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Left atrial appendage closure in atrial fibrillation – is a comparison against warfarin still meaningful?  

20 Dec, 14 | by Alistair Lindsay

The majority of patients with nonvalvular atrial fibrillation (AF) have an indication for anti-coagulation to reduce the risk of stroke. As the left atrial appendage (LAA) is thought to the be the predominant source of thromboembolic events in the setting of AF, LAA closure may provide an alternative to anti-coagulation for stroke risk reduction without the associated bleeding concerns of anti-coagulation. This multi-center, randomized, unblinded trial compared LAA closure to warfarin in patients with AF and at least one other stroke risk factor (i.e. CHADS2 scores ≥ 1).   Patients were followed for four years and the primary outcome was a composite of stroke, systemic embolism, and cardiovascular/unexplained death. In the intention to treat analysis for efficacy the LAA closure groups had 2.3 events per 100 patient-years compared to 3.8 events per 100 patient-years in the warfarin group (relative risk 0.60 favoring device; 95% credible interval, 0.41-1.05). The most frequent adverse event with the device was serious pericardial effusion and survival curves demonstrated an earlier risk of adverse events in the device group.

 Conclusion: These long term results comparing a LAA closure device with warfarin suggest a potential role for LAA closure in AF stroke prevention. However, in an era of rapid uptake of newer oral anticoagulants with better safety profiles and similar stroke reduction efficacy as warfarin, it remains unclear if LAA has a role in contemporary care.

Summarized by Lauren E. Thompson and Steven M. Bradley

Percutaneous Left Atrial Appendage Closure vs Warfarin for Atrial Fibrillation A Randomized Clinical Trial. Reddy VY, Sievert H, Halperin J, Doshi SK, Buchbinder M, Neuzil P, Huber K, Whisenant B, Kar S, Swarup V, Gordon N, Holmes D; for the PROTECT AF Steering Committee and Investigators. JAMA. 2014;312(19):1988-1998. doi:10.1001/jama.2014.15192.

The spectrum of coronary artery disease and risk of myocardial infarction  

20 Dec, 14 | by Alistair Lindsay

Clinicians often dichotomize coronary artery disease (CAD) on the basis of obstruction to blood flow given the implications of this threshold on considerations for revascularization. As a result, nonobstructive CAD is often characterized as less significant, although this may oversimplify the risks associated with nonobstructive disease. In this retrospective cohort of patients who underwent elective coronary angiography in the Veterans Affairs health care system, the authors evaluated the relationship between gradations of CAD burden and 1-year outcomes of non-fatal myocardial infarction (MI) and mortality. CAD burden was defined by both thresholds for no CAD, nonobstructive CAD, and obstructive CAD as well as the number of vessels involved (1-vessel, 2-vessel, or 3-vessel/left main). Among 37,674 patients who underwent elective angiography, 22.3% had non-obstructive CAD and 55.4% had obstructive CAD. Compared with patients with no CAD, risk adjusted 1-year MI rates progressively increased with greater CAD burden [1-vessel nonobstructive (HR 2.0; 95%CI, 0.8-5.1); 2-vessel nonobstructive (HR 4.6; 95%CI, 2.0-10.5); 3-vessel nonobstructive (HR 4.5; 95% CI, 1.6-12.5), 1-vessel obstructive (HR 9.0; 95% CI, 4.2-19); 2-vessel obstructive (HR 16.5; 95% CI, 8.1-33.7); 3-vessel/left main obstructive (HR 19.5; 95% CI, 9.9-38.2)]. Risk adjusted 1-year mortality was also significantly higher among patients with 3-vessel nonobstructive CAD and any level of obstructive CAD.

 Conclusion: This study highlights that CAD is not a dichotomous disease that is either present or absent, but is a spectrum of progressive disease with corresponding risk. Greater attention to the spectrum of CAD risk may result in better patient outcomes.

Summarized by Lauren E. Thompson

Nonobstructive Coronary Artery Disease and Risk of Myocardial Infarction. Maddox TM, Stanislawski MA, Grunwald GK, Bradley SM, Ho PM, Tsai TT, Patel MR, Sandhu A, Valle J, Magid DJ, Leon B, Bhatt DL, Fihn SD, Rumsfeld JS. JAMA. 2014;312(17):1754-1763. doi:10.1001/jama.2014.14681.

Temporal trends towards increased mortality despite Improved door-to-balloon times in ST-elevation myocardial infarction  

20 Dec, 14 | by Alistair Lindsay

A short door-to-balloon time (D2B) is considered a quality of care measure for patients of ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous intervention (pPCI). However, recent literature has documented reductions in D2B that were not associated with improved STEMI mortality. Using the National Cardiovascular Data Registry (NCDR) CathPCI Registry, Nallamothu et al. assessed this apparent contradiction at the individual and population levels. The authors examined 150,116 pPCI procedures performed on 146,940 patients at 423 US hospitals over the course of six years. They assessed both in-hospitality (in the entire cohort) and 6-month mortality (in Medicare beneficiaries ≥ 65 years old) using models that incorporated patient and population-level components relevant to the association between D2B time and outcomes. Over the 6 years included in this analysis, a significant annual decrease in D2B times [86 min (IQR 65–109) in 2005 to 63 min (IQR 47–80) in 2011 (p<0.0001)] was accompanied by an increase in risk-adjusted in-hospital (from 4.7% to 5.3%; p=0.06) and 6-month (from 12.9% to 14.4%; p=0.001) mortality. Multilevel modeling demonstrated that patient specific shorter D2B times were consistently associated with lower in-hospital (adjusted OR for each 10 min decrease 0.92; 95% CI 0.91–0.93; p<0.0001) and 6-month mortality (adjusted OR for each 10 min decrease, 0.94; 95% CI 0.93–0.95; p<0.0001) for individual patients. However, this protective association was not evident at the population level, where the overall annual increase in mortality was independent of patient-specific D2B times.

Conclusions

Shorter D2B times are associated with a patient-level mortality benefit for STEMI. These findings highlight the importance of avoiding interpretation about patient-level associations from studies of population-level results.

 Summarized by Jehu S. Mathew and Steven M. Bradley

Nallamothu BK, Normand SLT, Wang Y, Hofer TP, Brush JE Jr, Messenger JC, Bradley EH, Rumsfeld JS, Krumholz HM. Relation between door-to-balloon times and mortality after primary percutaneous coronary intervention over time: a retrospective study. Lancet. 2014. Nov 19. pii: S0140-6736(14)61932-2.

Gene mutation reduces risk of coronary disease  

20 Dec, 14 | by Alistair Lindsay

Niemann-Pick C1-like 1 (NPC1L1) protein is expressed in the small intestine and liver and facilitates the transport of intraluminal dietary cholesterol into enterocytes. This transporter is the target of the drug ezetimibe and inhibition of the transporter is known to significantly reduce plasma levels of LDL cholesterol. In this genetic study, the authors first sequenced NPC1L1 to search for mutations that inactivated the transporter and then determined whether these mutations were correlated with a lower risk of coronary heart disease. First, NPC1L1 was sequenced in 7364 patients with known coronary heart disease and in 14,728 healthy controls. The authors identified 15 distinct NPC1L1 inactivating mutations with the most common mutation being p.Arg406X. In a larger cohort of 22,590 patients with coronary heart disease and 68,412 controls, the authors genotyped study participants for p.Arg406X and data on LDL levels and coronary event rates were compared between patients with and without this mutation. After correction for statin use, heterozygous carriers of p.Arg406X were found to have a mean LDL cholesterol level that was 0.31 mmol/l lower than non-carriers (P=0.04). In addition, carriers of the mutation had a lower rate of coronary events (OR, 0.47; 95% CI, 0.25 to 0.87; P=0.008).

Conclusions: Mutations that disrupt the function of the NPC1L1 cholesterol transporter gene are associated with both lower LDL cholesterol levels and a lower coronary event rate. These findings provide support for LDL cholesterol contributing to coronary disease risk and promote the concept of LDL control in reducing event rates.

Summarized by Hussain Contractor and Steven M. Bradley

Stitziel NO, Won HH, Morrison AC, Peloso GM, Do R, Lange LA, Fontanillas P, Gupta N, Duga S, Goel A, Farrall M, Saleheen D, Ferrario P, König I, Asselta R, Merlini PA, Marziliano N, Notarangelo MF, Schick U, Auer P, Assimes TL, Reilly M, Wilensky R, Rader DJ, Hovingh GK, Meitinger T, Kessler T, Kastrati A, Laugwitz KL, Siscovick D, Rotter JI, Hazen SL, Tracy R, Cresci S, Spertus J, Jackson R, Schwartz SM, Natarajan P, Crosby J, Muzny D, Ballantyne C, Rich SS, O’Donnell CJ, Abecasis G, Sunyaev S, Nickerson DA, Buring JE, Ridker PM, Chasman DI, Austin E, Ye Z, Kullo IJ, Weeke PE, Shaffer CM, Bastarache LA, Denny JC, Roden DM, Palmer C, Deloukas P, Lin DY, Tang ZZ, Erdmann J, Schunkert H, Danesh J, Marrugat J, Elosua R, Ardissino D, McPherson R, Watkins H, Reiner AP, Wilson JG, Altshuler D, Gibbs RA, Lander ES, Boerwinkle E, Gabriel S, Kathiresan S. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med. 2014 Nov 27;371(22):2072-82.

 

 

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.

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