You don't need to be signed in to read BMJ Blogs, but you can register here to receive updates about other BMJ products and services via our site.

A new PARADIGM in heart failure treatment?

14 Oct, 14 | by Alistair Lindsay

Natriuretic peptides are released in response to cardiac-wall stress and other stimuli of heart failure. These potent natriuretic and vasodilatory peptides also inhibit the renin-angiotensin system and sympathetic drive. The neutral endopeptidase neprilysin is responsible for the degradation of several of these natriuretic peptides. Inhibition of neprilysin increases the level of these natriuretic peptides, thus potentially enhancing the beneficial effects of standard therapies to suppress the renin angiotensin system. In the PARADIGM-HF randomized controlled trial, the ACE inhibitor enalapril at a dose of 10mg twice a day was compared with the experimental drug LCZ696, which was a combination of the ARB valsartan and the neprilysin inhibitor sacubitril. This combination was chosen in response to prior studies that demonstrated combining a neprilysin inhibitor with an ARB reduced the risk of angioedema. A total of 8442 patients with an ejection fraction less than 35%, with NYHA class II (70%), III or IV symptoms, and who were already receiving evidence based therapy for heart failure, were randomly assigned in a double-blind fashion to receive enalapril or LCZ696. The primary end-point was a composite of death from cardiovascular causes and heart failure hospitalization. The trial was stopped early on the recommendation of the data safety monitoring committee at a median follow-up of 27 months due to evidence of an overwhelming benefit with LCZ696. Patients in the LCZ696 group were less likely to die from any cause (17.0% vs. 19.8%, HR 0.84; 95% CI, 0.76 to 0.93; P<0.001) or die from a cardiovascular cause (13.3% vs. 16.5%, HR 0.80; 95% CI, 0.71 to 0.89; P<0.001). LCZ696 also significantly decreased symptoms and improved quality of life indices (P=0.001), and decreased hospitalizations by 21% (P<0.001). The number-needed-to-treat to avoid one primary end-point event was 35. LCZ696 also demonstrated no significant increase in angioedema over enalapril and lower overall rates of renal impairment, hyperkalemia, and cough.

Conclusions: In this large, well-conducted randomized study, LCZ696 was superior to enalapril in reducing mortality among patients with heart failure and a reduced ejection fraction. LCZ696 represents a novel agent for heart failure management that may change the paradigm of best-practices for systolic heart failure therapy.

Summarized by Hussain Contractor and Steven M. Bradley

  • McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004.

No benefit to thrombus aspiration in STEMI

14 Oct, 14 | by Alistair Lindsay

Thrombus aspiration in acute ST-segment elevation myocardial infarction (STEMI) is clinically appealing and often used prior to PCI. However, the majority of trials evaluating thrombus aspiration have failed to demonstrate significant mortality benefit. The Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial is a multi-center study that randomized a total of 7244 presenting with a STEMI for primary PCI to either thrombus aspiration or PCI without prior aspiration. From this trial, the authors have previously reported no significant mortality difference at 30 days between routine thrombus aspiration and standard PCI. This publication is the 1-year follow-up data from the TASTE trial. At 1-year, there were no significant differences between aspiration and PCI alone for the outcomes of all-cause mortality (5.3% vs 5.6%; HR, 0.94; 95% CI, 0.78 to 1.15; P=0.57), recurrent myocardial infarction (2.7% vs. 2.7%, P=0.81) or stent thrombosis (0.7% vs. 0.9%, P=0.51). These results were consistent across all subgroups, including subgroups characterized by high TIMI thrombus burden where aspiration might be expected to have greater benefits.

Conclusions: In this large, well-conducted randomized controlled trial, mechanical thrombus aspiration demonstrated no benefit over standard PCI among patients presenting with STEMI. Although additional trials are ongoing, the weight of evidence increasingly suggests aspiration thrombectomy provides little to no benefit among patients with STEMI.

Summarized by Hussain Contractor and Steven M. Bradley

  • Lagerqvist B, Fröbert O, Olivecrona GK, Gudnason T, Maeng M, Alström P, Andersson J, Calais F, Carlsson J, Collste O, Götberg M, Hårdhammar P, Ioanes D, Kallryd A, Linder R, Lundin A, Odenstedt J, Omerovic E, Puskar V, Tödt T, Zelleroth E, Östlund O, James SK. Outcomes 1 year after thrombus aspiration for myocardial infarction. N Engl J Med. 2014 Sep 18;371(12):1111-20.

Patient Understanding of Elective PCI Benefit Varies by Hospital  

14 Oct, 14 | by Alistair Lindsay

Elective percutaneous coronary intervention (PCI) does not prevent mortality or myocardial infarction, but is an important therapy for the relief of ischemic symptoms.   However, a majority of patients believe that PCI for stable coronary artery disease (CAD) will prolong their lives and prevent heart attacks. In this study, investigators surveyed 991 patients undergoing elective PCI for stable CAD at 10 hospitals to assess patient perceptions about the procedure and determine if patient understanding of procedural benefit was associated with the PCI operator or the hospital. Patients believed that their elective PCI was emergent in 20% of cases, 90% of patients felt that the PCI would prolong their life, and 88% felt that elective PCI would prevent future heart attacks, while only 1% correctly identified symptom improvement as the primary benefit of the procedure. Patient beliefs about the benefits of elective PCI varied at the hospital level, but similar variation was not observed across operators within sites.

Conclusions: Hospital-level variation in patient perceptions of the benefits of elective PCI suggests a role for hospital-level interventions to improve patient understanding of their procedure.

Summarized by Javier A. Valle and Steven M. Bradley

  • Kureshi, F., et al., Variation in patients’ perceptions of elective percutaneous coronary intervention in stable coronary artery disease: cross sectional study. BMJ, 2014. 349: p. g5309.

PatientsUnderstandingPCI

Transcatheter aortic valve implantation – are we moving from equivalent to preferred in high-risk surgical patients?

23 Jul, 14 | by Alistair Lindsay

Transcatheter aortic valve implantation (TAVI) has expanded the options for the treatment of severe aortic stenosis, particularly in patients for whom the surgical risk of valve replacement is felt to be prohibitive.  Prior studies have demonstrated TAVI reduces mortality relative to medical management among patients unable to undergo valve surgery.  Among patients considered to be at high surgical risk, TAVI has been shown to have similar 1-year survival compared to surgery, but associated with a higher rate of stroke.  In this study of the CoreValve self-expanding transcatheter bioprosthethic valve, patients deemed to be at high surgical risk (estimated risk of death ≥ 15% within 30 days of surgery) were randomized in a 1:1 fashion to either TAVI or surgical valve replacement.  The primary end-point was mortality at 1 year.  A total of 795 patients were randomized at 45 experienced US centers.  Although the trial was powered for non-inferiority, TAVI demonstrated an absolute 1-year mortality reduction of 4.9% (14.2% vs. 19.1%) demonstrating not only non-inferiority (P<0.001), but actual superiority (P=0.04).  In additional analyses, paravalvular leak was more common in TAVI patients, while quality of life indices and rates of stroke were similar in TAVI and surgical patients.

Conclusions

In this study of the CoreValve bioprosthesis, 1-year survival was greater among patients with severe aortic stenosis and high operative risk treated with TAVI in comparison to conventional surgical valve replacement.  We now await studies evaluating the outcome of TAVI in lower risk patients with severe aortic stenosis.

Summarized by Steven M. Bradley and Hussain Contractor

  • Adams DH, Popma JJ, Reardon MJ, Yakubov SJ, Coselli JS, Deeb GM, Gleason TG, Buchbinder M, Hermiller J Jr, Kleiman NS, Chetcuti S, Heiser J, Merhi W, Zorn G, Tadros P, Robinson N, Petrossian G, Hughes GC, Harrison JK, Conte J, Maini B, Mumtaz M, Chenoweth S and Oh JK. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med. 2014 May 8;370(19):1790-8.

Cryptogenic stroke due to undetected atrial fibrillation – longer ECG monitoring may be the key

23 Jul, 14 | by Alistair Lindsay

Up to 40% of ischemic strokes remain unexplained after routine evaluation and thus are considered cryptogenic. However, a number of these strokes may be due to an undetected episode of paroxysmal atrial fibrillation (AF) where anticoagulation can reduce the risk of subsequent ischemic stokes. Although a minimum of 24 hours of ECG monitoring is guideline recommended in the evaluation of ischemic stroke to identify AF, the optimal duration of monitoring remains undetermined. Among patients with cryptogenic stroke, two concurrent publications evaluated the AF diagnostic yield of extended ECG monitoring.

In the first study, 572 patients with a history of cryptogenic stroke or transient ischemic attack in the prior 6 months were randomized to 30-day event triggered ECG monitoring or 24-hour ECG monitoring. Among patients with 30-day monitoring, an episode of AF lasting at least 30 seconds was identified in 16.1% of patients compared with 3.2% in 24-hour monitoring (absolute difference, 12.9 percentage points; 95% confidence interval [CI], 8.0 to 17.6; P<0.001; number needed to screen, 8). In the second study, 441 patients with cryptogenic stroke and 24 hours of ECG monitoring as part of the initial work-up were randomized to additional monitoring with an implantable loop recorder device with an AF detection algorithm or conventional follow-up during which any further monitoring was decided by local policy. The trial’s primary end-point was the time to first detection of AF (at least 30 seconds in duration).   At 6 months there was a marked difference in AF detection between groups with AF detected in 8.9% of patients monitored with an implantable loop recorder versus 1.4% of the control group (HR, 6.4; 95% CI, 1.9 to 21.7; P<0.001). By 12 months this difference in AF detection had increased to 12.4% in monitored patients versus 2.0% in controls (HR 7.3, 95% CI 2.6 to 20.8; P<0.001). The preponderance of detected AF episodes were asymptomatic in this trial.

Conclusions

In the evaluation of patients with cryptogenic stroke, prolonged ECG monitoring resulted in markedly increased rates of AF detection. Future studies are needed to both identify patient populations most likely to benefit from prolonged ECG monitoring and the outcome implications of improved AF detection in cryptogenic stroke.

Summarized by Steven M. Bradley and Hussain Contractor

  • Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, Hall J, Vaid H, O’Donnell M, Laupacis A, Côté R, Sharma M, Blakely JA, Shuaib A, Hachinski V, Coutts SB, Sahlas DJ, Teal P, Yip S, Spence JD, Buck B, Verreault S, Casaubon LK, Penn A, Selchen D, Jin A, Howse D, Mehdiratta M, Boyle K, Aviv R, Kapral MK, Mamdani M; EMBRACE Investigators and Coordinators. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 2014 Jun 26;370(26):2467-77

Opinion based guideline recommendations less likely to stand the test of time

29 Jun, 14 | by Alistair Lindsay

Limited data exists on how frequently guidelines change over time. This study examined how frequently class I recommendations (“procedure/treatment should be performed/administered”) in ACC/AHA guidelines were downgraded to a lower class over time. Four independent reviewers examined 619 class I ACC/AHA recommendations in 11 guidelines released between 1998-2007 and revised between 2006-2013. Overall, 495 recommendations (80.0%; 95% CI 76.6% – 83.1%) were retained in subsequent versions, 57 (9.2%; 95% 7.0% – 11.8%) were downgraded or reversed, and 67 (10.8%; 95% CI 8.4% – 13.3%) were omitted. Compared to recommendations based on multiple randomized trials, the probability of a guideline recommendation being omitted, reversed or downgraded was higher for recommendations based on opinion (OR 3.14; 95% CI 1.69-5.85) or on 1 trial or observational data (OR 3.49; 95% CI 1.45-8.40).

Conclusion: 1 in 5 class I guideline recommendations are omitted, reversed, or downgraded over time.  These changes in guidelines are far more common for recommendations based on little to no randomized trial data.  These findings question the wisdom of class I indications in the absence of solid evidence to support the recommendation.

 Summarized by Supriya Shore and Steven M. Bradley

  • Neuman MD, Goldstein JN, Cirullo MA, Schwartz JS. Durability of class I American College of Cardiology/American Heart Association clinical practice guideline recommendations. JAMA. May 28 2014;311(20):2092-2100.

Differences in Statin Eligible Patients across Guidelines

29 Jun, 14 | by Alistair Lindsay

Recent ACC/AHA guidelines recommend consideration of statin therapy among patients with a 7.5% 10-year risk of atherosclerotic cardiovascular disease (CVD).  In this study, the authors examined implications of these new guidelines as compared with previous European Society of Cardiology (ESC) and Adult Treatment Panel III (ATP III) guidelines in a Dutch population-based prospective cohort of 4,854 healthy participants over 55 years of age. In this cohort,  96.4% men and 65.8% women would be recommended statinsunder the new ACC/AHA guidelines. In contrast, 66.1% of men and 39.1% of women would be recommended statins under ESC guidelines and 52.0% of men and 35.5% of women would be recommended statins by ATP III guidelines.  Subgroup analyses demonstrated under ACC/AHA guidelines nearly all women age 65 or older would be recommended statin therapy.

Conclusion: Application of the new ACC/AHA CVD prevention guidelines to a Dutch cohort found that nearly all men age 55 or older and women age 65 or older were candidates for statin therapy.  This was a dramatic increase in statin eligible patients relative to prior ESC and ATP III guidelines. Given the near uniform statin recommendation at these age cutoffs, these findings raise questions as to the utility of the new ACC/AHA CVD risk prediction model in guiding treatment decisions.

 Summarized by Supriya Shore and Steven M. Bradley

  • Kavousi M, Leening MJ, Nanchen D, et al. Comparison of application of the ACC/AHA guidelines, Adult Treatment Panel III guidelines, and European Society of Cardiology guidelines for cardiovascular disease prevention in a European cohort. JAMA. 2014;311(14):1416-1423.

Validation of the Pooled Cohort Risk Equations from Recent ACC/AHA Guidelines

29 Jun, 14 | by Alistair Lindsay

Recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the assessment of cardiovascular risk recommend a new 10-year atherosclerotic cardiovascular disease (CVD) risk prediction tool called the Pooled Cohort risk equation. This new predictive model developed from cohorts of patients that were largely studied prior to the year 2000.  In light of the declining CVD incidence since 2000, the external validity of the Pooled Cohort risk equation has been questioned.  The present study sought to validate the Pooled Cohort equation in a contemporary cohort of 10,997 individuals aged 45-79 years without a prior history of atherosclerotic CVD for whom the guidelines would recommend consideration of a statin.  In 47,481 person-years of follow-up, 192 coronary heart disease events and 146 strokes were observed. Differences in observed and predicted risk were small in patients for whom a statin should be considered, consistent with good model calibration.  Further, the C-index was 0.72 (95% CI 0.70 – 0.75) consistent with moderate discrimination.

Conclusion: The recently published Pooled Cohort risk equations recommended by ACC/AHA guidelines demonstrated good calibration and discrimination among individuals who should be considered for statin therapy.  These findings support the validity of the model among patients being considered for statin therapy.

 Summarized by Supriya Shore and Steven M. Bradley

  • Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations. JAMA. 2014;311(14):1406-1415.

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.

Latest from Heart

Latest from Heart

Cardiology Masterclasses

Cardiology Masterclasses