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Diabetes drug Liraglutide reduces cardiovascular events and mortality

11 Jul, 16 | by flee

Type II diabetes, an epidemic fuelled by an unrelenting rise in obesity and sedentary behaviors, is a major risk factor for both micro- and macrovascular disease. An array of new treatments have recently come to trial with the aim of improving glycemic control and reducing disease complications. But lingering doubts remain regarding the cardiovascular implications of several of these agents, with FDA mandated studies now taking place to establish their safety.  Injectable liraglutide, a glucagon-like peptide 1 analogue,  improves HbA1c levels and also leads to weight loss but its cardiovascular effects are unknown.  In this post-approval double-blind study, 9340 patients with type 2 diabetes and at least one other major cardiovascular risk factor, were randomly allocated 1:1 to liraglutide or matching placebo, as well as usual care.  Patients were followed up for a median of 3.8 years with a primary composite study end-point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.  Designed as a non-inferiority study, liraglutide demonstrated statistically significant and clinically meaningful reductions in the primary end-point (13.0% vs. 14.9%, HR, 0.87; 95% CI, 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority) with reductions in both cardiovascular death (P=0.007) and all cause mortality (P=0.02).  Liraglutide also demonstrated a good safety profile with numerically lower rates of heart failure hospitalisations and no increase in rates of pancreatitis, a previous concern.  At 36 months HbA1c was 0.4 lower in the liraglutide group. Of note, significant differences in blood pressure (1.2 mmHg lower) and weight reduction (2.3 kg better) were observed in the trial group.  The NNT to prevent one primary end-point event was 66 and the NNT for all cause mortality 98.



Long-term survival benefit for CABG in ischemic cardiomyopathy

23 Jun, 16 | by flee

The STICH trial asked the important question whether CABG in patients with severe ischemic cardiomyopathy would provide a survival advantage over contemporary medical therapy alone. Reporting 5-year data in 2011, the study reported no significant difference but did demonstrate a tantalizing divergence in survival graphs between 2 and 5 years, which appeared to be increasing with time.  In an extension to the study, 10 year follow-up data is reported.  Out of the original 1212 patients in the study, data was available on 98% of the cohort at long-term follow-up.  Over this long time period the primary outcome of death from any cause occurred in 58.9% in the CABG group and in 66.1% in the medical-therapy group (HR with CABG vs. medical therapy, 0.84; 95% CI, 0.73 to 0.97; P=0.02).  Significant reductions were also seen in cardiovascular death (P=0.006) and hospitalizations for cardiovascular causes (P<0.001) in the CABG group. The overall number needed to treat to prevent 1 death was 14, equating to an overall 16% lower chance of cardiovascular death during the study period and an increase in longevity of approximately 18 months. The effect was consistent across all important sub-group analyses.

Conclusions: In patients with an ischemic cardiomyopathy, revascularization with CABG, when combined with optimal medical therapy confers a long-term survival benefit and a reduction in hospital admissions for cardiovascular causes.  These advantages are not realized immediately, perhaps due to countervailing perioperative risk, but appear sustained to 10 years.

Summarized by James M. McCabe, MD and Steven M. Bradley

Velazquez EJ, Lee KL, Jones RH, Al-Khalidi HR, Hill JA, Panza JA, Michler RE, Bonow RO, Doenst T, Petrie MC, Oh JK, She L, Moore VL, Desvigne-Nickens P, Sopko G, Rouleau JL; STICHES Investigators. Coronary-Artery Bypass Surgery in Patients with Ischemic Cardiomyopathy. N Engl J Med. 2016 Apr 3. [Epub ahead of print]

Transcatheter aortic valve implantation in intermediate risk patients

17 Jun, 16 | by flee

Transcatheter aortic valve implantation (TAVI) has had a major impact on both morbidity and mortality in high-risk and inoperable patients with severe aortic stenosis. Robust evidence has supported widespread adoption in this patient group but uncertainty exists as to whether TAVI may also achieve clinical equipoise with surgical aortic valve replacement (AVR)  in lower risk groups.  In the industry sponsored PARTNER 2 trial, patients deemed at intermediate surgical risk (generally with an STS score between 4 and 8) were randomized to either TAVI with the SAPIEN XT valve or conventional surgery (bioprosthetic valve of operative choice).  In a study powered for non-inferiority, a total of 2032 patients at 57 North American centers were recruited with a primary end-point of all cause mortality and disabling stroke measured at 24 months.  TAVI was found to be none-inferior to surgical AVR at 2 years with respective event rates of 19.3% and 21.1% (HR, 0.89; 95% CI, 0.73 to 1.09; P=0.25). The rates of stroke (6%) and death (17-18%) were very similar between groups. When analyzing only those patients whom underwent TAVI via transfemoral access (76% of the total population), there was a signal that TAVI resulted in a lower incidence of the primary end-point of death or stroke (P=0.05). The non-transfermoral (alternative) access cohort had similar outcomes to the surgical AVR group.  TAVI patients were found to have a lower incidence of major bleeding, kidney failure and new onset atrial fibrillation as well as having larger aortic valve areas.  In the surgical AVR group patients had less paravalvular leak and fewer vascular complications.  Interestingly, the rate of permanent pacemaker implantation was similar between the two groups at less than 10% (P=0.17)


In this landmark study, patients with intermediate surgical risk had similar, and in some instances, superior outcomes with TAVI as compared to conventional surgical AVR.  As with PCI before it, the rise of minimally invasive valve replacement appears inexorable and is likely to change the landscape of cardiac intervention over the coming years as both technology and operator experience improves.  In fact, these data reflect a TAVI technology that has already been supplanted in clinical practice by a next generation technology in most countries.


Leon MB, Smith CR, Mack MJ, Makkar RR, Svensson LG, Kodali SK, Thourani VH, Tuzcu EM, Miller DC, Herrmann HC, Doshi D, Cohen DJ, Pichard AD, Kapadia S, Dewey T, Babaliaros V, Szeto WY, Williams MR, Kereiakes D, Zajarias A, Greason KL, Whisenant BK, Hodson RW, Moses JW, Trento A, Brown DL, Fearon WF, Pibarot P, Hahn RT, Jaber WA, Anderson WN, Alu MC, Webb JG; PARTNER 2 Investigators. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med. 2016 374(17)1609-20


Summarized by  James McCabe, MD

Pre-operative aspirin does not influence CABG outcomes.

28 Apr, 16 | by flee

Aspirin is a common therapy for risk reduction among patients with coronary artery disease.  However, among patients undergoing coronary artery bypass surgery, the benefits of aspirin on the risk of myocardial infarction and stroke may be outweighed by perioperative bleeding risk.   To address this question, the ATACAS trial randomized 2100 patients to either receive 100 mg aspirin daily or matching placebo for 4 days immediately prior to the operation with all patients resuming aspirin within 24 hours of their bypass surgery. The primary outcome was a composite of death and thrombotic episodes (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days.  Overall rates of post-operative myocardial infarction were 14.8%, which is higher than typical for studies of post-bypass outcomes and may reflect use of troponin surveillance for the identification of this outcome.  There were no significant differences in the primary endpoint or individual components of the primary end-point between aspirin treatment and placebo groups.

Conclusions: In this large trial of perioperative aspirin therapy, there was no difference in clinical outcomes from administration or discontinuation of aspirin in the pre-operative period.  Although these findings suggest either strategy is safe, the trail appears to have limited outcomes assessment to the post-operative period.  As a result, this trial may underestimate the impact of aspirin therapy as it relates to events in the immediate preoperative period.  Additional analyses of event rates in this preoperative period may further inform optimal perioperative use of aspirin therapy.

Summarized by Hussain Contractor and Steven M. Bradley

Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, Cooper DJ, Marasco S, McNeil J, Bussières JS, Wallace S; ATACAS Investigators of the ANZCA Clinical Trials Network. Stopping vs. Continuing Aspirin before Coronary Artery Surgery. N Engl J Med. 2016 Feb 25;374(8):728-37.

Mailing Nicotine Patches Improves Smoking Abstinence

29 Mar, 16 | by flee

Although clinical trials of nicotine replacement therapy (NRT) have consistently demonstrated higher rates of smoking cessation, the effectiveness of NRT may be lower in real-world settings, especially in the absence of behavioral support.  Accordingly, there is a need for randomized clinical trials to evaluate the effectiveness of NRT alone.  Cunningham et al conducted a randomized trial on adult smokers across Canada testing the impact of mailing nicotine patches to smokers without behavioral support on quit rates.  A total of 500 adults smoking more than 10 cigarettes daily were randomized to the experimental arm (mailed a 5-week supply of nicotine patches) or control arm (no nicotine patches mailed).  The primary outcome was self-reported abstinence from smoking at 6 months.  Self-reported nicotine abstinence rates were higher in the experimental arm (OR 2.65, 95% CI 1.44-4.89, p=0.002).  Of those who claimed abstinence, biochemical validation via saliva analysis for cotinine was available in 50.9%.  Biochemically validated abstinence at 6 months was found in 14 patients (2.8%) of 500 in the experimental cohort compared to 5 (1.0%) of 499 in the control group (OR 2.85, 95% CI 1.02-7.96, p=0.046).


Conclusion:  This work suggests access to nicotine patches alone, without concurrent behavioral support, promotes tobacco cessation.  However, low rates of biochemically validated smoking cessation limits the significance of the study findings.


Summarized by Amneet Sandhu and Steven M. Bradley


Cunningham JA, Kushnir V, Selby P, Tyndale RF, Zawertailo L and Leatherdale ST.  Effect of Mailing Nicotine Patches on Tobacco Cessation Among Adult Smokers: A Randomized Clinical Trial.  JAMA Intern Med. 2016: 176(2): 184-190.


Statin does not protect against acute kidney injury following cardiac surgery

29 Mar, 16 | by flee

Although statins affect mechanisms that lead to postoperative acute kidney injury (AKI), observational studies have failed to demonstrate a consistent effect of statin therapy on the risk of AKI after cardiac surgery. The Statin AKI Cardiac Surgery randomized control trial sought to determine if high-dose, short-term atorvastatin reduced the risk of AKI following cardiac surgery.  This double-blind, placebo-controlled, single center trial, evaluated high-dose perioperative atorvastatin on AKI in 615 patients undergoing elective coronary artery bypass surgery, valvular heart surgery, or ascending aortic surgery.  The intervention arm received atorvastation 80mg the day prior to surgery, 40mg day of surgery, and 40mg daily for the duration of hospitalization. Patients were randomized with stratification for prior statin use, presence of chronic kidney disease (GFR < 60 ml/min/1.73m2), and history or diabetes. The primary outcome of AKI was defined as an increase of 0.3mg/dL in serum creatinine or initiation of renal replacement therapy within 48 hours of surgery.  The study was terminated after a second interim analysis for concern of increased risk of AKI among statin naïve patients and for futility among patients who were previously on a statin.



Conclusion: High-dose statin therapy does not reduce the risk of AKI following cardiac surgery.


Summarized by Lauren E. Thompson and Steven M. Bradley


Billings FT 4th, Hendricks PA, Schildcrout JS, Shi Y, Petracek MR, Byrne JG, Brown NJ. High-Dose Perioperative Atorvastatin and Acute Kidney Injury Following Cardiac Surgery: A Randomized Clinical Trial.

JAMA. 2016;315(9):877-888.

Genetic similarities in cardiomyopathies

29 Feb, 16 | by flee

The incidence of peripartum cardiomyopathy is 1 in 4000 pregnant women in Western Europe, but is as high as 1 in 100 in Haiti and Nigeria.  Although peripartum cardiomyopathy can resolve, it can also be devastating as evidenced by a 5 to 10% mortality rate and the condition accounting for 4% of all U.S. women receiving heart transplantation.  Although risk factors such as pre-eclampsia, twin pregnancies, and advanced maternal age have been identified, little is known about the pathophysiology of peripartum cardiomyopathy and an individual’s susceptibility to this condition.  In comparison, the genetic underpinnings of what was previously considered idiopathic dilated cardiomyopathy are increasingly understood.  Given phenotypic similarities between peripartum cardiomyopathy and dilated cardiomyopathy, the authors sought to evaluate the contribution of genetic variants previously described in dilated cardiomyopathy among women with peripartum cardiomyopathy.  In this study, 172 women with peripartum cardiomyopathy underwent genetic sequencing of 43 genes associated with dilated cardiomyopathy.  The prevalence of variants was compared both with a population of patients with dilated cardiomyopathy and healthy controls.  A total of 26 distinct truncating variants were identified in eight genes among the women with peripartum cardiomyopathy.  The prevalence of these variants in women with peripartum cardiomyopathy (15%) were similar to that of patients with dilated cardiomyopathy (17%, P=0.81) and more common than a healthy population (4.7%, P = 1.3×10−7). Two-thirds of these variants were in the gene TTN which encodes for the very large structural cardiac sarcomeric protein titin.  Seven of these TTN variants had been previously described in patients with dilated cardiomyopathy.  Furthermore, TTN truncating variants in women with peripartum cardiomyopathy were correlated with a lower ejection fraction at 1-year follow-up (P = 0.005).


In this study of a well-characterized cohort of women with peripartum cardiomyopathy, genetic variants of the structural protein titin, which have previously been described in dilated cardiomyopathy, were implicated in development of the peripartum cardiomyopathy.  Further characterization of the pathophysiology and genetics of this condition will afford better risk prediction and may eventually lead to more targeted therapeutics.

Summarized by Hussain Contractor and Steven M. Bradley

Ware JS, Li J, Mazaika E, Yasso CM, DeSouza T, Cappola TP, Tsai EJ, Hilfiker-Kleiner D, Kamiya CA, Mazzarotto F, Cook SA, Halder I, Prasad SK, Pisarcik J, Hanley-Yanez K, Alharethi R, Damp J, Hsich E, Elkayam U, Sheppard R, Kealey A, Alexis J, Ramani G, Safirstein J, Boehmer J, Pauly DF, Wittstein IS, Thohan V, Zucker MJ, Liu P, Gorcsan J 3rd, McNamara DM, Seidman CE, Seidman JG and Arany Z. Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies. N Engl J Med. 2016 Jan 6. [Epub ahead of print]

TAVR adoption and outcomes in German national practice

29 Feb, 16 | by flee

The advent of transcatheter aortic valve replacement (TAVR) has afforded an alternative to surgical aortic valve replacement (SAVR) for high-risk or non-operative candidates for aortic valve surgery.  However, the adoption of TAVR may not be limited to the patient population for who the procedure has studied and outcomes in routine clinical practice may not reflect those of prior randomized trials. In this retrospective study including data on all TAVR and SAVR procedures in Germany from 2007 to 2013, the authors examine the use of these procedures in clinical practice and associated patient outcomes.  A total of 32,581 TAVI and 55,992 SAVR (without concomitant revascularization) were performed during this period.  Use of TAVR increased from 144 procedures in 2007 to 9147 in 2013, while the number of SAVRs decreased from 8622 to 7048 over the same period.  Compared with patients receiving SAVR, patients receiving TAVR were older (81.0±6.1. years vs 70.2±10.0 years) and higher risk as assessed by logistic EuroScore (22.4% vs 6.3%).  Over the period of study, in-hospital mortality following TAVR decreased from 13.2% to 5.4%.  Concurrently, in-hospital mortality following SAVR declined from 3.8% to 2.2%.  Importantly, the risk-score for patients undergoing TAVR increased over time, suggesting improvements in mortality were not a result of increasing use of TAVR in a lower risk population.  Complications of permanent pacemaker implantation were higher following TAVR (17.7% vs. 4.0%, P<0.001) as were rates of stroke (2.5% vs. 1.8%, P<0.001), and acute kidney injury (5.5% vs. 3.0%, P<0.001) while bleeding events were less frequent following TAVR (8.2% vs. 14.0%,  P<0.001).


In a nationwide evaluation of TAVR and SAVR performed in Germany between 2007 and 2013, there was a large increase in the use of TAVR that did not appear related to expanded use in lower risk patients.  Furthermore, outcomes of both TAVR and SAVR improved during this period.  These findings are consistent with a learning curve in the use of TAVR and highlight the importance of continued evaluation of the use and outcomes of this procedure in routine practice to ensure optimal patient care.

Summarized by Hussain Contractor and Steven M. Bradley

Reinöhl J, Kaier K, Reinecke H, Schmoor C, Frankenstein L, Vach W, Cribier A, Beyersdorf F, Bode C and Zehender M. Effect of Availability of Transcatheter Aortic-Valve Replacement on Clinical Practice. N Engl J Med. 2015 Dec 17;373(25):2438-47.

Effect of caloric restriction on heart failure with preserved ejection fraction

2 Feb, 16 | by flee

Therapies that improve outcomes are lacking for heart failure with preserved ejection fraction (HFpEF). The impact of exercise and diet interventions on HFpEF patients has not been studied.  In this single center study of 100 patients,  the effect of caloric restriction (~400 kcal/day) and or aerobic exercise training (3x a week hour long supervised sessions) on co-primary outcomes of exercise capacity (measured by peak oxygen consumption) and quality of life (QOL) (measured by the Minnesota Living with Heart Failure Questionnaire) were evaluated using a 2×2 factorial design,.  Additional exploratory outcomes included: exercise time, 6-minute walk distance, ventilator anaerobic threshold, ventilation/carbon dioxide output slope, other QOL measures (Kansas City Cardiomyopathy Questionnaire, 36-item Short-Form Health Survey), and left ventricular mass and volume. Patient included were obese (BMI >30) with HFpEF (EF ≥ 50%) without segmental wall motion abnormalities, significant valvular or ischemic disease, or pulmonary disease.  The majority of patients in this trial were female, NYHA class II or III, hypertensive, and on diuretic therapy.Both diet and exercise interventions significantly increased exercise capacity (peak VO2, diet 1.3ml/kg body mass/min, 95% CI 0.8-1.8, P <0.001 and exercise, 1.2ml/kg body mass/min, 95% CI, 0.7-1.7, p <0.001) and had an additive effect with improvement in peak VO2 of 2.5ml/kg/min.  There was no difference in QOL by MLHF with either diet or exercise (exercise, -1 unit, 95% -8-5, p 0.7; diet -6 unit, -12-1, p 0.08).


Conclusion: Although the 20-week diet and exercise interventions improved peak VO2 amongh patients with HFpEF, the lack of improvement in QOL scores raise questions about the clinical significance of these findings.  While diet and exercise may not significantly impact HRpEF symptoms, optimizing diet and exercise remains central to cardiovascular health.


Summarized by Lauren E. Thompson and Steven M. Bradley


Kitzman DW, et al. Effect of Caloric Restriction or Aerobic Exercise Training
on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction
A Randomized Clinical Trial. JAMA. 2016 Jan 5;315(1):36-46

COURAGE at 15 years

2 Feb, 16 | by flee

Although PCI improves morbidity and mortality in the context of an acute coronary syndrome, the benefit of PCI in the setting of stable ischemic heart disease appears limited to symptom relief.  This was best demonstrated by the COURAGE trial that randomized 2287 patients with stable angina to either intensive medical therapy alone or medical therapy with PCI.  The study found symptom reduction was greater in the first 6 to 24 months following PCI, but PCI did not impact cardiovascular events or all cause survival.  A prior follow-up study of COURAGE patients suggested mortality at 5 years may have been trending toward benefit with PCI.  In the current study, 15 years of survival data was gathered on 1211 patients (53% of the original cohort) with nearly all of these patients coming from the U.S. Veterans Affairs system.  In this cohort, a total of 561 deaths had occurred in follow-up with 284 deaths (25%) in the PCI group and 277 (24%) in the medical-therapy group (HR, 1.03; 95% CI, 0.83 to 1.21; P=0.76); demonstrating no long-term survival advantage with PCI for stable ischemic heart disease. Data on cause of death and any additional therapies such as PCI or CABG outside of the initial 5yr trial period were unavailable.


Conclusions: In 15-year follow-up of approximately half of the original COURAGE trial cohort, there was no difference in mortality between those randomized to PCI and medical therapy.  Ongoing studies will inform whether PCI can improve outcomes beyond symptom burden when targeted to patients with significant demonstrable ischemia.


Summarized by Hussain Contractor and Steven M. Bradley


Sedlis SP, Hartigan PM, Teo KK, Maron DJ, Spertus JA, Mancini GB, Kostuk W, Chaitman BR, Berman D, Lorin JD, Dada M, Weintraub WS and Boden WE. Effect of PCI on Long-Term Survival in Patients with Stable Ischemic Heart Disease. N Engl J Med. 2015 Nov 12;373(20):1937-46.

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