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Lipid lowering drugs and risk of vascular events in older patients

7 Jul, 15 | by Alistair Lindsay

Although elderly patients are at higher risk of cardiovascular events, the majority cardiovascular trials exclude these patients.  Accordingly, little is known about the use of lipid lowering medications for prevention of cardiovascular events in elderly populations. This prospective cohort study evaluated the association between use of statins or fibrates for prevention of vascular events among a random sample of 7484 patients aged 65 years of older without prior vascular disease living in three French cities recruited from 1999-2000.  Patients were followed for a median of 9.1 years, with 732 vascular events (440 coronary events, 292 strokes) occurring during the study period.  The study found that 27.4% (n=2084) of patients reported baseline lipid lowering medication use (13.5% statins, 13.9% fibrates).   Patients using lipid lowering medications were more likely to have other cardiovascular risk factors (diabetes, hypertension, hyperlipidemia) or diagnoses (dysrhythmia).  After risk-adjustment, the use of a statin or fibrate was not associated with decreased vascular events (hazard ratio 0.91, 95% CI 0.76-1.09) in this population.  However, use of lipid lowering agent was associated with a reduced risk of ischemic stroke (hazard ratio 0.66, 95% confidence interval 0.49 to 0.90).  Results did not differ significantly when considering changes in the use of lipid lowering drugs during the first 7 years of follow-up, and were similar in secondary analyses including patients with a prior vascular event.

Conclusions: In summary, this study of elderly patients demonstrated that use of a statin or fibrate medication was associated with a decreased risk of ischemic stroke, but not coronary heart disease. Additional study is needed to fully appreciate the risk versus benefit tradeoff of these therapies in older individuals.

Summarized by Javier A. Valle and Steven M. Bradley

  • Alpérovitch A, Kurth T, Bertrand M, Ancelin ML, Helmer C, Debette S, Tzourio C. Primary prevention with lipid lowering drugs and long term risk of vascular events in older people: population based cohort study. BMJ. 2015 May 19;350:h233

Improved Atrial Fibrillation Outcomes Despite Rising Arrhythmia Prevalence

7 Jul, 15 | by Alistair Lindsay

Little is known about temporal trends in atrial fibrillation (AF) incidence, prevalence, and outcomes. Using the Framingham Heart Study, Schnabel and colleagues assessed AF incidence, prevalence, and outcomes over 50 years (202,417 person-years). Researchers drew on a cohort of 9,511 participants enrolled between 1958 and 2007 in which 1,544 incident AF cases (47% women) were identified. Over the study period, age-adjusted incidence increased threefold (3.7 to 13.4 new cases per 1000 person-years in men and from 2.5 to 8.6 new cases per 1000 person-years in women) and age-adjusted prevalence increased fourfold (20.4 to 96.2 cases per 1000 person-years in men and from 13.7 to 49.4 cases per 1000 person-years in women). To mitigate lead-time bias that could result from improved methods to detect AF over time, researchers also evaluated temporal trends by AF detected solely through routine ECG screening of the study cohort. While age-adjusted prevalence increased over the study period, age-adjusted incidence did not significantly change over time in this sensitivity analysis. Outcomes improved over time, with adjusted hazards models showing a 74% decrease in stroke (HR 3.77, 95% CI 1.98–7.20 in 1958–1967 compared with 1998–2007; ptrend=0.0001) and a 25% decrease in mortality (HR 1.34, 95% CI 0.97–1.86 in 1958–1967 compared with 1998–2007; ptrend=0.003).

Conclusions: Rising temporal AF trends are, in part, due to enhanced detection methods over time.  Improved outcomes of AF likely reflect advances in the delivery and quality of cardiovascular care. Future efforts to reduce AF burden must integrate improved screening measures with enhanced education and prevention.

  • Schnabel RB, Yin X, Gona P, Larson MG, Beiser AS, McManus DD, Newton-Cheh C, Lubitz SA, Magnani JW, Ellinor PT, Seshadri S, Wolf PA, Vasan RS, Benjamin EJ, Levy D. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the framingham heart study: A cohort study. Lancet. 2015 May 7. pii: S0140-6736(14)61774-8. [E-pub ahead of print]

Investigating chest pain: anatomy or function?

22 May, 15 | by Alistair Lindsay

Among patients with chest pain, it is unclear if anatomic assessment of coronary obstruction or functional assessment with stress testing leads to better patient outcomes. In this randomized controlled trial of 10,003 symptomatic patients, individuals were randomly assigned in a 1:1 fashion to either anatomical testing with coronary CT angiography (CTA) or to functional testing by one of several different modalities (exercise ECG (10%), nuclear stress testing (67%) or stress echo (23%)).  Instead of diagnostic accuracy, as is seen with most such studies, the trial was powered for clinical outcomes with a primary composite endpoint of death, myocardial infarction, hospitalization for unstable angina, or major procedural complication.  The study patients were a mean age 61 years, 53% were women, and the mean pretest probability of coronary artery disease was 53±21%.  Over a median follow-up of 25 months, the rate of the primary-end point was similar in patients undergoing CTA (3.3%) and functional testing (3.0%) (HR, 1.04; 95% CI, 0.83 to 1.29; P=0.75).  More patients in the CTA group underwent cardiac catheterization and there was greater radiation exposure in the CTA group (12.0 mSv vs. 10.1 mSv; P<0.001) with 32.6% of patients in the functional-testing group having no radiation exposure.

Conclusions

In patients presenting with chest pain who require diagnostic testing for coronary disease, an initial strategy of anatomic testing with CTA in comparison with a functional test does not lead to any appreciable improvement in patient outcomes.

  • Douglas PS, Hoffmann U, Patel MR, Mark DB, Al-Khalidi HR, Cavanaugh B, Cole J, Dolor RJ, Fordyce CB, Huang M, Khan MA, Kosinski AS, Krucoff MW, Malhotra V, Picard MH, Udelson JE, Velazquez EJ, Yow E, Cooper LS and Lee KL Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med. 2015 Apr 2;372(14):1291-300.

Written by Hussain Contractor and Steven Bradley.

Antiplatelet therapy in long-term risk reduction after myocardial infarction

22 May, 15 | by Alistair Lindsay

The activated platelet is central to development of ischemic cardiovascular events. Guidelines recommend treatment with a P2Y12 receptor antagonist for 1-year after myocardial infarction (MI) to reduce the risk of recurrent events.  The PEGASUS trial sought to determine the impact of using the P2Y12 antagonist ticagrelor as part of long-term therapy after MI.  In this trial, a total of 21,162 clinically stable patients with a MI in the prior 1 to 3 years (median 18 months) were randomized in a 1:1:1 fashion to either placebo, ticagrelor 90mg twice daily, or ticagrelor 60mg twice daily.  All patients remained on aspirin and standard secondary prevention as tolerated.  Follow up was for a median of 33 months with the primary outcome being a composite of cardiovascular death, myocardial infarction, or stroke and the primary safety end-point of bleeding.  Both doses of ticagrelor led to significant reductions in the primary end-point (HR for 90mg dosing 0.85; 95% CI, 0.75 to 0.96; P=0.008, and HR for 60mg dosing 0.84; 95% CI, 0.74 to 0.95; P=0.004) primarily driven by a reduction in recurrent myocardial infarction.  Rates of major bleeding were significantly higher with both doses of ticagrelor (~ 2.5%) compared with placebo (~1.0%) (P<0.001).

Conclusions

Among patients with prior MI, long-term antiplatelet therapy with the P2Y12 inhibitor ticagrelor in addition to aspirin reduces recurrent ischemic events.  This finding is independent of the consideration dual-antiplatelet therapy duration after coronary stenting. Given prior a post-hoc analysis that suggested benefit of clopidogrel in similar patient populations, questions remain as to how the choice of P2Y12 inhibitor impacts patient outcomes.

Written by Hussain Contractor and Steven Bradley

  • Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Ophuis TO, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E and Sabatine MS. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. N Engl J Med. 2015 Mar 14. [Epub ahead of print]

Written by Hussain Contractor and Steven Bradley.

Precision Medicine to Reduce Bleeding with PCI   

5 May, 15 | by Alistair Lindsay

 

Periprocedural bleeding remains one of the most common adverse events after percutaneous coronary intervention (PCI) and is associated with increased mortality.  Although strategies to minimize PCI bleeding have been identified, these strategies are infrequently applied to patients at highest bleeding risk.  Using a pre-post study design, Spertus et al. evaluated the impact of assessing individual patient bleeding risk from validated models and providing this bleeding risk estimate in personalized informed consent documents for PCI.  The intent of the intervention was to increase the procedural team’s awareness of patients at low, moderate, and risk for PCI related bleeding and thereby influence the use of bleeding avoidance strategies (i.e. bivalirudin, radial access, and vascular closure devices) and reduce periprocedural bleeding events.  The study included 7408 pre-intervention PCI and 3529 post-intervention PCI from 9 hospitals in the United States. Following implementation of the intervention, use of bleeding avoidance strategies increased (odds ratio for use of bleeding avoidance strategies: 1.81, 95% confidence interval 1.44-2.27), especially among higher risk individuals (OR 2.03, 95% CI 1.58-2.61).  Furthermore, bleeding rates were lower following implementation of the intervention (1.0 v. 1.7%, OR 0.62, 95% CI 0.44 to 0.87 after adjustment for contemporary trends).  Following the intervention, significant variation remained both between and within hospitals with regards to use of bleeding avoidance strategies.

Conclusion: Providing clinicians with individual patient bleeding risks immediately prior to PCI was associated with increased and targeted use of bleeding avoidance strategies and lower risk-adjusted bleeding rates.  However, significant variability in the approach to bleeding avoidance persisted after implementation of this tool.

Summarized by Javier A. Valle and Steven M. Bradley

  •  Spertus JA, Decker C, Gialde E, et al. Precision medicine to improve use of bleeding avoidance strategies and reduce bleeding in patients undergoing percutaneous coronary intervention: prospective cohort study before and after implementation of personalized bleeding risks. BMJ. 2015 Mar 24;350:h1302.

 

 

Relationship Between Physical Activity and Mortality     

5 May, 15 | by Alistair Lindsay

 

The 2008 Physical Activity Guidelines for Americans recommended 150 to 300 minutes of moderate-intensity or 75 to 150 minutes of vigorous-intensity aerobic activity weekly for optimal health. However, these guidelines acknowledged uncertainty on the upper threshold of benefit or potential harms of high activity levels.  Using data from 6 pooled cohorts from the National Cancer Institute Cohort Consortium (baseline 1992-2003) with self-reports of leisure-time physical activity (LTPA), Arem and colleagues aimed to address this question. The total cohort consisted of 661,137 men and women with a median age of 62 years and a median follow-up of 14.2 years in which 116,686 deaths were accrued. When compared to subjects with no reported LTPA, individuals exercising less than the recommended minimum of 7.5metabolic-equivalent hours per week exhibited a 20% mortality benefit (HR 0.80 [95% CI 0.78-0.82]), individuals exercising 1 to 2 times the recommended minimum exhibited a 31% mortality benefit (HR 0.69 [95%CI 0.67-0.70]), and individuals exercising 2 to 3 times the minimum experienced a 37% mortality benefit (HR 0.63 [95%CI 0.62-0.65]). Researchers observed a ceiling of mortality benefit at the threshold of 3 to 5 times the minimum suggested LTPA (HR 0.61 [95%CI 0.59-0.62]). Additionally, there was no evidence of harm associated with exercise at a level of 10 times or more than the recommended minimum (HR 0.69 [95%CI 0.59-0.78]). Similar dose-response and threshold effects were seen for cardiovascular and cancer mortality.

Conclusion: Achieving the minimum levels of physical activity recommended in the 2008 Physical Activity Guidelines was associated with a mortality benefit.  Increasing health benefits were observed with increasing levels of physical activity up to 5 times the minimum recommended activity level and no harm was associated with higher levels of physical activity.  These findings support physical activity as cornerstone of optimal health and reduce concerns for potential harm associated with high levels of physical activity.

 

Summarized by Jehu S. Mathew and Steven M. Bradley

  •  Arem H, Moore SC, Patel A, Hartge P, Berrington de Gonzalez A, Visvanathan K, Campbell PT, Freedman M, Weiderpass E, Adami HO, Linet MS, Lee IM, Matthews CE. Leisure time physical activity and mortality: A detailed pooled analysis of the dose-response relationship. JAMA Internal Med. 2015 Apr 6.

 

Long-Term Outcomes of Transcatheter Aortic Valve Replacement 

5 May, 15 | by Alistair Lindsay

The Placement of Aortic Transcatheter Valves (PARTNER) trial demonstrated that transcatheter aortic valve replacement (TAVR) for high-risk patients with aortic stenosis resulted in similar outcomes at 1, 2 and 3 years compared with surgical aortic valve replacement (SAVR). The present study reports the 5-year outcomes of this trial. The study enrolled 699 patients who were randomized to SAVR or TAVR (via a transfemoral or transapical approach). Overall, mean age was 84.1 years, 94% were NYHA Class 3 or 4, and the mean Society of Thoracic Surgeons Predicted Risk of Mortality at 30 days was 11.8%. At 5 years, there were no significant differences in mortality between groups (67.8% in the TAVR group versus 62.4% in the SAVR group; hazard ratio 1.04, 95% CI 0.86–1.24; p=0.76). Additionally, there were no significant differences in cardiovascular mortality, stroke, or need for repeat hospital admission. Patients receiving TAVR experienced more major vascular complications (11.9% vs 4.7%; p=0.0002) and fewer major bleeding events (26.6% vs 34.4%; p=0.003). Development of moderate or severe aortic regurgitation was more common following TAVR (14% vs 1%; p<0·0001) and this was associated with higher mortality at 5 years (72.4% for moderate or severe aortic regurgitation compared with 56.6% for those with mild aortic regurgitation or less; p=0·003).

Conclusion: Outcomes from the original PARTNER study continue to demonstrate that TAVR is a suitable alternative to SAVR in high-risk patients with aortic stenosis. The overall mortality of greater than 60% at 5 years following both TAVR and SAVR in this population is striking. Although advances in TAVR technology, improved imaging and valve sizing, and operator experience may lead to better outcomes, the underlying risk of mortality related to comorbid illness remains important to discuss with patients considering either approach to the management of severe aortic stenosis.

Summarized by Jehu S. Mathew and Steven M. Bradley

  • Mack MJ, Leon MB, Smith CR, Miller DC, Moses JW, Tuzcu EM, Webb JG, Douglas PS, Anderson WN, Blackstone EH, Kodali SK, Makkar RR, Fontana GP, Kapadia S, Bavaria J, Hahn RT, Thourani VH, Babaliaros V, Pichard A, Herrmann HC, Brown DL, Williams M, Davidson MJ, Svensson LG, investigators Pt, Akin J. 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (partner 1): A randomised controlled trial. Lancet. 2015 Mar 15. pii: S0140-6736(15)60308-7.

Clinical Outcomes at 1 Year Following Transcatheter Aortic Valve Replacement  

16 Apr, 15 | by Alistair Lindsay

To date, long-term outcome data following transcatheter aortic valve replacement (TAVR) has only been available from clinical trial data.  Evaluating long-term outcomes of TAVR in real-world use is important to ensure the anticipated benefits are observed in routine clinical practice.  Using data from the Society of Thoracic Surgeons/American College of Cardiology (STS/ACC) Transcatheter Valve therapies registry merged with Centers for Medicare & Medicaid Services administrative claims data, this study evaluated 1-year outcomes of mortality, stroke, and rehospitalization among 12,182 patients who underwent TAVR between November 2011 and June 2013.  In this cohort, the 1-year mortality rate 23.7%, the stroke rate was 4.1%, the rate of heart failure was 14.3%, and 1.4% had aortic valve reintervention.  A total of 53.2% were readmitted to the hospital within 1-year.   In multivariate analysis, patient characteristics associated with increased mortality included advancing age (age >95 hazard ratio [HR] 1.61; 95% confidence interval [CI] 1.24 to 2.09), male gender (HR 1.21; 95% CI 1.12 to 1.31), severe lung disease (HR 1.39; 95% CI 1.25 to 1.55), renal failure (dialysis HR 1.66; 95% CI 1.41 to 1.95) and Cr > 2mg/dL (HR 1.26; 95%CI 1.10 to 1.44), nontransfemoral access (HR 1.37; 95% CI 1.27 to 1.28), and STS Predicted Risk of Mortality (PROM) score greater than 15% compared with less than 8% (HR 1.82; 95% CI 1.60 to 2.06).  In addition, the authors found the median predicted mortality for this cohort was 7.1% which was lower than the median predicted mortality for patients in the clinical trials that established the efficacy of TAVR (~11% in these prior trials).

 

Conclusion: The 1-year outcomes of patients undergoing TAVR are similar to outcomes seen during prior clinical trials with a 1-year mortality of 23.7% and stroke 4.1%.  However, the lower predicted mortality in this observational cohort may reflect use of TAVR in a lower risk population than prior clinical trials.

 

Summarized by Lauren E. Thompson and Steven M. Bradley

 

  • Holmes DR Jr, Brennan JM, Rumsfeld JS, Dai D, O’Brien SM, Vemulapalli S, Edwards FH, Carroll J, Shahian D, Grover F, Tuzcu EM, Peterson ED, Brindis RG, Mack MJ; STS/ACC TVT Registry. JAMA. 2015;313(10):1019-1028. doi:10.1001/jama.2015.1474.

Second-generation stents fail to BEST CABG

16 Apr, 15 | by Alistair Lindsay

The technology of drug eluting stents for percutaneous coronary intervention (PCI) has improved over time with resultant improvements in patient outcomes.  Although prior studies have demonstrated the benefit of surgical coronary artery bypass grafting (CABG) over transcatheter PCI among patients with multivessel coronary artery disease (CAD), these studies did not incorporate newer generation drug-eluting stents.  The multicenter BEST trial randomized 880 patients with multivessel CAD to PCI with an everolimus-eluting stent or to CABG. The primary end point for this non-inferiority study was a composite of death, myocardial infarction, or target-vessel revascularization at 2 years.  The results of the study non-significantly favored CABG at 2 years of follow-up with the primary end-point occurring in 7.9% of the CABG group and 11% of the PCI group.  This advantage achieved statistical significance in longer term follow-up (median 4.6 years, 10.6% vs. 15.3%, HR, 1.47; 95% CI, 1.01 to 2.13; P=0.04).  The majority of this benefit was driven by a higher rate of repeat revascularization among patients treated with PCI; there were no significant differences in the rates of death, overall myocardial infarction or stroke between CABG and PCI.

 

Conclusions: In this large randomized trial of patients with multi-vessel coronary disease, CABG continued to demonstrate lower rates of adverse events in comparison to patients treated with modern generation drug-eluting stents.  This difference in outcomes was driven by higher rates of repeat revascularization with PCI and not by differences in the rates of myocardial infarction, stroke or death.

 

Summarized by Hussain Contractor and Steven M. Bradley

 

  • Park SJ, Ahn JM, Kim YH, Park DW, Yun SC, Lee JY, Kang SJ, Lee SW, Lee CW, Park SW, Choo SJ, Chung CH, Lee JW, Cohen DJ, Yeung AC, Hur SH, Seung KB, Ahn TH, Kwon HM, Lim DS, Rha SW, Jeong MH, Lee BK, Tresukosol D, Fu GS, Ong TK.  Trial of everolimus-eluting stents or bypass surgery for coronary disease.  N Engl J Med. 2015 Mar 26;372(13):1204-12.

Aspiration thrombectomy fails to demonstrate benefit in primary PCI  

16 Apr, 15 | by Alistair Lindsay

Although primary percutaneous coronary intervention (PPCI) restores epicardial coronary flow in the majority of patients with ST-segment myocardial infarction, this approach can lead to microvascular obstruction resulting from distal embolization of thrombus.  Manual thrombectomy (i.e. aspiration thrombectomy) prior to PPCI has been proposed as a method to reduce thrombus burden and resultant distal embolization with PPCI.  Although results from early studies of aspiration thrombectomy suggested improvements in patient outcomes, subsequent trials have failed to demonstrate a clinical benefit of aspiration thrombectomy prior to PPCI.  This large, multi-centre, international trial furthers the evidence that aspiration does not offer benefit in the routine care of patients undergoing PPCI.  This study randomized 10,732 patients with ST elevation myocardial infarction to routine manual thrombectomy prior to PCI or standard PCI alone.  The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days with a primary safety end-point of stroke within 30 days.  Crossover rates between groups were low and the primary analysis was by intention-to-treat.  Compared to standard PPCI, treatment with aspiration thrombectomy did not reduce rates of the primary outcome (6.9% vs. 7.0%, HR, 0.99; 95% CI, 0.85 to 1.15; P=0.86) or individual components of the primary outcome.  In a pre-specified sub-group analysis, there was no difference in patient outcomes as a function of initial thrombus burden. Furthermore, there was a significant increase in stroke in the thrombectomy group (0.7% vs. 0.3%, HR, 2.06; 95% CI, 1.13 to 3.75; P=0.02) within the first 30 days. 

Conclusions: In this large randomised controlled trial, routine aspiration thrombectomy did not improve patient outcomes for patients presenting with acute ST-elevation myocardial infarction.  Rates of stroke in patients undergoing thrombectomy were significantly elevated at 30 days.  Aspiration thrombectomy should no longer be a part of routine PCI care.

 

Summarized by Hussain Contractor and Steven M. Bradley

 

  • Jolly SS, Cairns JA, Yusuf S, Meeks B, Pogue J, Rokoss MJ, Kedev S, Thabane L, Stankovic G, Moreno R, Gershlick A, Chowdhary S, Lavi S, Niemelä K, Steg PG, Bernat I, Xu Y, Cantor WJ, Overgaard CB, Naber CK, Cheema AN, Welsh RC, Bertrand OF, Avezum A, Bhindi R, Pancholy S, Rao SV, Natarajan MK, Ten Berg JM, Shestakovska O, Gao P, Widimsky P and Džavík V.  Randomized Trial of Primary PCI with or without Routine Manual Thrombectomy.  N Engl J Med. 2015 Mar 16. [Epub ahead of print]

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