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Cholesterol Lowering in Intermediate-risk Persons without Cardiovascular Disease.

11 Jul, 16 | by flee

Implementation of statin therapy in practice for primary prevention of cardiovascular disease is controversial due to concerns over costs and side-effects with broader use and uncertainty regarding LDL goals in the primary prevention population. Previous primary prevention trials suggest a reduction in cardiovascular outcomes in largely white patients with significant risk factors for coronary disease. The HOPE-3 trial randomized a diverse population of 12,000 individuals over 55 years of age (women over 60) with 1-2 relatively modest risk factors for cardiovascular disease (annual risk ~1%) but otherwise no indication for statin therapy to 10 mg of rosuvastatin daily vs placebo. The composite primary outcome was death from cardiovascular causes, non- fatal MI or stroke. Nearly 13% of patients were excluded following roll-in based on side-effects or lab abnormalities. For remaining patients, over median follow of 5.6 years there was a significant reduction in the primary endpoint: 3.7% vs 4.8% favoring treatment (HR 0.76 [CI 0.64-0.91]) with a NNT of 91. An expanded ‘co-primary’ outcome which also included heart failure, revascularization and resuscitated cardiac arrest resulted in a NNT of 73. Of note, there was a significant increase in muscle aches and weakness in the rosuvastatin group (5.8% vs 4.7%) but this did not clearly impact drug discontinuation, which was common at 23.7%. In fact, therapy discontinuation was 2.5% higher in the placebo group. Myopathy or rhabdomyolysis events were very rare, but there was a significant increase in cataracts in the rosuvastin group.

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Genetic variant protects against coronary disease

11 Jul, 16 | by flee

The links between cholesterol and coronary artery disease are well established and incontrovertible, with modification of serum LDL cholesterol levels repeatedly shown to reduce risk of myocardial infarction and cardiovascular death. But total non-HDL cholesterol levels, encompassing multiple other lipid fractions including Lp(a) and chylomicrons, have the strongest overall association with the risk of incipient coronary artery disease. In this large genome-wide association study, the authors identify a novel noncoding 12-base-pair deletion in intron 4 of the ASGR1 gene that appears to be associated with lower levels of non-HDL cholesterol.  In an initial discovery cohort of 2636 Icelanders, the polymorphism was associated with a reduced risk of atherosclerotic coronary disease. Further testing in a cohort of 398,000 Icelanders demonstrated a prevalence of heterozygous carriers of approximately 1 in 120. These carriers had lower levels of non-HDL cholesterol and a significant 34% reduction in rates of coronary artery disease (95% CI, 21 to 45; P=4.0×10(-6)).  To further validate these associations, five other large European cohorts containing a total of 42,524 case patients and 249,414 controls were analyzed with results consistent to those seen in the Icelandic cohort.  Finally, the authors describe a second loss of function polymorphism in the same ASGR1 gene that again leads to significantly reduced levels of non-HDL cholesterol in carriers, validating their initial hypothesis that ASGR1 is directly implicated in non-HDL cholesterol homeostasis.

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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.

 

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Heart’s Twitter Journal Club

8 Jul, 16 | by James Rudd

TwitterLogo_#55aceeJoin in our Journal Club on Twitter and engage with readers from across the world!

Each month we will discuss a paper from Heart.

We will select a recent paper ahead of time and then discuss four different aspects of it for about 15 minutes each.

The paper under discussion will be free to access for a week prior to the Journal Club.

Feel free to join the next journal club – they happen monthly, on the first Thursday of each month at 8PM GMT). All Welcome!


To join in you will need to have a Twitter account. To sign up to Twitter, click here (it doesn’t take long and make sure you follow us –@Heart_BMJ).

When it comes to the tweet chat itself, we suggest you use tchat.io. This is a specific site used for tweetchats as it cuts out all the other distractions on Twitter. Log into tchat.io using your Twitter details, then type #HeartJC into the search bar. This pulls up all the tweets using the hashtag. You can tweet from here and it will automatically add the correct hashtag at the end of each tweet for those overexcited tweeps!

You can otherwise tweet using Twitter, but you need to make sure you add the hashtag to each tweet otherwise we won’t see it.

Follow Heart (@Heart_BMJ) for all the latest updates on Twitter. The Journal Club tweets can be identified by the hashtag #HeartJC


The following links take you to transcripts of the discussions and related Analytics, for those interested.

2016

May 5th – Transcript: Chocolate and MI risk and Analytics: Symplur

June 2nd – Transcript : Exercise and Heart Disease and Analytics : Symplur

July 7th – Transcript : Gender differences in CAD and Analytics : Symplur

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)

Conclusions

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).

Conclusions

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]

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