Cardiac resynchronization therapy: mechanisms of action and scope for further improvement in cardiac function.

AIMS: Cardiac resynchronization therapy (CRT) may exert its beneficial haemodynamic effect by improving ventricular synchrony and improving atrioventricular (AV) timing. The aim of this study was to establish the relative importance of the mechanisms through which CRT improves cardiac function and explore the potential for additional improvements with improved ventricular resynchronization. METHODS AND RESULTS: We performed simulations using the CircAdapt haemodynamic model and performed haemodynamic measurements while adjusting AV delay, at low and high heart rates, in 87 patients with CRT devices. We assessed QRS duration, presence of fusion, and haemodynamic response. The simulations suggest that intrinsic PR interval and the magnitude of reduction in ventricular activation determine the relative importance of the mechanisms of benefit. For example, if PR interval is 201 ms and LV activation time is reduced by 25 ms (typical for current CRT methods), then AV delay optimization is responsible for 69% of overall improvement. Reducing LV activation time by an additional 25 ms produced an additional 2.6 mmHg increase in blood pressure (30% of effect size observed with current CRT). In the clinical population, ventricular fusion significantly shortened QRS duration (Δ-27 ± 23 ms, P < 0.001) and improved systolic blood pressure (mean 2.5 mmHg increase). Ventricular fusion was present in 69% of patients, yet in 40% of patients with fusion, shortening AV delay (to a delay where fusion was not present) produced the optimal haemodynamic response. CONCLUSIONS: Improving LV preloading by shortening AV delay is an important mechanism through which cardiac function is improved with CRT. There is substantial scope for further improvement if methods for delivering more efficient ventricular resynchronization can be developed. CLINICAL TRIAL REGISTRATION: Our clinical data were obtained from a subpopulation of the British Randomised Controlled Trial of AV and VV Optimisation (BRAVO), which is a registered clinical trial with unique identifier: NCT01258829, https://clinicaltrials.gov.

Automatic detection of end-diastolic and end-systolic frames in 2D echocardiography.

BACKGROUND: Correctly selecting the end-diastolic and end-systolic frames on a 2D echocardiogram is important and challenging, for both human experts and automated algorithms. Manual selection is time-consuming and subject to uncertainty, and may affect the results obtained, especially for advanced measurements such as myocardial strain. METHODS AND RESULTS: We developed and evaluated algorithms which can automatically extract global and regional cardiac velocity, and identify end-diastolic and end-systolic frames. We acquired apical four-chamber 2D echocardiographic video recordings, each at least 10 heartbeats long, acquired twice at frame rates of 52 and 79 frames/s from 19 patients, yielding 38 recordings. Five experienced echocardiographers independently marked end-systolic and end-diastolic frames for the first 10 heartbeats of each recording. The automated algorithm also did this. Using the average of time points identified by five human operators as the reference gold standard, the individual operators had a root mean square difference from that gold standard of 46.5 ms. The algorithm had a root mean square difference from the human gold standard of 40.5 ms (P<.0001). Put another way, the algorithm-identified time point was an outlier in 122/564 heartbeats (21.6%), whereas the average human operator was an outlier in 254/564 heartbeats (45%). CONCLUSION: An automated algorithm can identify the end-systolic and end-diastolic frames with performance indistinguishable from that of human experts. This saves staff time, which could therefore be invested in assessing more beats, and reduces uncertainty about the reliability of the choice of frame.

The effect of duration of follow-up and presence of competing risk on lifespan-gain from implantable cardioverter defibrillator therapy: who benefits the most?

BACKGROUND: In at-risk patients with left ventricular dysfunction, implantable cardioverter defibrillators (ICDs) prolong life. Implantable cardioverter defibrillators are increasingly implanted for primary prevention and therefore into lower risk patients. Trial data have demonstrated the benefit of these devices but does not provide an estimate of potential lifespan-gain over longer time periods, e.g. a patient's lifespan. METHODS: Using data from landmark ICD trials, lifespan-gain was plotted against baseline annual mortality in the individual trials. Lifespan-gain was then extrapolated to a time-horizon of >20 years while adjusting for increasing 'competing' risk from ageing and non-sudden cardiac death (pump failure). RESULTS: At 3 years, directly observed lifespan-gain was strongly dependent on baseline event rate (r = 0.94, P < 0.001). However, projecting beyond the duration of the trial, lifespan-gain increases rapidly and non-linearly with time. At 3 years, it averages 1.7 months, but by 10 years up to 9-fold more. Lifespan-gain over time horizons >20 years were greatest in lower risk patients (∼5 life-years for 5% baseline mortality, ∼2 life-years for 15% baseline mortality). Increased competing risks significantly reduce lifespan-gain from ICD implantation. CONCLUSION: While high-risk patients may show the greatest short-term gain, the dramatic growth of lifespan-gain over time means that it is the lower risk patients, e.g. primary prevention ICD implantation, who gain the most life-years over their lifetime. Benefit is underestimated when only trial data are assessed as trials can only maintain randomization over limited periods. Lifespan-gain may be further increased through advances in ICD device programming.

Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment.

BACKGROUND: Most people who begin statins abandon them, most commonly because of side effects. OBJECTIVES: The purpose of this study was to assess daily symptom scores on statin, placebo, and no treatment in participants who had abandoned statins. METHODS: Participants received 12 1-month medication bottles, 4 containing atorvastatin 20 mg, 4 placebo, and 4 empty. We measured daily symptom intensity for each using an app (scale 1-100). We also measured the "nocebo" ratio: the ratio of symptoms induced by taking statin that was also induced by taking placebo. RESULTS: A total of 60 participants were randomized and 49 completed the 12-month protocol. Mean symptom score was 8.0 (95% CI: 4.7-11.3) in no-tablet months. It was higher in statin months (16.3; 95% CI: 13.0-19.6; P < 0.001), but also in placebo months (15.4; 95% CI: 12.1-18.7; P < 0.001), with no difference between the 2 (P = 0.388). The corresponding nocebo ratio was 0.90. In the individual-patient daily data, neither symptom intensity on starting (OR: 1.02; 95% CI: 0.98-1.06; P = 0.28) nor extent of symptom relief on stopping (OR: 1.01; 95% CI: 0.98-1.05; P = 0.48) distinguished between statin and placebo. Stopping was no more frequent for statin than placebo (P = 0.173), and subsequent symptom relief was similar between statin and placebo. At 6 months after the trial, 30 of 60 (50%) participants were back taking statins. CONCLUSIONS: The majority of symptoms caused by statin tablets were nocebo. Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo. (Self-Assessment Method for Statin Side-effects Or Nocebo [SAMSON]; NCT02668016).

Distribution of lifespan gain from primary prevention intervention.

OBJECTIVE: When advising patients about possible initiation of primary prevention treatment, clinicians currently do not have information on expected impact on lifespan, nor how much this increment differs between individuals. METHODS: First, UK cardiovascular and non-cardiovascular mortality data were used to calculate the mean lifespan gain from an intervention (such as a statin) that reduces cardiovascular mortality by 30%. Second, a new method was developed to calculate the probability distribution of lifespan gain. Third, we performed a survey in three UK cities on 11 days between May-June 2014 involving 396 participants (mean age 40 years, 55% male) to assess how individuals evaluate potential benefit from primary prevention therapies. RESULTS: Among numerous identical patients, the lifespan gain, from an intervention that reduces cardiovascular mortality by 30%, is concentrated within an unpredictable minority. For example, men aged 50 years with national average cardiovascular risk have mean lifespan gain of 7 months. However, 93% of these identical individuals gain no lifespan, while the remaining 7% gain a mean of 99 months. Many survey respondents preferred a chance of large lifespan gain to the equivalent life expectancy gain given as certainty. Indeed, 33% preferred a 2% probability of 10 years to fivefold more gain, expressed as certainty of 1 year. CONCLUSIONS: People who gain lifespan from preventative therapy gain far more than the average for their risk stratum, even if perfectly defined. This may be important in patient decision-making. Looking beyond mortality reduction alone from preventative therapy, the benefits are likely to be even larger.

Renal artery sympathetic denervation: observations from the UK experience.

BACKGROUND: Renal denervation (RDN) may lower blood pressure (BP); however, it is unclear whether medication changes may be confounding results. Furthermore, limited data exist on pattern of ambulatory blood pressure (ABP) response-particularly in those prescribed aldosterone antagonists at the time of RDN. METHODS: We examined all patients treated with RDN for treatment-resistant hypertension in 18 UK centres. RESULTS: Results from 253 patients treated with five technologies are shown. Pre-procedural mean office BP (OBP) was 185/102 mmHg (SD 26/19; n = 253) and mean daytime ABP was 170/98 mmHg (SD 22/16; n = 186). Median number of antihypertensive drugs was 5.0: 96 % ACEi/ARB; 86 % thiazide/loop diuretic and 55 % aldosterone antagonist. OBP, available in 90 % at 11 months follow-up, was 163/93 mmHg (reduction of 22/9 mmHg). ABP, available in 70 % at 8.5 months follow-up, was 158/91 mmHg (fall of 12/7 mmHg). Mean drug changes post RDN were: 0.36 drugs added, 0.91 withdrawn. Dose changes appeared neutral. Quartile analysis by starting ABP showed mean reductions in systolic ABP after RDN of: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively (p < 0.001 for trend). Use of aldosterone antagonist did not predict response (p > 0.2). CONCLUSION: In 253 patients treated with RDN, office BP fell by 22/9 mmHg. Ambulatory BP fell by 12/7 mmHg, though little response was seen in the lowermost quartile of starting blood pressure. Fall in BP was not explained by medication changes and aldosterone antagonist use did not affect response.

A novel curve fitting method for AV optimisation of biventricular pacemakers.

In this study, we designed and tested a new algorithm, which we call the 'restricted parabola', to identify the optimum atrioventricular (AV) delay in patients with biventricular pacemakers. This algorithm automatically restricts the hemodynamic data used for curve fitting to the parabolic zone in order to avoid inadvertently selecting an AV optimum that is too long.We used R, a programming language and software environment for statistical computing, to create an algorithm which applies multiple different cut-offs to partition curve fitting of a dataset into a parabolic and a plateau region and then selects the best cut-off using a least squares method. In 82 patients, AV delay was adjusted and beat-to-beat systolic blood pressure (SBP) was measured non-invasively using our multiple-repetition protocol. The novel algorithm was compared to fitting a parabola across the whole dataset to identify how many patients had a plateau region, and whether a higher hemodynamic response was achieved with one method.In 9/82 patients, the restricted parabola algorithm detected that the pattern was not parabolic at longer AV delays. For these patients, the optimal AV delay predicted by the restricted parabola algorithm increased SBP by 1.36 mmHg above that predicted by the conventional parabolic algorithm (95% confidence interval: 0.65 to 2.07 mmHg, p-value = 0.002).AV optima selected using our novel restricted parabola algorithm give a greater improvement in acute hemodynamics than fitting a parabola across all tested AV delays. Such an algorithm may assist the development of automated methods for biventricular pacemaker optimisation.

Effect of study design on the reported effect of cardiac resynchronization therapy (CRT) on quantitative physiological measures: stratified meta-analysis in narrow-QRS heart failure and implications for planning future studies.

BACKGROUND: Biventricular pacing (CRT) shows clear benefits in heart failure with wide QRS, but results in narrow QRS have appeared conflicting. We tested the hypothesis that study design might have influenced findings. METHOD AND RESULTS: We identified all reports of CRT-P/D therapy in subjects with narrow QRS reporting effects on continuous physiological variables. Twelve studies (2074 patients) met these criteria. Studies were stratified by presence of bias-resistance steps: the presence of a randomized control arm over a single arm, and blinded outcome measurement. Change in each endpoint was quantified using a standardized effect size (Cohen's d). We conducted separate meta-analyses for each variable in turn, stratified by trial quality. In non-randomized, non-blinded studies, the majority of variables (10 of 12, 83%) showed significant improvement, ranging from a standardized mean effect size of +1.57 (95%CI +0.43 to +2.7) for ejection fraction to +2.87 (+1.78 to +3.95) for NYHA class. In the randomized, non-blinded study, only 3 out of 6 variables (50%) showed improvement. For the randomized blinded studies, 0 out of 9 variables (0%) showed benefit, ranging from -0.04 (-0.31 to +0.22) for ejection fraction to -0.1 (-0.73 to +0.53) for 6-minute walk test. CONCLUSIONS: Differences in degrees of resistance to bias, rather than choice of endpoint, explain the variation between studies of CRT in narrow-QRS heart failure addressing physiological variables. When bias-resistance features are implemented, it becomes clear that these patients do not improve in any tested physiological variable. Guidance from studies without careful planning to resist bias may be far less useful than commonly perceived.

Opportunity to increase life span in narrow QRS cardiac resynchronization therapy recipients by deactivating ventricular pacing: evidence from randomized controlled trials.

OBJECTIVES: This study examined the time course of clinical events in cardiac resynchronization therapy (CRT) trials. BACKGROUND: Recent randomized controlled trial results suggest that in heart failure with narrow QRS, biventricular pacing (CRT) may increase mortality. The authors proposed implant complications as the cause, rather than a progressive adverse physiological effect. METHODS: The study identified all trials comparing CRT with no CRT, which reported Kaplan-Meier curves in groups defined by QRS: narrow, non-left bundle branch block (LBBB) broad, and LBBB broad. For each trial, the change in life span every 3 months up to 3.5 years (the longest time for which data are available) was calculated and a power law was fitted, that is, ∝ time(n). RESULTS: Four trials (MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure Trial], REVERSE [REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction], and EchoCRT [Echocardiography Guided Cardiac Resynchronization Therapy]), totaling 4,717 patients, reported curves for mortality or heart failure-related hospitalization, or for mortality. In patients with LBBB broad QRS (within MADIT-CRT), life span gain increased in proportion to time(1.94). In contrast, in patients with non-LBBB broad QRS (within MADIT-CRT) and patients with narrow QRS (EchoCRT), life span was lost in proportion to time(1.92) and time,(1.96) respectively. Hospitalization-free survival showed similar patterns. CONCLUSIONS: The nonlinear growth of life span gained when a CRT device is implanted in patients with LBBB broad QRS is unfortunately mirrored by a similarly progressive loss in life span in narrow QRS heart failure. This suggests the culprit is a progressive physiological effect of pacing rather than implant complications. If these data are not sufficient, a randomized controlled trial of deactivating CRT in patients with narrow QRS may now be needed, with a primary endpoint of increasing survival.

Intra-aortic Balloon Pump Therapy for Acute Myocardial Infarction: A Meta-analysis.

IMPORTANCE: Intra-aortic balloon pump (IABP) therapy is a widely used intervention for acute myocardial infarction with cardiogenic shock. Guidelines, which previously strongly recommended it, have recently undergone substantial change. OBJECTIVE: To assess IABP efficacy in acute myocardial infarction. DATA SOURCES: Human studies found in Pubmed, Embase, and Cochrane libraries through December 2014 and in reference lists of selected articles. Search strings were "myocardial infarction" or "acute coronary syndrome" and "intra-aortic balloon pump" or "counterpulsation." STUDY SELECTION: Randomized clinical trials (RCTs) and observational studies comparing use of IABP with no IABP in patients with acute myocardial infarction. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted the data, and risk of bias in RCTs was assessed using the Cochrane risk of bias tool. We conducted separate meta-analyses of the RCTs and observational studies. Data were quantitatively synthesized using random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: Thirty-day mortality. RESULTS: There were 12 eligible RCTs randomizing 2123 patients. In the RCTs, IABP use had no statistically significant effect on mortality (odds ratio [OR], 0.96 [95% CI, 0.74-1.24]), with no significant heterogeneity among trials (I2 = 0%; P = .52). This result was consistent when studies were stratified by the presence (OR, 0.94 [95% CI, 0.69-1.28]; P = .69, I2 = 0%) or absence (OR, 0.98 [95% CI, 0.57-1.69]; P = .95, I2 = 17%) of cardiogenic shock. There were 15 eligible observational studies totaling 15 530 patients. Their results were mutually conflicting (heterogeneity I2 = 97%; P < .001), causing wide uncertainty in the summary estimate for the association with mortality (OR, 0.96 [95% CI, 0.54-1.70]). A simple index of baseline risk marker imbalance in the observational studies appeared to explain much of the heterogeneity in the observational data (R2meta = 46.2%; P < .001). CONCLUSIONS AND RELEVANCE: Use of IABP was not found to improve mortality among patients with acute myocardial infarction in the RCTs, regardless of whether patients had cardiogenic shock. The observational studies showed a variety of mutually contradictory associations between IABP therapy and mortality, much of which was explained by the differences between studies in the balance of risk factors between IABP and non-IABP groups.

2014 global geographic analysis of mortality from ischaemic heart disease by country, age and income: statistics from World Health Organisation and United Nations.

BACKGROUND: Ischaemic heart disease (IHD) is the leading cause of death worldwide and its prevention is a public health priority. METHOD: We analysed worldwide IHD mortality data from the World Health Organisation as of February 2014 by country, age and income. Age-standardised mortality rates by country were calculated. We constructed a cartogram which is an algorithmically transformed world map that conveys numbers of deaths in the form of spatial area. RESULTS: Of the countries that provided mortality data, Russia, the United States of America and Ukraine contributed the largest numbers of deaths. India and China were estimated to have even larger numbers of deaths. Death rates from IHD increase rapidly with age. Crude mortality rates appear to be stable whilst age-standardised mortality rates are falling. Over half of the world's countries (113/216) have provided IHD mortality data for 2008 or later. Of these, 13 countries provided data in 2012. No countries have yet provided 2013 data. Of the 103 remaining countries, 24 provided data in 2007 or earlier, and 79 have never provided data in the ICD9 or ICD10 format. CONCLUSIONS: In the countries for which there are good longitudinal data, predominantly European countries, recent years have shown a continuing decline in age-standardised IHD mortality. However, the progressive aging of populations has kept crude IHD mortality high. It is not known whether the pattern is consistent globally because many countries have not provided regular annual data including wealthy countries such as the United Arab Emirates and large countries such as India and China.

What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice.

OBJECTIVE: Discussions about statin efficacy in cardiovascular prevention are always based on data from blinded randomized controlled trials (RCTs) comparing statin to placebo; however, discussion of side effects is not. Clinicians often assume symptoms occurring with statins are caused by statins, encouraging discontinuation. We test this assumption and calculate an evidence-based estimate of the probability of a symptom being genuinely attributable to the statin itself. METHODS: We identified RCTs comparing statin to placebo for cardiovascular prevention that reported side effects separately in the two arms. RESULTS: Among 14 primary prevention trials (46,262 participants), statin therapy increased diabetes by absolute risk of 0.5% (95% CI 0.1-1%, p = 0.012), meanwhile reducing death by a similar extent: -0.5% (-0.9 to -0.2%, p = 0.003). In the 15 secondary prevention RCTs (37,618 participants), statins decreased death by 1.4% (-2.1 to -0.7%, p < 0.001). There were no other statin-attributable symptoms, although asymptomatic liver transaminase elevation was 0.4% more frequent with statins across all trials. Serious adverse events and withdrawals were similar in both arms. CONCLUSIONS: Only a small minority of symptoms reported on statins are genuinely due to the statins: almost all would occur just as frequently on placebo. Only development of new-onset diabetes mellitus was significantly higher on statins than placebo; nevertheless only 1 in 5 of new cases were actually caused by statins. Higher statin doses produce a detectable effect, but even still the proportion attributable to statins is variable: for asymptomatic liver enzyme elevation, the majority are attributable to the higher dose; in contrast for muscle aches, the majority are not.

International RCT-based guidelines for use of preoperative stress testing and perioperative beta-blockers and statins in non-cardiac surgery.

BACKGROUND: Cardiologists frequently advise on perioperative care for non-cardiac surgery and require guidance based on randomised controlled trials that are not discredited by misconduct or misreporting. Regional political bodies currently do not provide this. We therefore examined the credible randomised controlled trial (RCT) evidence on key cardiac perioperative questions which currently have 14 recommendations. METHODS: Three aspects of perioperative measures were considered: perioperative statins, preoperative stress-testing and perioperative beta-blockade. One author searched PubMed for RCTs considering these topics. All authors independently assessed the RCTs and then collaboratively composed guidelines. RESULTS: Perioperative statin therapy has been examined by three RCTs, DECREASE III and IV, which are discredited and a third containing serious inconsistencies undermining its validity. Preoperative stress testing has been examined by two RCTs: one discredited trial, DECREASE II, and a second which found no benefit. Perioperative beta-blockade has been examined by eleven RCTs, two of which are discredited. The nine remaining trials together suggest that perioperative beta-blockade increases mortality. CONCLUSIONS: When the non-credible RCTs are omitted, the evidence base on these three subjects is much smaller than previously believed: 14 recommendations can be replaced by 3. Current guideline arrangements collectively paralyse the numerous signatories from making urgent amendments after initial publication, even when important new information comes to light. Clinicians simply have to wait for the routine five-year expiry. We present a concise scientifically based guideline and commit to updating it responsibly.

Automated aortic Doppler flow tracing for reproducible research and clinical measurements.

In clinical practice, echocardiographers are often unkeen to make the significant time investment to make additional multiple measurements of Doppler velocity. Main hurdle to obtaining multiple measurements is the time required to manually trace a series of Doppler traces. To make it easier to analyze more beats, we present the description of an application system for automated aortic Doppler envelope quantification, compatible with a range of hardware platforms. It analyses long Doppler strips, spanning many heartbeats, and does not require electrocardiogram to separate individual beats. We tested its measurement of velocity-time-integral and peak-velocity against the reference standard defined as the average of three experts who each made three separate measurements. The automated measurements of velocity-time-integral showed strong correspondence (R(2) = 0.94) and good Bland-Altman agreement (SD = 1.39 cm) with the reference consensus expert values, and indeed performed as well as the individual experts ( R(2) = 0.90 to 0.96, SD = 1.05 to 1.53 cm). The same performance was observed for peak-velocities; ( R(2) = 0.98, SD = 3.07 cm/s) and ( R(2) = 0.93 to 0.98, SD = 2.96 to 5.18 cm/s). This automated technology allows > 10 times as many beats to be analyzed compared to the conventional manual approach. This would make clinical and research protocols more precise for the same operator effort.

Mortality from ischaemic heart disease by country, region, and age: statistics from World Health Organisation and United Nations.

BACKGROUND: Ischaemic heart disease (IHD) is the leading cause of death worldwide. The World Health Organisation (WHO) collects mortality data coded using the International Statistical Classification of Diseases (ICD) code. METHODS: We analysed IHD deaths world-wide between 1995 and 2009 and used the UN population database to calculate age-specific and directly and indirectly age-standardised IHD mortality rates by country and region. RESULTS: IHD is the single largest cause of death worldwide, causing 7,249,000 deaths in 2008, 12.7% of total global mortality. There is more than 20-fold variation in IHD mortality rates between countries. Highest IHD mortality rates are in Eastern Europe and Central Asian countries; lowest rates in high income countries. For the working-age population, IHD mortality rates are markedly higher in low-and-middle income countries than in high income countries. Over the last 25 years, age-standardised IHD mortality has fallen by more than half in high income countries, but the trend is flat or increasing in some low-and-middle income countries. Low-and-middle income countries now account for more than 80% of global IHD deaths. CONCLUSIONS: The global burden of IHD deaths has shifted to low-and-middle income countries as lifestyles approach those of high income countries. In high income countries, population ageing maintains IHD as the leading cause of death. Nevertheless, the progressive decline in age-standardised IHD mortality in high income countries shows that increasing IHD mortality is not inevitable. The 20-fold mortality difference between countries, and the temporal trends, may hold vital clues for handling IHD epidemic which is migratory, and still burgeoning.

Quantification of survival gain from cardiac resynchronization therapy: nonlinear growth with time, and greater gain in low-risk patients, make raw trial data an underestimate of real-world behavior.

OBJECTIVES: The goal of this study was to examine the impact of calculation-window duration on lifespan gain (as observed in trials) and on who gains most. BACKGROUND: The landmark trials of biventricular pacing (cardiac resynchronization therapy [CRT]) typically ran for <1 device battery life, and they may therefore underestimate lifespan benefit over longer durations. METHODS: We conducted a meta-analysis of biventricular pacing trials to calculate lifespan gained: first, within the duration of randomized controlled trial data up to 2 years; second, over a 5-year typical battery life; and third, over >1 battery life. Importantly, we applied the Gompertz method for age-related increase in mortality from non-CRT-preventable causes. RESULTS: Five landmark trials (COMPANION [Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure], CARE-HF (CArdiac REsynchronization-Heart Failure), MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT (Resynchronization-Defibrillation for Ambulatory Heart Failure)) provided data for 2 years (6,561 patients), with an average hazard ratio of 0.71. Lifespan gained across all trials increased nonlinearly with time from 0.1 month at 1 year, to 0.5 month at 2 years, and a projected 6.5 months at 5 years (65 times more than at 1 year). After multiple devices, it reached 14 months, involving on average 1.6 devices (i.e., 8.8 months per device implanted). Moreover, while over a short window (e.g., 2 years), lower-mortality patients may gain less than higher-mortality patients (1.4 vs. 2.3 months), their positions reverse by 15 years (16.0 vs. 13.7 months). CONCLUSIONS: Lifespan gain from biventricular pacing rises nonlinearly with time. Early on, higher-risk patients exhibit more gain, but later, lower-risk patients exhibit more gain. Quantifying gain over less than a patient's lifetime underestimates lifespan gain. Over the first 1 or 2 years, lower-risk patients may seem to gain less, although they may ultimately be the ones who gain the most.

Choosing between velocity-time-integral ratio and peak velocity ratio for calculation of the dimensionless index (or aortic valve area) in serial follow-up of aortic stenosis.

BACKGROUND: It remains unclear which echocardiographic measure is most suitable for serial measurement in real-world aortic stenosis (AS) follow-up. We determine whether the dimensionless index (DI) between aortic valve and left ventricular outflow tract velocities is measured more consistently using velocity-time-integral (VTI) or peak velocities (V(peak)) in real life. METHODS: Serial echocardiograms acquired within 6 months in subjects with AS were analysed with blinding, to compare the variability over time of DI calculated using V(peak), with that of DI calculated using VTI. RESULTS: Paired echocardiograms, acquired on average 72 days apart, were analysed from 70 patients with a range of severities of AS (59% severe). DI, calculated using either V(peak) or VTI, did not significantly change over this short time. Coefficient of variation was significantly better when DI was calculated using V(peak) than VTI (12.6 versus 25.4%, p<0.0001). The variabilities of mean and peak trans-aortic valve 4v(2) and left ventricular outflow tract VTI were no better: 26.9%, 19.1% and 22.1% respectively. CONCLUSIONS: Serially-followed variables require minimal noise to maximise detection of genuine change. For AS surveillance, calculating DI--or effective orifice area--from the ratio of V(peak) rather than VTIs would reduce 95% confidence intervals from ± 51% to a still-disappointing ± 25%. Guidelines recommend noisy surveillance measures, causing conscientious echocardiographers to 'peek' at previous values, and impairing clinicians' faith in echocardiographically-observed changes when making clinical decisions. For us in echocardiography to improve our ability to contribute to AS follow-up requires us to first acknowledge and discuss this honestly.