unmeasured confounders on the findings.  This analysis demonstrated the primary results are robust as an unmeasured confounder would need a very high prevalence (75%) and strong association with the outcome (relative risk of 66%) to negate the observed findings.

Conclusions: This study strongly suggests that joint replacement has a significant effect on future cardiovascular events in patients with osteoarthritis.  However, it is unclear if this benefit is predominantly related to improved physical activity, reduced use of NSAIDs after surgery, or other factors.  Understanding the predominant mediator of these findings would further guide the optimal approach to all patients with osteoarthritis to reduce cardiovascular risk.

  • Ravi B, Croxford R, Austin PC, et al. The relation between total joint arthroplasty and risk for serious cardiovascular events in patients with moderate-severe osteoarthritis: propensity score matched landmark analysis. BMJ 2013;347.

Clinical Impact of Echocardiography Not Aligned with Appropriateness

28 Nov, 13 | by Alistair Lindsay

Echocardiography is a widely available diagnostic procedure with minimal patient risk.  However, there are concerns that echocardiography may be overused relative to clinical need.  To this end, appropriate use criteria have been developed to support the effective and efficient use of echocardiography. However, the clinical impact of echocardiography in relation to appropriateness has not been described.

In this study from a single academic center, the appropriateness and clinical impact of 535 consecutive transthoracic echocardiograms (TTEs) was determined from chart review. Chart reviewers rated TTE appropriateness based on 2011 criteria and were blinded to the results of the echo and subsequent clinical course.  Clinical impact was defined by categories of active change in care, continuation of current care, or no change in care.  Overall, 91.8% of TTE were classified as appropriate, 4.3% as inappropriate and 3.9% were rated as uncertain appropriateness. Overall, 31.8% of echocardiograms resulted in a change in care, 46.9% led to continuation of same management and 21.3% led to no change. There was no difference in the proportion of appropriate and inappropriate TTEs that led to a change in clinical management (32.2% vs. 21.7%, p=0.29).

Conclusions: In this retrospective study, the majority of TTEs were appropriate and a similar proportion of appropriate and inappropriate TTEs led to a change in clinical management. However, diagnostic studies are often important for their ability to refute a diagnosis in the evaluation of patients and this relationship may be underappreciated in this study.  Continued refinement, evaluation, and application of the appropriate use criteria are needed to optimize patient selection in the use of diagnostic tests.

  • Matulevicius SA, Rohatgi A, Das SR, et al. Appropriate use and clinical impact of transthoracic echocardiography. JAMA internal medicine. 2013;173:1600-1607


Echocardiographic screening of general population of no benefit

28 Nov, 13 | by Alistair Lindsay

While echocardiographic screening for structural heart disease is recommended in patients with a family history of cardiac arrest or hereditary conditions affecting the heart or great vessels, whether echocardiographic screening is warranted in the general population is unknown.

The study consisted of 6,861 patients randomized to echocardiographic screening (n=3,272) or a control group (n=3,589). The study population was drawn from the Tromsø Study—a prospective, population-based cohort study conducted in Norway.  Extensive data on participants was obtained through self-reported questionnaires and physical examinations. Individuals with pre-defined echocardiographic abnormalities were referred for clinical follow-up. The primary outcome was all-cause mortality. In the group screened by echocardiography, 362 (8.9%) patients met criteria for clinical referral.  A total of 15.2% of referred individuals with echocardiographic abnormalities did not obtain clinical follow-up. Of 290 patients seen in follow-up, pathologic cardiac conditions were verified in 249 (7.6%) individuals who subsequently received treatment. During the 15-year follow-up, no difference was seen in all cause-mortality (HR 0.97; 95% CI 0.89 – 1.06) or cardiac mortality (HR 0.91; 95% CI 0.77 – 1.08) in the echocardiographically screened group compared with the control group.

Conclusions: Echocardiographic screening of the general population does not appear to reduce mortality. However, the generalizability of these findings is limited given the homogenous Norwegian population studied. Moreover, 15% of individuals with abnormal echocardiograms did not obtain clinical follow-up, which may have attenuated the results.

  • Lindekleiv H, Lochen ML, Mathiesen EB, et al. Echocardiographic screening of the general population and long-term survival: A randomized clinical study. JAMA internal medicine. 2013;173:1592-1598

The AQUARIUS trial: Aliskiren does not slow progression of atherosclerosis

28 Nov, 13 | by Alistair Lindsay

The renin-angiotensin-aldosterone system (RAAS) appears to have an important role in the development of atherosclerosis.  The Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS) sought to determine if direct renin inhibition with aliskiren slows atherosclerosis progression in patients with already controlled blood pressure.

The AQUARIUS study was a randomized, double-blinded trial comparing the effect of aliskiren versus placebo on atherosclerosis progression in coronary arteries as measured by intravascular ultrasound (IVUS) imaging. Eligible patients had at least one 20% stenosis on clinically indicated coronary angiography, controlled blood pressure (systolic blood pressure 125-139 mmHg and diastolic <90 mmHg), and 2 additional cardiovascular risk factors. Primary efficacy outcome was change in percent atheroma volume (PAV) and secondary efficacy outcome was change in normalized total atheroma volume (TAV) as assessed by IVUS.

Overall, 458 (74.7%) of randomized patients had evaluable IVUS data at baseline and follow-up. There were no significant differences in PAV (between group PAV difference = -0.43%, 95% CI -0.92% to 0.05%) or TAV (between group TAV difference= -2.04mm3, 95% CI -5.03 to 0.95mm3) outcomes in patients on aliskiren compared to placebo. In pre-specified exploratory analyses, treatment with aliskiren was associated with lower major adverse cardiovascular events (HR 0.50, 95% CI 0.31-0.81).

Conclusions: Treatment with aliskiren did not slow progression of atherosclerosis in patients without hypertension. While there was a lower incidence of major adverse cardiovascular events with aliskiren, this analysis was exploratory. Accordingly, current evidence does not support use of aliskiren for secondary prevention in patients with prehypertension and coronary artery disease.

  •  Nicholls SJ, Bakris GL, Kastelein JJ,  et al. Effect of aliskiren on progression of coronary disease in patients with prehypertension: The aquarius randomized clinical trial. JAMA : the journal of the American Medical Association. 2013;310:1135-1144

Dabigatran Unsuitable for Use with Mechanical Heart Valves

28 Nov, 13 | by Alistair Lindsay

Dabigatran and other novel oral anticoagulants are effective and safe for reducing thromboembolic risk in the setting non-valvular AF.  However, it remains unclear whether these newer anticoagulants are as effective as warfarin for reducing thromboembolic complications among patients with mechanical heart valves.  As oral anticoagulation is a mainstay of therapy in patients with mechanical valves, this is a critical question as it relates to potential expanded indications for dabigatran use.

The Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN) sought to validate a regimen of dabigatran to prevent thromboembolic complications from mechanical heart valves. Patients with either mechanical aortic or mitral valves were randomized to dabigatran or warfarin. Dabigatran dosing was guided by renal function and plasma trough levels.  Warfarin was adjusted by INR with target range determined by thromboembolic risk.  The trial was stopped early after recruitment of 252 patients out of a planned 405 when an interim analysis revealed a large excess of both thromboembolic and bleeding episodes in patients randomized to dabigatran. In the dabigatran group, 9 patients (5%) suffered non-haemorrhagic strokes and 5 (3%) had valve thrombosis, compared to no stroke or valve thrombosis event among patients on warfarin.  Furthermore, major bleeding was twice as common in the dabigatran group.


In this phase II study, dabigatran failed to demonstrate efficacy or safety in comparison to warfarin for anticoagulation in patients with mechanical heart valves.  As both thrombotic and bleeding events were higher with dabigatran, there appears little promise that revised dosing regimens with dabigatran could achieve outcomes equivalent to those seen with warfarin. This study also highlights the potential for harm when clinical benefits from one setting (non-valvular atrial fibrillation) are extrapolated to another (mechanical heart valves).  For this reason, warfarin should remain the anticoagulant of choice for mechanical heart valves until further safety and efficacy trials of novel anticoagulants are completed.

  •  Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML and Van de Werf F. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013 Sep 26;369(13):1206-14.

No Benefit from Cardiac Resynchronization Therapy in Patients with a Narrow QRS Complex

28 Nov, 13 | by Alistair Lindsay

Cardiac-resynchronization therapy (CRT) has known benefits in patients with severe left ventricular systolic dysfunction and prolonged QRS duration (>120 ms).  However, up to half of patients with systolic dysfunction appear to have left ventricular dyssynchrony by echocardiographic measures, despite a QRS duration of less than 120 ms.  As a result, CRT is often used for patients with echocardiographic evidence of dyssynchrony and a narrow QRS complex, despite a lack of clear benefit to this approach.  The Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) study sought to determine the effect of CRT on patient outcomes in the setting of symptomatic heart failure, echocardiographic findings of dyssynchrony, and QRS duration <120 ms.

In this multicenter double blind trial, patients with severe symptomatic left ventricular failure (EF<35% and NYHA class III or IV) with a QRS duration of <130ms (mean 105ms) and evidence of dyssynchrony either on tissue Doppler or speckle tracking echo parameters, were all implanted with CRT devices with ICDs and then randomized so that half of study participants had the CRT function turned off.  The primary outcome was a composite of all cause death or hospitalization for heart failure.  Following a pre-planned interim analysis, the study was terminated prematurely after recruitment of 809 out of a planned 1132 patients due to futility.  By study close, 116 patients in the CRT group had met the primary outcome as opposed to 102 in the control group (28.7% vs. 25.2%; HR, 1.20; 95% CI, 0.92 to 1.57; P=0.15).  Device related adverse events were also much more common in the CRT group (P=0.003), largely driven by lead displacements.  Most worryingly of all, mortality was significantly increased in the CRT group (45 deaths vs 26 deaths, HR, 1.81; 95% CI, 1.11 to 2.93; P=0.02).


CRT is not beneficial, and may cause significant harm, in patients with severe systolic heart failure and a narrow QRS.  These findings raise questions about the importance of echocardiographic measures of mechanical dyssynchrony.  Further, patient selection for CRT should remain based on current ECG criteria.

  • Ruschitzka F, Abraham WT, Singh JP, Bax JJ, Borer JS, Brugada J, Dickstein K, Ford I, Gorcsan J 3rd, Gras D, Krum H, Sogaard P and Holzmeister J.  Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med. 2013 Oct 10;369(15):1395-405.

Smoking and antiplatelet agents – smoke and mirrors or something more?

22 Nov, 13 | by Alistair Lindsay

Many antiplatelet therapies are prodrugs that require metabolic activation.  It has been hypothesized that smoking may activate this metabolic conversion for some antiplatelets (i.e. clopidogrel) more than others (i.e. prasugrel and ticagrelor).  In this systematic review and meta-analysis, the authors identified 9 randomized controlled trials of clopidogrel, prasugrel, or ticagrelor which examined outcomes among subgroups of smokers and non-smokers.  In the studies of clopidogrel, smokers on clopidogrel saw a 25% reduction in the primary composite outcome of cardiovascular death, MI, and stroke compared with patients in the control group (RR 0.75, 95% CI 0.67 – 0.83).  However, in non-smokers there was only an 8% reduction in the primary end point (RR 0.92, 95% CI 0.87 – 0.98).  Similarly, greater risk reduction was observed for smokers on ticagrelor or prasugrel when compared to clopidogrel while risk reduction was similar for all three drugs in non-smokers.


It is unclear if the relative effect of antiplatelet therapies in smokers simply reflects differences in baseline clinical risk or differences in the metabolic activation of antiplatelet drugs.  Study of antiplatelet therapies stratified by patient cardiovascular disease risk may provide further insight.

  • Gagne JJ, Bykov  K, Choudhry NK, et al.  Effect of smoking on comparative efficacy if anti platelet agents: systematic review, meta-analysis, and indirect comparison.  BMJ 2013;347:f5307 doi:10.1136/bmj.f5307 (Pulished 17th September 2013).

Blood pressure control, not the specific medication regimen, is what matters

22 Nov, 13 | by Alistair Lindsay

The Blood Pressure Lowering Treatment Trialists’ Collaboration examined primary data from 23 trials as well as summary data from an additional 3 trials to define the cardiovascular effects of lowering blood pressure in people with and without chronic kidney disease.  This study included randomized trials of drugs to lower blood pressure that were compared to placebo or other drugs with at least 1000 patient years of follow up in each treatment arm.  The primary outcome was major cardiovascular events (the composite of stroke, myocardial infarction, heart failure or cardiovascular death), with secondary outcomes of each element of the composite outcome as well as all-cause mortality.  These 26 trials included 152,290 patients, of which 30,295 had impaired renal function (estimated glomerular filtration rate [eGFR] of < 60 mL/min/1.73m2).   Meta-analysis according to baseline kidney function was performed and pooled hazard ratios were estimated per 5 mm Hg lower systolic blood pressure.   Blood pressure lowering was found to reduce the risk of the primary outcome by approximately 17% per 5 mm Hg reduction in systolic blood pressure, regardless of eGFR .  Furthermore, there was no evidence of any difference in effect by choice of blood pressure control regimen.


This meta-analysis suggests the change in blood pressure, not the regimen chosen for blood pressure control, is most influential in preventing cardiovascular events.

  • Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials. BMJ 2013;347:f5680.

Low awareness, treatment and control of hypertension across the globe

22 Nov, 13 | by Alistair Lindsay

Hypertension is associated with 7.6 million deaths worldwide and is the leading modifiable risk factor for cardiovascular disease (CVD). However, global studies of hypertension prevalence, awareness, treatment, and control are lacking. The PURE (Prospective Urban Rural Epidemiology) study involves urban and rural communities in 3 high-income, 10 middle-income, and 4 low-income countries. CVD risk factors including blood pressure readings were collected by trained professionals from 142,042 adults aged 35 – 70 years between January 2003 and December 2009. Overall, 40.8% of participants had hypertension, only 46.5% of hypertensive patients were aware of their condition, and 40.6% of hypertensive patients were receiving treatment. Only 13.2% of hypertensive patients were controlled (<140/90 mmHg). Lowest rates of awareness, treatment and control were seen in low-income countries.


There is a large gap between detection and control of hypertension worldwide. Substantial efforts are needed to address this worldwide problem.

  • Chow CK, Teo KK, Rangarajan S, et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA : the journal of the American Medical Association. Sep 4 2013;310(9):959-968

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