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The article discusses the use of the win ratio as a method for evaluating evidence from clinical trials. The win ratio allows for the inclusion of patient-reported outcomes and surrogate measures in addition to traditional clinical outcomes like death and hospitalization. However, the win ratio has limitations, such as the difficulty in prioritizing component events and the potential for the inclusion of unimportant events. The article provides examples of how the win ratio can lead to overestimation of treatment effects or be driven by biased measures. Overall, the utility of the win ratio depends on the prespecified definition and ranking of clinically relevant components. [Extracted from the article]

As previously reported, PARAGON-HF narrowly missed statistical significance for its primary end point (rate ratio, 0.87 [95% CI, 0.75-1.01]; I P i =0.059).[2] It is noteworthy that 28% (566 cases) of potential HF hospitalizations identified by investigators were negatively adjudicated by the CEC. This mean probability for each event was then used in a multiple imputation procedure, creating 1000 imputed data sets with CEC-unconfirmed events included or not based on their probability (random draw from a respective Bernoulli distribution), such that an event with an average probability of 40% would be expected to be included as a HF hospitalization in 400 of 1000 data sets. Keywords: clinical trial; heart failure; hospitalization; probability; sacubitril-valsartan; valsartan EN clinical trial heart failure hospitalization probability sacubitril-valsartan valsartan 2316 2318 3 06/10/21 20210608 NES 210608 Heart failure with preserved ejection fraction is a highly morbid condition with few proven treatment options. [Extracted from the article]

To explore whether HR analysis was appropriate, we reconstructed patient-level survival data from the Kaplan-Meier curves presented in the CHARM-Overall article.[3] Here, the reconstructed Kaplan-Meier curves are presented in Figure, A. Because the Kaplan-Meier curves separate initially but remain parallel after 0.5 years, the PH assumption was not met, as was confirmed via the Schoenfeld goodness-of-fit test ( I P i =0.0005). Using the reconstructed Kaplan-Meier curves in the Figure (D), the 12-month RMSTs were 11.41 and 11.36 months for biodegradable and durable stents, respectively. [Extracted from the article]

Background--Guidelines for the management of patients with suspected coronary artery disease (CAD) rely on the age, sex, and angina typicality-based pretest probabilities of angiographically significant CAD derived from invasive coronary angiography (guideline probabilities). Reliability of guideline probabilities has not been investigated in patients referred to noninvasive CAD testing. Methods and Results--We identified 14048 consecutive patients with suspected CAD who underwent coronary computed tomographic angiography. Angina typicality was recorded with the use of accepted criteria. Pretest likelihood of CAD with ≥50% diameter stenosis (CAD50) and ≥70% diameter stenosis (CAD70) were calculated from guideline probabilities. Computed tomographic angiography images were evaluated by ≥1 expert reader to determine the presence of CAD50 and CAD70. Typical angina was associated with the highest prevalence of CAD50 (40% in men, 19% in women) and CAD70 (27% men, 11% women) compared with other symptom categories (P<0.001 for all). Observed CAD50 and CAD70 prevalences were substantially lower than those predicted by guideline probabilities in the overall population (18% versus 51% for CAD50, 10% versus 42% for CAD70: P<0.001), driven by pronounced differences in patients with atypical angina (15% versus 47% tbr CAD50, 7% versus 37% for CAD71)) and typical angina (29% versus 86% for CAD50, 19% versus 71% for CAD70). Marked overestimation of disease prevalence by guideline probabilities was found at all participating centers and across all sex and age subgroups. Conclusion--In this multinational study of patients referred for coronary computed tomographic angiography, determination of pretest likelihood of angiographically significant CAD by the invasive angiography-based guideline probabilities greatly overestimates the actual prevalence of disease. [ABSTRACT FROM AUTHOR]

Keywords: confidence intervals; decision making; physics; probability; randomized controlled trial When the effect of a new drug is evaluated in a clinical trial, the investigators report an estimate of the effect size, which is presented in probabilistic terms (ie, confidence intervals). Confidence intervals, decision making, physics, probability, randomized controlled trial. [Extracted from the article]

Background: Whether knowledge of genetic risk for coronary heart disease (CHD) affects health-related outcomes is unknown. We investigated whether incorporating a genetic risk score (GRS) in CHD risk estimates lowers low-density lipoprotein cholesterol (LDL-C) levels., Methods and Results: Participants (n=203, 45-65 years of age, at intermediate risk for CHD, and not on statins) were randomly assigned to receive their 10-year probability of CHD based either on a conventional risk score (CRS) or CRS + GRS ((+)GRS). Participants in the (+)GRS group were stratified as having high or average/low GRS. Risk was disclosed by a genetic counselor followed by shared decision making regarding statin therapy with a physician. We compared the primary end point of LDL-C levels at 6 months and assessed whether any differences were attributable to changes in dietary fat intake, physical activity levels, or statin use. Participants (mean age, 59.4±5 years; 48% men; mean 10-year CHD risk, 8.5±4.1%) were allocated to receive either CRS (n=100) or (+)GRS (n=103). At the end of the study period, the (+)GRS group had a lower LDL-C than the CRS group (96.5±32.7 versus 105.9±33.3 mg/dL; P=0.04). Participants with high GRS had lower LDL-C levels (92.3±32.9 mg/dL) than CRS participants (P=0.02) but not participants with low GRS (100.9±32.2 mg/dL; P=0.18). Statins were initiated more often in the (+)GRS group than in the CRS group (39% versus 22%, P<0.01). No significant differences in dietary fat intake and physical activity levels were noted., Conclusions: Disclosure of CHD risk estimates that incorporated genetic risk information led to lower LDL-C levels than disclosure of CHD risk based on conventional risk factors alone., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936675., (© 2016 American Heart Association, Inc.)

Background: Learning curves are vigorously discussed and viewed as a negative aspect of adopting new procedures. However, very few publications have methodically examined learning curves in cardiac surgery, which could lead to a better understanding and a more meaningful discussion of their consequences. The purpose of this study was to assess the learning process involved in the performance of minimally invasive surgery of the mitral valve using data from a large, single-center experience., Methods and Results: All mitral (including tricuspid, or atrial fibrillation ablation) operations performed over a 17-year period through a right lateral mini-thoracotomy with peripheral cannulation for cardiopulmonary bypass (n=3907) were analyzed. Data were obtained from a prospective database. Individual learning curves for operation time and complication rates (using sequential probability cumulative sum failure analysis) and average results were calculated. A total of 3895 operations by 17 surgeons performing their first minimally invasive surgery of the mitral valve operation at our institution could be evaluated. The typical number of operations to overcome the learning curve was between 75 and 125. Furthermore, >1 such operation per week was necessary to maintain good results. Individual learning curves varied markedly, proving the need for good monitoring or mentoring in the initial phase., Conclusions: A true learning curve exists for minimally invasive surgery of the mitral valve. Although the number of operations required to overcome the learning curve is substantial, marked variation exists between individual surgeons. Such information could be very helpful in structuring future training and maintenance of competence programs for this kind of surgery.

Background: The ability of echocardiographic dyssynchrony to predict response to cardiac resynchronization therapy (CRT) has been unclear., Methods and Results: A prospective, longitudinal study was designed with predefined dyssynchrony indexes and outcome variables to test the hypothesis that baseline dyssynchrony is associated with long-term survival after CRT. We studied 229 consecutive class III to IV heart failure patients with ejection fraction ≤35 and QRS duration ≥120 milliseconds for CRT. Dyssynchrony before CRT was defined as tissue Doppler velocity opposing-wall delay ≥65 milliseconds, 12-site SD (Yu Index) ≥32 milliseconds, speckle tracking radial strain anteroseptal-to-posterior wall delay ≥130 milliseconds, or pulsed Doppler interventricular mechanical delay ≥40 milliseconds. Outcome was defined as freedom from death, heart transplantation, or left ventricular assist device implantation. Of 210 patients (89) with dyssynchrony data available, there were 62 events: 47 deaths, 9 transplantations, and 6 left ventricular assist device implantations over 4 years. Event-free survival was associated with Yu Index (P=0.003), speckle tracking radial strain (P=0.003), and interventricular mechanical delay (P=0.019). When adjusted for confounding baseline variables of ischemic origin and QRS duration, Yu Index and radial strain dyssynchrony remained independently associated with outcome (P<0.05). Lack of radial dyssynchrony was particularly associated with unfavorable outcome in those with QRS duration of 120 to 150 milliseconds (P=0.002)., Conclusions: The absence of echocardiographic dyssynchrony was associated with significantly less favorable event-free survival after CRT. Patients with narrower QRS duration who lacked dyssynchrony had the least favorable long-term outcome. These observations support the relationship of dyssynchrony and CRT response.

Background: Using automated external defibrillators (AEDs) that implement the Guidelines 2000 resuscitation protocol constrains administration of cardiopulmonary resuscitation (CPR) to <50% of AED connection time. We tested a different AED protocol aimed at increasing the CPR administered to patients with out-of-hospital cardiac arrest., Methods and Results: In a randomized controlled trial, patients with out-of-hospital cardiac arrest requiring defibrillation were treated with 1 of 2 AED protocols. In the control protocol, based on Guidelines 2000, sequences of up to 3 stacked countershocks were delivered, with rhythm analyses initially and after the first and second shocks. The study protocol featured 1 minute of CPR before the first shock, shorter CPR interruptions before and after each shock, and no stacked shocks. The primary end point was survival to hospital admission. Of 5107 out-of-hospital cardiac arrest patients connected to an AED, 1238 required defibrillation, and 845 were included in the final analysis. Study patients (n=421) had shorter preshock pauses (9 versus 19 seconds; P<0.001), had shorter postshock pauses (11 versus 33 seconds; P<0.001), and received more CPR (61% versus 48%; P<0.001) and fewer shocks (2.5 versus 2.9; P<0.001) than control patients (n=424). Similar proportions survived to hospital admission (43.2% versus 42.7%; P=0.87), survived to hospital discharge (13.3% versus 10.6%; P=0.19), achieved return of spontaneous circulation before physician arrival (47.0% versus 48.6%; P=0.65), and survived to 1 year (P=0.77)., Conclusions: Following prompts from AEDs programmed with a protocol similar to Guidelines 2005, firefighters shortened pauses in CPR and improved overall hands-on time, but survival to hospital admission of patients with ventricular fibrillation out-of-hospital cardiac arrest did not improve. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique identifier: NCT00139542.

Background: Predicting the risk of recurrent venous thromboembolism (VTE) in an individual patient is often not feasible. We aimed to develop a simple risk assessment model that improves prediction of the recurrence risk., Methods and Results: In a prospective cohort study, 929 patients with a first unprovoked VTE were followed up for a median of 43.3 months after discontinuation of anticoagulation. We excluded patients with a strong thrombophilic defect such as a natural inhibitor deficiency, the lupus anticoagulant, and homozygous or combined defects. A total of 176 patients (18.9%) had recurrent VTE. Preselected clinical and laboratory variables (age, sex, location of VTE, body mass index, factor V Leiden, prothrombin G20210A mutation, D-dimer, and in vitro thrombin generation) were analyzed in a Cox proportional hazards model, and those variables that were significantly associated with recurrence were used to compute risk scores. Male sex (hazard ratio versus female sex 1.90, 95% confidence interval 1.31 to 2.75), proximal deep vein thrombosis (hazard ratio versus distal 2.08, 95% confidence interval 1.16 to 3.74), pulmonary embolism (hazard ratio versus distal thrombosis 2.60, 95% confidence interval 1.49 to 4.53), and elevated levels of D-dimer (hazard ratio per doubling 1.27, 95% confidence interval 1.08 to 1.51) were related to a higher recurrence risk. Using these variables, we developed a nomogram that can be used to calculate risk scores and to estimate the cumulative probability of recurrence in an individual patient. The model was cross validated, and patients were assigned to different risk categories based on their risk score. Recurrence rates corresponded well with the different risk categories., Conclusions: By use of a simple scoring system, the assessment of the recurrence risk in patients with a first unprovoked VTE and without strong thrombophilic defects can be improved.

Background: Long-QT syndrome (LQTS) is a potentially lethal cardiac channelopathy that can be mistaken for palpitations, neurocardiogenic syncope, and epilepsy. Because of increased physician and public awareness of warning signs suggestive of LQTS, there is the potential for LQTS to be overdiagnosed. We sought to determine the agreement between the dismissal diagnosis from an LQTS subspecialty clinic and the original referral diagnosis., Methods and Results: Data from the medical record were compared with data from the outside evaluation for 176 consecutive patients (121 females, median age 16 years, average referral corrected QT interval [QTc] of 481 ms) referred with a diagnosis of LQTS. After evaluation at Mayo Clinic's LQTS Clinic, patients were categorized as having definite LQTS (D-LQTS), possible LQTS (P-LQTS), or no LQTS (No-LQTS). Seventy-three patients (41%) were categorized as No-LQTS, 56 (32%) as P-LQTS, and only 47 (27%) as D-LQTS. The yield of genetic testing among D-LQTS patients was 78% compared with 34% for P-LQTS and 0% among No-LQTS patients (P<0.0001). The average QTc was greater in either D-LQTS or P-LQTS than in No-LQTS (461 versus 424 ms, P<0.0001). Vasovagal syncope was more common among the No-LQTS subset (28%) than the P-LQTS/D-LQTS group (8%; P=0.04). Determinants for discordance (ie, positive outside diagnosis versus No-LQTS) included overestimation of QTc, diagnosing LQTS on the basis of "borderline" QTc values, and interpretation of a vasovagal fainting episode as an LQTS-precipitated cardiac event., Conclusions: Diagnostic concordance was present for less than one third of the patients who sought a second opinion. Two of every 5 patients referred with the diagnosis of LQTS departed without such a diagnosis. Miscalculation of the QTc, misinterpretation of the normal distribution of QTc values, and misinterpretation of symptoms appear to be responsible for most of the diagnostic miscues.

Background: Estimation of an individual patient's risk for postoperative dialysis can support informed clinical decision making and patient counseling., Methods and Results: To develop a simple bedside risk algorithm for estimating patients' probability for dialysis after cardiac surgery, we evaluated data of 449,524 patients undergoing coronary artery bypass grafting (CABG) and/or valve surgery and enrolled in >600 hospitals participating in the Society of Thoracic Surgeons National Database (2002-2004). Logistic regression was used to identify major predictors of postoperative dialysis. Model coefficients were then converted into an additive risk score and internally validated. The model also was validated in a second sample of 86,009 patients undergoing cardiac surgery from January to June 2005. Postoperative dialysis was needed in 6451 patients after cardiac surgery (1.4%), ranging from 1.1% for isolated CABG procedures to 5.1% for CABG plus mitral valve surgery. Multivariable analysis identified preoperative serum creatinine, age, race, type of surgery (CABG plus valve or valve only versus CABG only), diabetes, shock, New York Heart Association class, lung disease, recent myocardial infarction, and prior cardiovascular surgery to be associated with need for postoperative dialysis (c statistic=0.83). The risk score accurately differentiated patients' need for postoperative dialysis across a broad risk spectrum and performed well in patients undergoing isolated CABG, off-pump CABG, isolated aortic valve surgery, aortic valve surgery plus CABG, isolated mitral valve surgery, and mitral valve surgery plus CABG (c statistic=0.83, 0.85, 0.81, 0.75, 0.80, and 0.75, respectively)., Conclusions: Our study identifies the major patient risk factors for postoperative dialysis after cardiac surgery. These risk factors have been converted into a simple, accurate bedside risk tool. This tool should facilitate improved clinician-patient discussions about risks of postoperative dialysis.

Background: Intravenous (IV) amiodarone has proven efficacy in adults. However, its use in children is based on limited retrospective data., Methods and Results: A double-blind, randomized, multicenter, dose-response study of the safety and efficacy of IV amiodarone was conducted in 61 children (30 days to 14.9 years; median, 1.6 years). Children with incessant tachyarrhythmias (supraventricular arrhythmias [n=26], junctional ectopic tachycardia [JET, n=31], or ventricular arrhythmias [n=4]) were randomized to 1 of 3 dosing regimens (low, medium, or high: load plus 47-hour maintenance) with up to 5 open-label rescue doses. The primary efficacy end point was time to success. Of 229 patients screened, 61 were enrolled during 13 months by 27 of 48 centers in 7 countries. Median time to success was significantly related to dose (28.2, 2.6, and 2.1 hours for the low-, medium-, and high-dose groups, respectively; P=0.028). There was no significant association with dose for any arrhythmia subgroup, including JET, but the subgroups were too small for an accurate assessment. Adverse events (AEs) were common (87%), leading to withdrawal of 10 patients. There were 5 deaths in the 30-day follow-up period (2 possibly related to the study drug). Dose-related AEs included hypotension (36%), vomiting (20%), bradycardia (20%), atrioventricular block (15%) and nausea (10%)., Conclusions: In children, the overall efficacy of IV amiodarone, as measured by time to success, was dose related but not significantly for any arrhythmia subgroup. AEs were common and appeared to be dose related. Although efficacious for critically ill patients, the dose-related risks of IV amiodarone should be taken into account when treating children with incessant arrhythmias. Prospective, placebo-controlled trials would be helpful in assessing antiarrhythmic drug efficacy in children, because their results may differ from retrospective series and adult studies.

Background: Published rates of coronary restenosis have fallen below 10% in drug-eluting stent trials. Early evaluations of new stents have used continuous end points that are presumed surrogates for restenosis, but the generalizability and power of such end points have not been examined systematically., Methods and Results: We examined the relationship between incremental changes in observed late loss in lumen diameter and the probability of restenosis using reported late loss from 22 published trials of various types of stents (bare-metal, drug-eluting, and small-vessel stents). Next, the power of late loss differences was compared with that of corresponding binary restenosis rates. The relationship between mean late loss and its SD was linear and did not vary with stent type (drug-eluting or bare-metal) or vessel diameter. At all levels of late loss examined (0 to 1 mm), incremental changes were associated with increasing restenosis risk (with an increasing magnitude of effect at higher levels of late loss). The power to detect a treatment effect was greater for late loss than for binary angiographic restenosis (> or =32% relative increase in power, > or =24% absolute increase for late loss between 0.2 and 0.6 mm)., Conclusions: Late loss is monotonically related to restenosis risk in published stent trials. It is a generalizable and powerful angiographic end point in early or small trials of new drug-eluting stents.

Background: Observed rates of restenosis after drug-eluting stenting are low (<10%). Identification of a reliable and powerful angiographic end point will be useful in future trials., Methods and Results: Late loss (postprocedural minimum lumen diameter minus 8-month minimum lumen diameter) was measured in the angiographic cohorts of the SIRIUS (n=703) and E-SIRIUS (n=308) trials. Two techniques, the standard normal approximation and an optimized power transformation, were used to predict binary angiographic restenosis rates and compare them with observed restenosis rates. The mean in-stent late loss observed in the SIRIUS trial was 0.17+/-0.45 mm (sirolimus) versus 1.00+/-0.70 mm (control). If a normal distribution was assumed, late loss accurately estimated in-stent binary angiographic restenosis for the control arm (predicted 35.4% versus observed 35.4%) but underestimated it in the sirolimus arm (predicted 0.6% versus observed 3.2%). Power transformation improved the reliability of the estimate in the sirolimus arm (predicted 3.2% [CI 1.0% to 6.7%]) with similar improvements in the E-SIRIUS trial (predicted 4.0% [CI 1.2% to 7.0%] versus observed 3.9%). In the sirolimus-eluting stent arm, in-stent late loss correlated better with target-lesion revascularization than in-segment late loss (c-statistic=0.915 versus 0.665)., Conclusions: Because distributions of late loss with a low mean are right-skewed, the use of a transformation improves the accuracy of predicting low binary restenosis rates. Late loss is monotonically correlated with the probability of restenosis and yields a more efficient estimate of the restenosis process in the era of lower binary restenosis rates.

Background: We sought to incorporate electron beam tomography-derived calcium scores in a model for prediction of angiographically significant coronary artery disease (CAD). Such a model could greatly facilitate clinical triage in symptomatic patients with no known CAD., Methods and Results: We examined 1851 patients with suspected CAD who underwent coronary angiography for clinical indications. An electron beam tomographic scan was performed in all patients. Total per-patient calcium scores and separate scores for the major coronary arteries were added to logistic regression models to calculate a posterior probability of the severity and extent of angiographic disease. These models were designed to be continuous, adjusted for age and sex, corrected for verification bias, and independently validated in terms of their incremental diagnostic accuracy. The overall sensitivity was 95%, and specificity was 66% for coronary calcium to predict obstructive disease on angiography. With calcium scores >20, >80, and >100, the sensitivity to predict stenosis decreased to 90%, 79%, and 76%, whereas the specificity increased to 58%, 72%, and 75%, respectively. The logistic regression model exhibited excellent discrimination (receiver operating characteristic curve area, 0.842+/-0.023) and calibration (chi2 goodness of fit, 8.95; P=0.442)., Conclusions: Electron beam tomographic calcium scanning provides incremental and independent power in predicting the severity and extent of angiographically significant CAD in symptomatic patients, in conjunction with pretest probability of disease. This algorithm is most useful when applied to an intermediate-risk population.

Background: The role of the L-type calcium channel in human heart failure is unclear, on the basis of previous whole-cell recordings., Methods and Results: We investigated the properties of L-type calcium channels in left ventricular myocytes isolated from nonfailing donor hearts (n= 16 cells) or failing hearts of transplant recipients with dilated (n=9) or ischemic (n=7) cardiomyopathy. The single-channel recording technique was used (70 mmol/L Ba2+). Peak average currents were significantly enhanced in heart failure (38.2+/-9.3 fA) versus nonfailing control hearts (13.2+/-4.5 fA, P=0.02) because of an elevation of channel availability (55.9+/-6.7% versus 26.4+/-5.3%, P=0.001) and open probability within active sweeps (7.36+/-1.51% versus 3.18+/-1.33%, P=0.04). These differences closely resembled the effects of a cAMP-dependent stimulation with 8-Br-cAMP (n= 11). Kinetic analysis of the slow gating shows that channels from failing hearts remain available for a longer time, suggesting a defect in the dephosphorylation. Indeed, the phosphatase inhibitor okadaic acid was unable to stimulate channel activity in myocytes from failing hearts (n=5). Expression of calcium channel subunits was measured by Northern blot analysis. Expression of alpha1c- and beta-subunits was unaltered. Whole-cell current measurements did not reveal an increase of current density in heart failure., Conclusions: Individual L-type calcium channels are fundamentally affected in severe human heart failure. This is probably important for the impairment of cardiac excitation-contraction coupling.

Background: A previous retrospective study by our group suggested that shocks timed to the upslope of the shocking lead electrogram improved defibrillation efficacy. The goal of this study was to prospectively determine whether defibrillation threshold could be reduced by use of an algorithm that timed shocks to the upslope of coarse ventricular fibrillation (test treatment) compared with shocks delivered asynchronously after 10 seconds of fibrillation (control treatment)., Methods and Results: Ten pigs were instrumented with a 3-lead system for internal defibrillation. Initial estimates of the energy required to achieve defibrillation E50 for both treatments were made by an up/down method. Subsequently, additional shocks at V50+/-10% and V50-20% were given for each treatment to obtain data points at higher and lower intensities. Probability-of-success curves were estimated for both treatments by the best-fit method. Energies required were significantly lower for the timed shocks than for the asynchronous shocks (P<0.00 1). E80 was reduced 15.5%, from 27.1+/-2.5 to 22.9+/-1.8 J (P<0.002). The width of the probability-of-success curve (E80-E20) for the test treatment was also significantly narrower than that for the control treatment (7.1+/-0.9 versus 10.8+/-1.7, P<0.01). Normalized curve width (E80-E20)/E50 was decreased from 51+/-5% of E50 for control shocks to 37+/-4% of E50 for synchronous shocks (P<0.02)., Conclusions: In this model, defibrillation threshold is lower and more deterministic when shocks are timed to the upslope of the shocking lead electrogram. If a similar reduction is observed in humans, shock timing may lower defibrillation threshold and simplify programming of shock intensity.

Background: Elevated lipoprotein(a) [Lp(a)] levels have been associated with the presence of atherosclerotic disease. However, the results of prospective studies of Lp(a) and cardiovascular disease have been contradictory., Methods and Results: From 1968 through 1982, lipoprotein analysis was performed in 11,335 Olmsted County residents. Quantitative cholesterol and triglycerides were obtained along with semiquantitative Lp(a) levels based on electrophoretic pattern. Lp(a) bands were scored from 0 (absent) to 3 (increased). A cohort of 4967 men and 4968 women with no prior history of atherosclerotic disease who had baseline Lp(a) determinations were followed up for 14 years for development of coronary artery disease (CAD) and cerebrovascular disease (CVD). During 131,330 person-years of follow-up, there were 1848 CAD events and 841 CVD events. Age, diabetes, hypertension, cholesterol, and triglycerides were significantly and independently associated with an increased risk of CAD and CVD in men and women. There was a significant increase in the adjusted hazards ratio for CAD with increasing Lp(a) levels for men and women. For Lp(a) level 3, the hazard ratio was 1.9 (range, 1.3 to 2.9) in women and 1.6 (range, 1.0 to 2.5) in men. The adjusted hazard ratio for CVD showed an irregular association with Lp(a) levels in men and no association in women., Conclusions: In this cohort of 9936 men and women initially free of cardiovascular disease who were followed up for 14 years, Lp(a) was a significant predictor of risk of future CAD. Lp(a) was a weak risk factor for CVD in men and was not a significant predictor of CVD risk in women.

Background: The long-term effects of double valve replacement on left ventricular function in patients with combined severe rheumatic aortic and mitral regurgitation have not been reported previously. Furthermore, the importance of chordal preservation in this group of patients is unknown., Methods and Results: Serial clinical and echocardiographic evaluations were performed prospectively in 44 patients who underwent double valve replacement for combined aortic and mitral regurgitation. Chordae to the posterior mitral leaflet were preserved in 27 patients. Mean follow-up was 40 +/- 19 months. Left ventricular end-diastolic diameter decreased significantly 3 months after surgery (from 66 +/- 10 to 52 +/- 11 mm; P < .001) without a substantial change in end-systolic diameter, resulting in a significant decline in ejection fraction (from 60 +/- 9% to 48 +/- 15%; P < .001). At 1 year, a significant reduction in end-systolic dimension was observed without a concomitant decline in end-diastolic diameter, thus normalizing the ejection fraction (55 +/- 12%; P = .17 versus baseline). No further changes were seen at latest follow-up. Multivariate regression analysis identified baseline end-systolic diameter and ejection fraction as independent predictors of postoperative systolic performance. Chordal preservation did not emerge as a univariate or multivariate predictor., Conclusions: After an initial postoperative decline in ejection fraction, normalization in left ventricular systolic function may be expected 1 year after double valve replacement for combined rheumatic mitral and aortic regurgitation. End-systolic diameter and ejection fraction are the only independent predictors of postoperative left ventricular performance.

Background: Epidemiological studies and animal experiments have provided evidence supporting the role of lipid peroxidation in atherogenesis and cardiovascular diseases. Direct evidence linking lipid oxidation to atherosclerotic progression in humans, however, has been lacking. We investigated the association of lipid oxidation products with the progression of early carotid atherosclerosis in hypercholesterolemic men from eastern Finland., Methods and Results: Twenty subjects with a fast progression and 20 with no progression of carotid atherosclerosis in 3 years were selected from > 400 participants in the Kuopio Atherosclerosis Prevention Study. Progression of carotid atherosclerosis was assessed by high-resolution B-mode ultrasonography. Serum 7 beta-hydroxycholesterol, a major oxidation product of cholesterol in membranes and lipoproteins, and seven other cholesterol oxidation products were measured by isotope dilution-mass spectrometry, lipid hydroperoxides in LDL fluorometrically as thiobarbituric acid-reactive substances (TBARS) and oxidation susceptibility of LDL and VLDL kinetically. High concentrations of serum 7 beta-hydroxycholesterol (beta = 47, P = .0005), cigarette smoking (beta = .35, P = .0167), and LDL TBARS (beta = .23, P = .0862) and an increased oxidation susceptibility of VLDL + LDL (beta = .22 P = .1114) were the strongest predictors of a 3-year increase in carotid wall thickness of more than 30 variables tested in step-up least-squares regression models. A 10-variable model explained 60% of the atherosclerotic progression. In a multivariate logistic model, the risk of experiencing a fast progression increased by 80% (P = .013) per unit (microgram/L) of 7 beta-hydroxycholesterol., Conclusions: The findings of this study provide further evidence to support an association between lipid oxidation and atherogenesis in humans.

Background: Left ventricular assist devices (LVADs) are increasingly used as a bridge to transplantation. Infection is a frequent and major complication associated with the use of these devices, however, the correlation of infection and outcome has not yet been evaluated in a prospective fashion., Methods and Results: Twenty-five patients (24 male, 1 female) with end-stage cardiac failure and resulting organ dysfunction were included. Patients were bridged with the Novacor N100 portable LVAD (median duration of support, 55 days) and were evaluated prospectively by device surface cultures on explantation, molecular typing of isolates, and correlation of infection with survival to transplant. Twelve (48%) of 25 patients had LVAD infection as defined by recovery of multiple isolates of identical genotype from the device surface. Whereas only 5 (42%) of 12 patients with LVAD infection survived until transplantation, 11 (85%) of 13 patients without infection were successfully transplanted (P < .05). Death of the 7 patients with proven LVAD infection was associated with multiple organ failure or other signs of acute infection., Conclusions: LVAD infection is associated with a significantly decreased survival probability. It does not preclude successful bridging but rather may pose an indication for urgent transplantation.

Background: Several lines of evidence indicate a two-stage failure mode for the Björk-Shiley convexo-concave (C/C) heart valve, in which one of the two outlet strut legs separates from the flange before the other, potentially providing an opportunity to identify and prophylactically replace failure-prone valves. Radiographic single leg separation (SLS) detection, although successful, is subjective and skill intensive, implying a need for both an objective preliminary screen and subsequent corroboration of the radiographic findings., Methods and Results: We developed a time-windowed, power density analysis of C/C valve closing sounds to detect the vibrational resonance that characterizes the presence of an intact outlet strut in clinically functioning, 29-mm-flange size C/C valves. Recordings from more than 800 patients enrolled in radiographic SLS detection studies were analyzed, and the assessment algorithm was evaluated through a blinded test of 32 study valves for which the true status became known consequent to an autopsy or surgical explantation. Valves were objectively scored on a 0-to- 1 scale, with 1 being assuredly intact and scores of < 0.50 indicating a probable SLS. All except five valves (incorrectly designated probable SLS) were classified correctly, for a sensitivity of 1.00 (95% confidence interval, 0.79 to 1.00) and a specificity of 0.69 (0.41 to 0.89)., Conclusions: This level of accuracy is sufficient to serve as an effective preliminary screen, potentially allowing a threefold concentration of SLS prevalence among the C/C valves of patients undergoing radiographic assessment. The value of acoustic classification in avoiding unnecessary operations prompted by false-positive radiographs is less certain.

Background: We hypothesized that for the diagnosis of endocarditis, (1) transthoracic echocardiography (TTE) would be most valuable in patients with an intermediate clinical probability of the disease and (2) transesophageal echocardiography (TEE) would be most useful in patients with an intermediate probability when TTE either does not yield an adequate study or indicates an intermediate probability of endocarditis. We also sought to investigate the influence of echocardiographic results on antibiotic usage and its duration., Methods and Results: TTE and TEE were performed in 105 consecutive patients with suspected endocarditis. Patients were classified as having either low, intermediate, or high probability of endocarditis on the basis of clinical criteria and separately on the basis of both TTE and TEE findings. TTE and TEE classified the majority (82% and 85%, respectively) of the 67 patients with a low clinical probability of endocarditis as having a low likelihood of the disease. Of the 14 patients with intermediate clinical probability, 12 had technically adequate TTE studies; 10 of these (83%) were classified as either high or low probability. All patients with intermediate clinical probability were classified as high or low probability by TEE. The majority of the 24 patients with high clinical probability were placed in the low-likelihood category by echocardiography (15 by TTE and 12 by TEE). There was concordance between TTE and TEE in 83% of all cases. TEE was useful for the diagnosis of endocarditis in patients with prosthetic valves and in those in whom TTE indicated an intermediate probability; these constituted < 20% of patients in our study. The course of antibiotic therapy was influenced only by the clinical profile and not by the echocardiographic results., Conclusions: Echocardiography should not be used to make a diagnosis of endocarditis in those with a low clinical probability of the disease. In those with an intermediate or high clinical probability, TTE should be the diagnostic procedure of choice. TEE for the diagnosis of endocarditis should be reserved only for patients who have prosthetic valves and in whom TTE is either technically inadequate or indicates an intermediate probability of endocarditis.

Background: An upper limit to the strength of shocks that induce fibrillation during the vulnerable period, the upper limit of vulnerability (ULV), has been shown to exist in both humans and animals. The purpose of this study was to compare ULV and defibrillation (DF) probability of success curves for a clinically useful nonthoracotomy lead system., Methods and Results: Sixteen pentobarbital-anesthetized pigs were studied. Single-capacitor biphasic waveforms with both phases 5.5 ms in duration were used for ULV and DF testing. A right ventricular catheter electrode served as first-phase cathode and a superior vena cava catheter electrode coupled with a cutaneous R2 patch electrode served as common first-phase anodes. A pacing catheter was placed in the right ventricle to deliver a train of 15 S1 stimuli at a pacing interval of 250 to 300 ms. A ULV shock was delivered on the peak of the T wave as measured from the surface ECG; if ventricular fibrillation was induced, a DF shock was delivered after 10 seconds of fibrillation. Shock voltages were determined by an up-down protocol. Ventricular fibrillation was induced an average of 53 times in each animal. The composite data indicate that below V97, that is, the voltage that leaves the animal in normal sinus rhythm 97% of the time when delivered on the peak of the T wave or the voltage that defibrillates 97% of the time, ULV is lower than DF. ULV and DF became significantly correlated at V80 and maximally correlated at V97. Even at V97, however, ULV and DF differed by more than 100 V in 2 of the 16 animals., Conclusions: ULV approximately equaled DF at V97. This is fortunate because it is clinically important to set the device voltage at the uppermost portion of the probability of success curve. Estimating DF V97 from ULV V97 would reduce the number of fibrillation inductions needed to establish defibrillation shock strength requirements. However, the large difference between ULV V97 and DF in a few animals indicates that further improvement and testing of algorithms for determining ULV V97 must be developed before the technique is used clinically.

Background: Left ventricular hypertrophy is often found very early in the course of hypertension. It is not known whether increased left ventricular mass contributes to the pathogenesis of hypertension. The purpose of this study was to examine the impact of left ventricular mass and other echocardiographically assessed cardiac structural features on the incidence of hypertension., Methods and Results: Subjects for this investigation included participants in the Framingham Heart Study and the Framingham Offspring Study who were normotensive at the baseline examination (systolic blood pressure, < 140 mm Hg; diastolic blood pressure, < 90 mm Hg; not receiving antihypertensive medications) and free of coronary heart disease, congestive heart failure, valvular heart disease, hypertrophic cardiomyopathy, diabetes mellitus, and renal insufficiency. The study sample included 1121 men (mean age, 44.4 years) and 1559 women (mean age, 45.6 years). Four years after the baseline examination, 202 men (18.0%) and 257 women (16.5%) were hypertensive (systolic blood pressure, > or = 140 mm Hg; diastolic blood pressure, > or = 90 mm Hg; or use of antihypertensive medications). Baseline echocardiographic left ventricular mass (P = .01) and the sum of septal and posterior left ventricular wall thicknesses (P = .02) were associated with progression to hypertension. After adjusting for sex, baseline age, systolic and diastolic blood pressures, body mass index, alcohol intake, and systolic blood pressure from an examination 8 years earlier, the odds ratio for developing hypertension for a 1-SD increment in left ventricular mass index was 1.20 (95% confidence interval, 1.04 to 1.39), and the odds ratio for a 1-SD increment in left ventricular wall thickness was 1.16 (95% confidence interval, 1.02 to 1.33)., Conclusions: In these normotensive adults, increased left ventricular mass and wall thickness were associated with the development of hypertension. Further studies are warranted to examine the utility of echocardiography in determining the need for antihypertensive therapy and to assess the effect of earlier intervention on the course of progression to hypertension.

Background: Low cholesterol levels have been associated with increased mortality from stroke, cancer, and other noncardiovascular diseases, but the reasons for this association remain unclear. One explanation is that persons with low cholesterol levels have early or occult disease that eventually leads to their deaths., Methods and Results: This possibility was explored in 2,091 men and 2,714 women 65-100 years old in the Cardiovascular Health Study, a multicenter observational study of risk factors for heart disease and stroke in older adults. Cholesterol levels < or = 160 mg/dL were present in 11.6% of men and 3.7% of women and increased in prevalence with age. After adjustment for age, total cholesterol levels in this range were associated with a twofold increased prevalence of treated diabetes in men and women and with a twofold increased prevalence of cancer diagnosed in the preceding 5 years in women only. Low cholesterol was also associated with lower levels of hemoglobin, albumin, and factor VII, suggesting a link with hepatic synthetic function. On multivariate analysis, factors most strongly associated with low cholesterol levels in men and women were decreased factor VII levels, decreased albumin, and diabetes., Conclusions: Cross-sectional associations with low cholesterol levels differ by sex and suggest poorer health by some measures. The observed relations with treated diabetes and impaired hepatic synthetic function should be examined for risk of mortality in longitudinal data from this and other observational studies.

Background: Two hundred eighteen patients were evaluated in a two-phase approach (time to first appropriate discharge, survival after discharge) to identify factors that may be related to maximal benefit derived from use of an automatic implantable cardioverter-defibrillator (AICD)., Methods and Results: One hundred ninety-seven patients survived implantation of AICD, with or without concomitant cardiac surgery. One hundred five patients had an AICD discharge associated with syncope, presyncope, documented sustained ventricular tachycardia or fibrillation, or sleep at 9.1 +/- 11.1 months after implantation. Patients survived 23.8 +/- 18.0 months after AICD discharge. Left ventricular dysfunction (p = 0.008 for ejection fraction less than 25%) was associated with earlier AICD discharge and shortened survival after AICD discharge (p = 0.008 for ejection fraction less than 25%; p = 0.01 for New York Heart Association functional class III and IV). beta-Blocker administration (p = 0.006) and coronary bypass surgery (p = 0.06) were associated with later AICD discharge. Coronary bypass surgery (p = 0.035) but not beta-blockers was associated with more prolonged survival after AICD discharge., Conclusions: These data suggest that a relatively easy algorithm can be applied to predict which patient will benefit most from AICD implantation.

Logistic regression was applied to the clinical, risk factor, and exercise data of consecutive angiographic referrals without prior myocardial infarction to determine an algorithm predicting the probability of triple-vessel/left main coronary artery disease. These data were obtained from a total of 1,074 such subjects from patient populations at four centers (Cleveland Clinic Foundation, Cleveland, Ohio; Hungarian Institute of Cardiology, Budapest, Hungary; the university hospitals, Zurich and Basel, Switzerland; and the Veterans Administration Medical Center, Long Beach, Calif.) and used to derive four separate probability algorithms. Each algorithm is based on patient data from study samples at three of the four centers and consists of 272 logistic functions, which are related to linear combinations of 13 variables (age, sex, type of chest pain, systolic blood pressure, resting electrocardiogram, serum cholesterol, fasting blood sugar, achieved exercise work load, achieved heart rate, exercise-induced angina and hypotension, heart rate-adjusted resting ST depression, and exercise ST slope). The four algorithms were cross validated by testing them on the populations not involved in their derivation. The resulting probabilities in the four test groups were then compared with the angiographic findings of triple-vessel/left main coronary artery disease. The discriminatory power of all the algorithms was fair to good (area under receiver operating characteristic curve, 0.68, 0.75, 0.82, 0.85) in the test groups. The algorithm did not significantly underestimate or overestimate disease probability except in one center (Long Beach).(ABSTRACT TRUNCATED AT 250 WORDS)

Certain biphasic waveforms require less energy to defibrillate than do monophasic pulses of equal duration, although the mechanisms of this increased effectiveness remain unclear. This study used strength-duration and percent success curves for defibrillation with monophasic and biphasic truncated exponential waveforms to explore these mechanisms. In part 1, defibrillation thresholds were determined for both high- and low-tilt waveforms. The monophasic pulses tested ranged in duration from 1.0 to 20.0 msec, and the biphasic waveforms had first phases of either 3.5 or 7.0 msec and second phases ranging from 1.0 to 20.0 msec. In part 2, defibrillation percent success curves were constructed for 6.0 msec/6.0 msec biphasic waveforms with a constant phase-one amplitude and with phase-two amplitudes of approximately 21%, 62%, 94%, and 141% of phase one. This study shows that if the first phase of a biphasic waveform is held constant and the second phase is increased in either duration or amplitude, defibrillation efficacy first improves, then declines, and then again improves. For pulse durations of at least 14 msec, the second-phase defibrillation threshold voltage of a high-tilt biphasic waveform is higher than that of a monophasic pulse equal in duration to the biphasic second phase (p less than 0.05), indicating that the previously proposed hypothesis of stimulation by the second phase is not the sole mechanism of biphasic defibrillation. These facts indicate the importance of the degree of tilt for the defibrillation efficacy of biphasic waveforms and suggest at least two mechanisms exist for defibrillation with these waveforms, one that is more effective for smaller second phases and another that becomes more effective as the second phase is increased.

Of 22 randomized trials of rehabilitation with exercise after myocardial infarction (MI), one trial had results that achieved conventional statistical significance. To determine whether or not these studies, in the aggregate, show a significant benefit of rehabilitation after myocardial infarction, we performed an overview of all randomized trials, involving 4,554 patients; we evaluated total and cardiovascular mortality, sudden death, and fatal and nonfatal reinfarction. For each endpoint, we calculated an odds ratio (OR) and 95% confidence interval (95% CI) for the trials combined. After an average of 3 years of follow-up, the ORs were significantly lower in the rehabilitation than in the comparison group: specifically, total mortality (OR = 0.80 [0.66, 0.96]), cardiovascular mortality (OR = 0.78 [0.63, 0.96]), and fatal reinfarction (OR = 0.75 [0.59, 0.95]). The OR for sudden death was significantly lower in the rehabilitation than in the comparison group at 1 year (OR = 0.63 [0.41, 0.97]). The data were compatible with a benefit at 2 (OR = 0.76 [0.54, 1.06]) and 3 years (OR = 0.92 [0.69, 1.23]), but these findings were not statistically significant. For nonfatal reinfarction, there were no significant differences between the two groups after 1 (OR = 1.09 [0.76, 1.57]), 2 (OR = 1.10 [0.82, 1.47]), or 3 years (OR = 1.09 [0.88, 1.34]) of follow-up. The observed 20% reduction in overall mortality reflects a decreased risk of cardiovascular mortality and fatal reinfarction throughout at least 3 years and a reduction in sudden death during the 1st year after infarction and possibly for 2-3 years. With respect to the independent effects of the physical exercise component of cardiac rehabilitation, the relatively small number of "exercise only" trials, combined with the possibility that they may have had a formal or informal nonexercise component precludes the possibility of reaching any definitive conclusion. To do so would require a randomized trial of sufficient size to distinguish between no effect and the most plausible effect based on the results of this overview.

Retrospective surgery data were obtained from 358 coronary artery bypass surgery patients 4-22 months (mean 12.5 months) after surgery. Before surgery, 69% of the subjects were working, 10% were unemployed, and 21% were retired. At follow-up, only 58% were working and 29% were retired. Employment before surgery was the most significant predictor of work status after surgery. Other factors that were positively related to returning to work include higher presurgery income and job classification, higher pre- and postoperative ejection fraction, and subjective improvement in tolerance for physical activity. Factors that were negatively related to returning to work were age, number of chronic medical problems, presence of cardiac symptoms, and receipt of disability compensation. Reported improvement in symptoms was not related to postoperative work status. Job classification, physical demands of the job, and time out of work before surgery were also related to how soon patients returned to work. Participation in an outpatient rehabilitation program was significantly related to postoperative work status for men employed before surgery. Questions were raised regarding the role of outpatient cardiac rehabilitation in altering patient perceptions and maintaining "work habits" that might facilitate work resumption after coronary artery bypass surgery. The results suggest that multiple physical, social and psychological factors interact to influence postoperative work status.

To determine the incremental value of the exercise test (ETT) for diagnosing coronary artery disease (CAD), we derived a multivariate logistic regression model for the pre-ETT prediction of CAD using data from 3840 patients at Duke University. We then applied the model to 324 patients at the Brigham and Women's Hospital. Using seven clinical factors, the multivariate model had an 84% overall predictive accuracy on both the training (Duke) and the validation (Brigham) sets of patients. Three ETT factors (ST-segment change in patients not taking digitalis, absence of ST-segment change in patients taking digitalis, ETT stopped because of ECG or blood pressure changes) had incremental, significant predictive power, but overall predictive accuracy based on both clinical and ETT factors improved only to 87%. When the ETT result was important enough to move the probability of CAD across a potential therapeutic threshold, the direction of the change in probability was correct only two-thirds of the time. Thus, the ETT was of limited value in predicting the presence or absence of CAD after other easily obtainable clinical data were taken into account.

A multivariate logistic regression equation was used to evaluate variables related to successful intracoronary thrombolytic therapy. One hundred seventeen patients with a totally occluded infarct-related artery were randomly given ostial infusions of urokinase or streptokinase in a blinded study. The opening rate was 57%. The agent used and time from onset of symptoms to beginning of treatment did not significantly influence opening rate (p greater than .25). The site of occlusion was a strong predictor of opening rate (p = .0004). The anterior descending coronary artery was successfully opened more frequently than the left circumflex or right coronary artery (p = .012). Presence of collaterals adversely affected the recanalization rate in all groups (p = .0004). These variables had an additive effect on the probability of opening. Patients with proximal anterior descending occlusion and no collaterals had a 90% recanalization rate, while those with distal occlusions in vessels other than the anterior descending and with collaterals had only a 24% chance for reperfusion. Thus location of occlusion and presence or absence of collaterals may strongly influence opening rates.

A review of the current literature of the high-risk factors associated with cardiac morbidity and mortality in patients with established coronary heart disease is presented. Univariate risk factors include age, comorbidity, characteristics of the index coronary event, electrocardiographic findings including ventricular premature beats and response to exercise tests, angiographic severity of the coronary disease, cigarette smoking, psychosocial status, and the chronometric interval after the index coronary event. Multivariate analysis of risk factor combinations is discussed. Risk reduction requires not only an understanding of the clinical course of a disease process, but also, modification of the amenable factors which contribute to excess risk of death.

The clinician may often be uncertain about the presence of digoxin toxicity. This uncertainty is particularly important when the clinician must make initial therapeutic decisions about continuing or discontinuing digoxin. We describe a method that helps to clarify the role of the serum digoxin test in decreasing the uncertainty surrounding the diagnosis and treatment of toxicity. The relation between the test and toxicity was first determined in our patient population. An approach to the interpretation of the test based on the likelihood ratio was then developed by combining our data with selected data from the literature. The relation between the pretest risk of toxicity (the estimated risk of toxicity in the population under investigation before the test result is known) and the predictive value of the test was established. This relation was also used to analyze the importance of the degree of elevation of the test. The appropriate threshold probability for institution of treatment of toxicity was then determined by an interview technique. The test was able to make the patient's probability of toxicity cross the threshold probability for treatment of toxicity for an intermediate range of pretest risk. Our analysis suggests that the serum digoxin test may have a critical effect on therapeutic decisions and can be best considered as contributing to the spectrum of risk.

In this study we assessed whether various responses to exercise testing could be quantified in order to derive the probabilities of presence of coronary disease, and if present, to assess its severity. A treadmill score based on the exercise response was determined in 405 patients who had both treadmill tests and coronary angiograms. The score was derived using discriminant function analysis, by weighting and combining depth and configuration of ST depression (downsloping, horizontal or slowly upsloping), timing onset and duration of ischemia, grading ventricular arrhythmias, heart rate and blood pressure change, coexistence of exercise-induced chest pain and sex. The treadmill score was effective in detecting coronary disease (lesions with an greater than or equal to 50% narrowing), with a predictive accuracy (PA) (probability that a subject manifesting a positive test has disease) of 87%, a true negative rate (TNR) (probability of a subject with a negative test having no disease) of 80%, and sensitivity of 94%. The treadmill score also detected severe disease (triple-vessel, main left and/or greater than 90% proximal occlusion of the left anterior descending artery), with a PA of 73%, TNR of 79% and sensitivity of 82%. We conclude that the exercise response, expressed numerically as a treadmill score, permits analysis of most of the relevant data from exercise testing, increases test accuracy by 10-15% compared with standard criteria for treatmill test interpretation, and enables the derivation of probability statements for presence and severity of coronary disease. The validity of any prediction on the basis of exercise performance may thus be quantitatively judged.