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Outcomes with increased length of dual antiplatelet therapy after PCI  

20 Dec, 14 | by Alistair Lindsay

The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is uncertain. Although observational studies have suggested DAPT for longer than a year post-PCI reduces ischemic events, other studies suggest longer durations of DAPT confer no benefits despite increased bleeding risk. This randomized controlled trial evaluated patient outcomes with 12-months vs 30-months of DAPT after PCI. A total of 22866 patients after PCI with a drug-eluting stent (approximately 40% in the context of an ACS) were enrolled. After 12 months of standard DAPT (with either clopidogrel or prasugrel alongside aspirin) a total of 9961 patients who had tolerated DAPT without complications and who had not undergone any further procedures were randomly assigned to continue receiving DAPT treatment or to aspirin and placebo for an additional 18 months. The co-primary end-point was stent thrombosis and major adverse cardiovascular events (MACE) with a primary safety end-point of moderate or severe bleeding. Long-term continuation of DAPT significantly reduced the rate of stent thrombosis (0.4% vs. 1.4%; HR, 0.29 [95% CI, 0.17 to 0.48]; P<0.001) and MACE (4.3% vs. 5.9%; HR, 0.71 [95% CI, 0.59 to 0.85]; P<0.001) with an approximate 50% reduction in infarcts related to the non-stented artery (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). This reduction in ischemic events did not translate into all-cause mortality benefit, potentially due to an excess of malignancies in the DAPT group (2.0% vs. 1.5%, HR, 1.36 [95% CI, 1.00 to 1.85]; P=0.052). Bleeding events with extended DAPT were more frequent (2.5% vs. 1.6%, P=0.001).

Conclusions: Extending DAPT to 30 months after PCI reduces the risk of stent thrombosis and myocardial infarction among patients who have already tolerated 12 months of DAPT well. These benefits are balanced by an increased bleeding risk and no overall mortality benefit. Future study may guide approaches to select patients for which the benefits of extended DAPT outweigh the risks.

Summarized by Hussain Contractor and Steven M. Bradley

 

Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR Jr, Krucoff MW, Hermiller J,Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Lee PV, Rinaldi MJ, Massaro JM; the DAPT Study Investigators. Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents. N Engl J Med. 2014 Dec 4;371(23):2155-66.

Long-term outcomes of mechanical versus bioprosthetic aortic valve replacement in younger adults  

20 Dec, 14 | by Alistair Lindsay

Younger adults requiring aortic valve replacement often receive a mechanical valve given concerns over durability of bioprosthetic valves. However, prior studies have been underpowered to compare long-term survival implications of mechanical versus bioprosthetic valve replacement in younger adults. In this retrospective cohort from the New York Statewide Planning and Research Cooperative System (SPARCS) , 4253 patients age 50-69 receiving surgical aortic valve replacement (AVR) were studied to determine the relationship between valve type (bioprosthetic vs mechanical) and all-cause mortality. From this cohort, 1001 pairs of patient were matched on propensity scores for bioprosthetic valve replacement as determined from nonparsimonious hierarchical regression modeling accounting for clustering of patients within surgeons. In addition to assessing for adequacy of matching on propensity scores using statistical methods, 30-day complication rates were similar in the matched groups consistent with balanced operative risk. During the study period, the proportion of patients who underwent bioprosthetic AVR increased from 15% in 1997 to 74% in 2012. Over a median follow-up of 10 years, there was no difference in overall survival (p=0.74) with 15-year actuarial survival 60.6% (95% CI, 56.3%-64.9%) in the bioprosthetic group compared to 62.1% (95% CI, 58.2%-66.0%) in the mechanical prosthesis group (HR=0.97; 95% CI 0.83-1.14). For secondary endpoints there was no significant different risk for stroke (ischemic or hemorrhagic) (P=0.84), the mechanical group demonstrated a higher risk of major bleeding with cumulative incidence at 15 years of 13.0% (95% CI, 9.9%-16.1%) in mechanical group compared with 6.6% (95% CI, 48% vs 8.4%) in bioprosthetic group. The bioprosthetic group had a higher risk of reoperation with cumulative incidence of 12.1% (95%CI, 8.8%-15.4%) vs 6.9% (95% CI, 4.2%-9.6%) in the mechanical group. These findings persisted when extended to comparisons among the entire cohort.

Conclusions: Use of bioprosthetic valves is increasing among patients 50-69 years old. Long-term survival is similar between patients receiving bioprosthetic and mechanical aortic valves, at a tradeoff of greater bleeding risk with mechanical valves and greater reoperation risk with bioprosthetic valves. The reoperation risk of bioprosthetic aortic valve replacement may become less pertinent in the near future given advancing options for transcutaneous valve replacement.

 Summarized by Lauren E. Thompson and Steven M. Bradley

Chiang YP, Chikwe J, Moskowitz AJ, Itagaki S, Adams DH, Egorova NN. Survival and Long-term Outcomes Following Bioprosthetic vs Mechanical Aortic Valve Replacement in Patients Aged 50 to 69 Years. JAMA. 2014;312(13):1323-1329. doi:10.1001/jama.2014.12679.

Ivabradine ineffective as add-on therapy for stable ischemic heart disease  

20 Dec, 14 | by Alistair Lindsay

Ivabradine reduces heart rate without affecting blood pressure or left ventricular systolic performance. Given studies demonstrating a relationship between heart rate and cardiovascular risk, modifying heart rate with ivabradine may reduce risk in patients with coronary disease. In the Study Assessing the Morbidity–Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) trial, patients with coronary artery disease, a heart rate of 70 bpm or more, and without heart failure, were studied to assess whether they would benefit from ivabradine. In this large international randomized controlled trial,19102 eligible patients were randomized to placebo or ivabradine up to 10mg twice daily (mean dose 8.2±1.7 mg twice daily) in addition to standard therapy that included beta-blockers in over 80% of patients. The dose of ivabradine was titrated to achieve a resting heart rate between 55 and 60 bpm and the primary end-point was a composite of death from cardiovascular causes or nonfatal myocardial infarction. At a median follow-up of 27.8 months, there was no significant difference between ivabradine and placebo in the incidence of cardiovascular death or non-fatal myocardial infarction (6.8% and 6.4%, respectively; HR 1.08; 95% CI, 0.96 to 1.20; P=0.20). Ivabradine was associated with an increased rate of adverse events, including symptomatic bradycardia (7.9%, vs. 1.2%; p<0.001) and atrial fibrillation (5.3% vs. 3.8%; p<0.001).

Conclusion: In patients with stable coronary artery disease, the addition of ivabradine to standard therapy did not reduce rates of cardiovascular death or non-fatal myocardial infarction and increased rates of adverse events. These findings also highlight that heart rate is likely a marker, rather than a mediator, of cardiovascular risk.

Summarized by Hussain Contractor and Steven M. Bradley

Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R; SIGNIFY Investigators. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014 Sep 18;371(12):1091-9.

 

 

Long-term benefit with blood pressure control, but not tight glucose control, in established type 2 diabetics  

20 Dec, 14 | by Alistair Lindsay

Prior studies of type 1 diabetics and newly diagnosed type 2 diabetics have suggested long-term reduction in mortality and macrovascular event risk resulting from earlier periods of tight glucose control. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, blood pressure control in patients with type 2 diabetes resulted in lower risk of death, macrovascular, and microvascular events. However, this study did not find similar benefit from tight glycemic control. The present study extends the observation of patients in this trial to 6-years after completion of the trial to assess for a long-term benefit associated with a period of tight glycemic control. Of the 10261 patients eligible for continuation, 8494 consented to continued observation. Between-group differences in blood pressure and glycemic control observed during the trial period were no longer evident by the first post-trial visit (median of 3.5 years after completion of the trial). Over a median follow-up of nearly 6 years (for a total of nearly 10 years including time in trial), patients in the blood pressure treatment group demonstrated a significant reduction in their risk of death or death from cardiovascular causes (HR=0.91, 95% CI, 0.84 to 0.99; P=0.03). Similar benefit was not observed for patients previously randomized to tight glycemic control (HR=1.00, 95% CI, 0.92 to 1.08). However, a period of tight glycemic control was associated with a lower risk of end-stage renal disease (HR 0.54; 95% CI, 0.34 to 0.85; P = 0.007).

 Conclusions: In this large study of patients with established type 2 diabetes, a period of tight glycemic control was not associated with reduced mortality or macrovascular risk in 10-years of follow-up. In light of prior studies, these findings suggest the relative benefit of glycemic control may be influenced by how long a patient has had underlying diabetes. Relative to glycemic control, blood pressure control appears to be a larger contributor to reducing cardiovascular risk in patients with established diabetes.

Summarized by Hussain Contractor and Steven M. Bradley

Zoungas S1, Chalmers J, Neal B, Billot L, Li Q, Hirakawa Y, Arima H, Monaghan H, Joshi R, Colagiuri S, Cooper ME, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Lisheng L, Mancia G, Marre M, Matthews DR, Mogensen CE, Perkovic V, Poulter N, Rodgers A, Williams B, MacMahon S, Patel A, Woodward M; ADVANCE-ON Collaborative Group. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014 Oct 9;371(15):1392-406.

Trends in the Use of Stress Testing in the United States  

20 Dec, 14 | by Alistair Lindsay

Stress testing is a cornerstone in the evaluation of patients with possible symptoms of ischemic heart disease. The use of stress tests, and stress tests with imaging in particular, has increased over time raising concerns for inappropriate use that may include screening stress tests in asymptomatic patients. This study evaluated trends in the use of stress testing between 1993 and 2010 in the United States using data from the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS). The primary outcome was the referral or performance of a stress test, with a subgroup evaluation of stress testing with imaging. Diagnosis codes and reasons for office visits were identified including the presence or absence of chest pain. Finally, the study evaluated the appropriateness of stress tests using appropriate use criteria that were collaboratively developed by a number of cardiovascular professional societies. Use of stress testing increased during the study period (28 per 10000 visits in 1993-1995 up to 45 per 10000 visits in 2008-2010), however this trend did not reach statistical significance when adjusted for patient and provider characteristics (p=0.134). The proportion of stress tests performed with imaging increased from 59% to 87% over the same timeframe and this trend was not explained by patient or provider characteristics. Appropriateness assessment determined 30% of the stress tests with imaging were inappropriate (i.e. no anticipated patient benefit) as compared with 14% of those without imaging.

Conclusions: Stress testing with imaging in the U.S. has increased at a rate that is not explained by changes in patient characteristics with nearly a third of these tests being considered inappropriate, consistent with procedural overuse. Given the challenges of assessing symptom burden from structured data fields taken from visit codes, incorporation of patient-reported symptom burden may guide a more nuanced understanding of potential overuse of stress testing in future studies.

Summarized by Javier A. Valle and Steven M. Bradley

 

Ladapo, J.A., S. Blecker, and P.S. Douglas, Physician Decision Making and Trends in the Use of Cardiac Stress Testing in the United States: An Analysis of Repeated Cross-sectional Data. Ann Intern Med, 2014. 161(7): p. 482-90.

Risks and Benefits of Percutaneous Coronary Interventions in Stable Coronary Disease: A Qualitative Analysis of Cardiologists’ Bedside Discussions  

20 Dec, 14 | by Alistair Lindsay

Although the benefits of PCI for stable CAD are limited to symptom reduction, prior studies have shown that patients often believe PCI for stable coronary artery disease (CAD) will mitigate the future risks of myocardial infarction or death. This study examined discussions between cardiologists and patients regarding angiograms and PCI in stable CAD to identify potential areas of misperception. Qualitative content analysis was performed on transcripts created from recordings of 40 patient-provider encounters with cardiologists participating in the Verilogue Point-of-Practice Database. Physician-patient encounters were coded for five major categories and subcategories that may explain patients’ perceptions of PCI benefit including the rationale for recommending the procedure, a discussion of benefits, a discussion of risks, provider communication style, and patients and family members contributions to the discussion. Cardiologist employed a range of accurate and empathic approaches to discussing consideration of PCI (e.g., “people have this misconception if they get a stent, they’re going to live longer. That’s not true. The main thing stents do is they prevent symptoms.”). However, this qualitative study also found evidence of implicit and explicit inaccuracies (e.g., claiming PCI “fixes the problem” or reduces risk of future heart attack) as cardiologists discussed consideration of PCI with stable CAD patients.

Conclusions: Physician discussions may contribute to patient misperceptions in the therapeutic benefit of coronary procedures. Further study of standardized patient decision support tools is warranted to assist patients and providers to achieve evidence based and patient-centric treatment decisions.

 

Summarized by Jehu S. Mathew and Steven M. Bradley

 

Goff SL, Mazor KM, Ting HH, Kleppel R, Rothberg MB. How cardiologists present the benefits of percutaneous coronary interventions to patients with stable angina: a qualitative analysis. JAMA Intern Med. 2014; 174:1614-21.

Dual Antiplatelet Therapy Beyond 1-year after Percutaneous Coronary Interventions for Stable Coronary Artery Disease Results in Harm  

20 Dec, 14 | by Alistair Lindsay

The benefit of extended dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is uncertain. The ARTIC-Interruption Trial examined discontinuation of DAPT at 1-year after PCI vs continuation for an additional 6-18 months. The study randomized patients 1-year after PCI to continuation (N=635) or interruption (N=624) groups, and examined the primary composite endpoint of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization over a median follow-up of 17 months. No significant differences were observed between the treatment groups for the primary outcome (hazard ratio [HR] 1.17; 95% confidence interval [CI] 0.68–2.03]; p=0.58). Bleeding events (as defined by STEEPLE criteria) occurred significantly more frequently in the continuation group (HR 0.26; 95% CI 0.07–0.91; p=0.04) when major and minor bleeding events were combined. As this study was a follow on to an evaluation of antiplatelet regimens guided by platelet reactivity at the time of index PCI, there was variation in the type of DAPT between patients at randomization for this study. Furthermore, there was crossover between treatment arms that was not evaluated with an on-treatment analysis.

Conclusion: These results add to a growing body of literature suggesting harm with extended DAPT beyond 1-year after PCI in the absence of recurrent ischemic events in the year following PCI.

           

Summarized by Jehu S. Mathew and Steven M. Bradley

 

Collet JP, Silvain J, Barthelemy O, Range G, Cayla G, Van Belle E, Cuisset T, Elhadad S, Schiele F, Lhoest N, Ohlmann P, Carrie D, Rousseau H, Aubry P, Monsegu J, Sabouret P, O’Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Beygui F, Vicaut E, Montalescot G, for the Ai. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (arctic-interruption): A randomised trial. Lancet. 2014 Jul 15. pii: S0140-6736(14)60612-7. doi: 10.1016/S0140-6736(14)60612-7. [Epub ahead of print]

Quality of Life following Coronary Artery Bypass Graft Surgery versus Guideline-based Medical Therapy in Ischemic Cardiomyopathy  

14 Oct, 14 | by Alistair Lindsay

It remains uncertain if surgical revascularization improves patient outcomes in the setting of coronary artery disease with reduced systolic function. This is particularly true in light of the STICH trial, a contemporary randomized control trial of coronary artery bypass graft surgery (CABG) with optimal medical therapy compared to optimal medical therapy alone in patients with ischemic left ventricular dysfunction. The primary results of the STICH trial demonstrated no overall mortality benefit to CABG with medical therapy compared to medical therapy alone. In this study, the trial authors report quality of life outcomes from the STICH trial. The trial randomized 1212 patients with an ejection fraction ≤35% with coronary anatomy suitable for surgical revascularization to either CABG with medical therapy or medical therapy alone. Quality of life assessments were performed at 4, 12, 24, and 36 months using validated patient-reported outcome measures, including the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Seattle Angina Questionnaire (SAQ), Center for Epidemiologic Studies Depression Scale, Cardiac Self-Efficacy Questionnaire, and EuroQol-5D. Patients receiving CABG with medical therapy had better quality of life scores in follow-up. Given the challenges of interpreting the clinical importance of these quality of life scores, the authors also reported the proportion of patients who achieved clinically meaningful improvements in KCCQ scores. This analysis demonstrated a number-needed-to-treat with CABG of between 9 and 14 patients to achieve one additional patient with a clinically meaningful improvement in KCCQ score.

Conclusions:

Although the CABG for ischemic cardiomyopathy did not reduce all-cause mortality in the STICH trial, health-related quality of life measures consistently favored CABG with medical therapy over medical therapy alone through 36 months of follow-up.

 Summarized by Javier A. Valle and Steven M. Bradley.

  • Mark, D.B., et al., Quality-of-Life Outcomes With Coronary Artery Bypass Graft Surgery in Ischemic Left Ventricular Dysfunction: A Randomized Trial. Ann Intern Med, 2014. 161(6): p. 392-9.

Beta-blockers in heart failure – what is the impact of concurrent atrial fibrillation?            

14 Oct, 14 | by Alistair Lindsay

Beta-blockers form an essential cornerstone of therapy for heart failure with reduced ejection fraction. However, the benefits of beta-blockade for heart failure in patients with concurrent atrial fibrillation are less certain. In this meta-analysis of individual-patient data from 10 randomized control trials comparing beta-blockers to placebo for systolic heart failure, investigators assessed the impact of beta-blockade by the presence of sinus rhythm or atrial fibrillation at baseline. Of the 18,254 patients assessed, 76% were in sinus rhythm and 17% were in atrial fibrillation at baseline. Over 1.5 years of mean follow-up, beta-blocker therapy was associated with a significant mortality benefit in sinus rhythm patients (HR 0.73, 0.67-0.80; p<0.001) but not in patients with atrial fibrillation (HR 0.97, 0.83-1.14; p=0.73). Results did not vary by subgroup of patients with atrial fibrillation or for secondary outcomes which included cardiovascular death, cardiovascular hospital admission, and non-fatal stroke.

Conclusion

The benefits of beta-blocker treatment in heart failure appear reduced by concomitant atrial fibrillation. Although the authors suggest β blockers should not be used preferentially for rate control in patients with atrial fibrillation and systolic heart failure, it is important to note this was not a comparative effectiveness study and there is insufficient data to support this conclusion.           

Summarized by Steven M. Bradley and Jehu S. Mathew

  •  Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JG, Lip GY, Coats AJ, Andersson B, Kirchhof P, von Lueder TG, Wedel H, Rosano G, Shibata MC, Rigby A, Flather MD, on behalf of the Beta-Blockers in Heart Failure Collaborative G. Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: An individual-patient data meta-analysis. Lancet. 2014 Sep 2. pii: S0140-6736(14)61373-8. doi: 10.1016/S0140-6736(14)61373-8.

 

 

 

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.

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