Despite the identification of numerous gene-drug associations, few have been incorporated into clinical practice or guidelines. Georgios D Kitsios and David M Kent argue that if personalised medicine is to become a reality we have to look beyond our genes
For patients with cryptogenic stroke (CS) and patent foramen ovale (PFO), it is unknown whether the magnitude of right-to-left shunt (RLSh) measured by contrast transcranial Doppler (c-TCD) is correlated with the likelihood an identified PFO is related to CS as determined by the Risk of Paradoxical Embolism (RoPE) score. Additionally, for patients with CS, it is unknown whether PFO assessment by c-TCD is more sensitive for identifying RLSh compared with transesophageal echocardiography (TEE). Our aim was to determine the significance of RLSh grade by c-TCD in patients with PFO and CS.
We evaluated patients with CS who had RLSh quantified by c-TCD in The Multicenter Study into RLSh in Cryptogenic Stroke (CODICIA) to determine whether there is an association between c-TCD shunt grade and the RoPE Score. For patients who underwent c-TCD and TEE, we determined whether there is agreement in identifying and grading RLSh between these two modalities.
The RoPE score predicted the presence versus the absence of RLSh documented by contrast transcranial Doppler (c-statistic = 0.66). For patients with documented RLSh by c-TCD, shunt severity was correlated with increasing RoPE score (rank correlation (r) = 0.15, p = 0.01). Among 293 patients who had both c-TCD and TEE performed, c-TCD was more sensitive (98.7%) for detecting RLSh. Of the 97 patients with no PFO identified on TEE, 28 (29%) had a large amount of RLSh seen on c-TCD.
For patients with CS, severity of RLSh by c-TCD is positively correlated with the RoPE score, indicating this technique for shunt grading identifies patients more likely to have pathogenic rather than incidental PFOs. C-TCD is also more sensitive in detecting RLSh than TEE. These findings suggest an important role for c-TCD in the evaluation of PFO in the setting of CS.
Cerebrovascular disease; Stroke; Doppler; Cryptogenic Stroke; Patent Foramen Ovale; Echocardiography
Clinical prediction models (CPMs) estimate the probability of clinical outcomes and hold the potential to improve decision making and individualize care. For patients with cardiovascular disease (CVD) there are numerous CPMs available though the extent of this literature is not well described.
Methods and Results
We conducted a systematic review for articles containing CPMs for CVD published between January 1990 through May 2012. CVD includes coronary heart disease (CHD), heart failure (HF), arrhythmias, stroke, venous thromboembolism (VTE) and peripheral vascular disease (PVD). We created a novel database and characterized CPMs based on the stage of development, population under study, performance, covariates, and predicted outcomes. There are 796 models included in this database. The number of CPMs published each year is increasing steadily over time. 717 (90%) are de novo CPMs, 21 (3%) are CPM recalibrations, and 58 (7%) are CPM adaptations. This database contains CPMs for 31 index conditions including 215 CPMs for patients with CAD, 168 CPMs for population samples, and 79 models for patients with HF. There are 77 distinct index/ outcome (I/O) pairings. Of the de novo models in this database 450 (63%) report a c-statistic and 259 (36%) report some information on calibration.
There is an abundance of CPMs available for a wide assortment of CVD conditions, with substantial redundancy in the literature. The comparative performance of these models, the consistency of effects and risk estimates across models and the actual and potential clinical impact of this body of literature is poorly understood.
prediction; cardiovascular disease risk factors; cerebrovascular disease/stroke; modeling; prognostic factor
The Stroke–Thrombolytic Predictive Instrument (Stroke-TPI) predicts the probability of good and bad outcomes with and without recombinant tissue plasminogen activator (rtPA). We sought to rebuild and externally validate a simpler Stroke-TPI to support implementation in routine clinical care.
Using the original derivation cohort of 1,983 patients from a combined database of randomized clinical trials (NINDS [National Institute of Neurological Disorders and Stroke] 1 and 2; ATLANTIS [Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke] A and B; and ECASS [European Cooperative Acute Stroke Study] II), we simplified the Stroke-TPI by reducing variables and interaction terms and by exploring simpler (3- and 8-item) stroke severity scores. External validation was performed in the ECASS III trial (n = 821).
The following 6 variables were most predictive of good outcomes: age, systolic blood pressure, diabetes, stroke severity, symptom onset to treatment time, and rtPA therapy. Treatment effect modifiers included onset to treatment time and systolic blood pressure. For the models predicting a bad outcome (modified Rankin Scale [mRS] score ≥5), significant variables included age, stroke severity, and serum glucose. rtPA therapy did not change the risk of a poor outcome. Compared with models using the full NIH Stroke Scale, models using the 3-item severity score showed similar discrimination and excellent calibration. External validation on ECASS III showed similar performance (C statistics 0.75 [mRS score ≤1] and 0.80 [mRS score ≤2]).
A simpler model using a 3-item stroke severity score, instead of the 15-item NIH Stroke Scale, has similar prognostic value and may be easier to use in routine care. Future studies are needed to test whether it can improve process and clinical outcomes.
The preferred antithrombotic strategy for secondary prevention in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) is unknown. We pooled multiple observational studies and used propensity score-based methods to estimate the comparative effectiveness of oral anticoagulation (OAC) compared with antiplatelet therapy (APT).
Methods and results
Individual participant data from 12 databases of medically treated patients with CS and PFO were analysed with Cox regression models, to estimate database-specific hazard ratios (HRs) comparing OAC with APT, for both the primary composite outcome [recurrent stroke, transient ischaemic attack (TIA), or death] and stroke alone. Propensity scores were applied via inverse probability of treatment weighting to control for confounding. We synthesized database-specific HRs using random-effects meta-analysis models. This analysis included 2385 (OAC = 804 and APT = 1581) patients with 227 composite endpoints (stroke/TIA/death). The difference between OAC and APT was not statistically significant for the primary composite outcome [adjusted HR = 0.76, 95% confidence interval (CI) 0.52–1.12] or for the secondary outcome of stroke alone (adjusted HR = 0.75, 95% CI 0.44–1.27). Results were consistent in analyses applying alternative weighting schemes, with the exception that OAC had a statistically significant beneficial effect on the composite outcome in analyses standardized to the patient population who actually received APT (adjusted HR = 0.64, 95% CI 0.42–0.99). Subgroup analyses did not detect statistically significant heterogeneity of treatment effects across clinically important patient groups.
We did not find a statistically significant difference comparing OAC with APT; our results justify randomized trials comparing different antithrombotic approaches in these patients.
Cryptogenic stroke; Patent foramen ovale; Secondary stroke prevention; Medical stroke treatment; Cardiogenic stroke
Although models exist for predicting hospital readmission after coronary artery bypass surgery, no such models exist for predicting readmission after heart valve surgery (HVS).
Methods and Results
Using a geographically and structurally diverse sample of US hospitals (Premier Inpatient Database, January 2007–June 2011), we examined patient, hospital, and clinical factors predictive of short‐ and medium‐term hospital readmission post‐HVS. We set aside 20% of hospitals for model validation. A generalized estimating equation model accounted for clustering within hospitals. At 219 hospitals, we identified 38 532 patients (67 years, 56% male, 62% aortic valve surgery) who underwent HVS. A total of 3125 (7.8%) and 4943 (12.8%) patients were readmitted to the index hospital within 1 and 3 months, respectively. Our 3‐month model predicted readmission rates between 3% and 61% with fair discrimination (C‐statistic, 0.67) and good calibration (predicted vs observed differences in validation cohort averaged 1.9% across all deciles of predicted readmission risk). Results were similar for our 1‐month model and our simplified 3‐month model (suitable for clinical use), which used the 5 strongest predictors of readmission: transfused units of packed Red blood cells, presence of End‐stage renal disease, type of Valve surgery, Emergency hospital admission, and hospital Length of stay (REVEaL).
We described and validated key factors that predict short‐ and medium‐term hospital readmission post‐HVS. These models should enable clinicians to identify individuals with HVS who are at increased risk for hospital readmission and are most likely to benefit from improved postdischarge care and follow‐up.
aortic valve; mitral valve; model; prediction statistics; readmission; surgery; Health Services; Quality and Outcomes; Cardiovascular Surgery; Valvular Heart Disease
To better risk stratify patients, utilizing baseline characteristics, in order to help optimize decision making for men with moderate to severe lower urinary tract symptoms (LUTS) secondary to BPH through a secondary analysis of the Medical Therapy of Prostatic Symptoms (MTOPS) trial.
Materials and Methods
After review of the literature, we identified potential baseline risk factors for BPH progression. Using bivariate tests in a secondary analysis of MTOPS data, we determined which variables retained prognostic significance. We then utilized these factors in Cox Proportional Hazard modeling to 1) more comprehensively risk stratify the study population based on pre-treatment parameters and 2) to determine which risk strata stood to benefit most from medical intervention.
3047 men were followed in MTOPS for a mean of 4.5 years. We demonstrated varying risks of progression across quartiles. Baseline BPH Impact Index score, post-void residual, serum prostate specific antigen, age, AUA Symptom Index score, and maximum urinary flow rate were found to significantly correlate with overall BPH progression in multivariable analysis.
Utilizing baseline factors permits estimation of individual patient risk for clinical progression and the benefits of medical therapy. A novel clinical decision tool based on these analyses will allow clinicians to weigh patient-specific benefits against possible risks of adverse effects for a given patient.
benign prostatic hyperplasia; lower urinary tract symptoms; risk factors
Case series suggest that chronic use of proton pump inhibitors (PPIs) is associated with hypomagnesemia but current literature lacks systematically collected data. Our aim was to examine whether hypomagnesemia at time of hospital admission is associated with out-of-hospital use of PPIs.
Nested case-control study matched for age and sex.
Setting & Participants
Data was collected retrospectively from a tertiary acute care facility. Eligible cases consisted of 402 adults with hypomagnesemia (serum magnesium <1.4 mEq/L) at time of hospital admission to medical services, age- and sex- matched with 402 control subjects with normal serum magnesium level (1.4–2.0 mEq/L).
Out-of-hospital PPI use was identified in the hospital record. An omeprazole equivalent dose was calculated when possible. Covariates included the Charlson-Deyo comorbidity index, diabetes, diuretic use, estimated glomerular filtration rate (eGFR), and gastro-esophageal reflux.
Multivariable conditional logistic regression analyses were used to examine the association of PPI use with hypomagnesemia at time of hospital admission.
PPI use was not associated with hypomagnesemia (adjusted odds ratio [OR] 0.82; 95% CI 0.61, 1.11). Neither PPI type nor omeprazole-equivalent daily dose was associated with hypomagnesemia. Sensitivity analyses of PPI use restricted to patients with esophageal disorders (adjusted OR 1.00; 95% CI 0.69, 1.45), severe hypomagnesemia (≤1.0 mEq/L) (adjusted OR 0.78; 95% CI 0.13, 4.61), or eGFR ≥60 ml/min per 1.73m2 (adjusted OR 0.84; 95% CI 0.53, 1.34) were unrevealing.
Exposure misclassification; hospitalized patients on medical services may not be representative of a broader ambulatory-based population.
In a hospital-based adult population, out-of-hospital PPI use is not associated with hypomagnesemia at time of hospital admission to medical services. In light of these inconclusive results, prospective cohort studies are needed to address this rare potential medication-related adverse effect.
hypomagnesemia; proton pump inhibitors; PPIs; electrolyte disorders
Despite combination antiretroviral therapy (cART), people living with HIV (PLWH) continue to have more systemic inflammation and metabolic disturbances than the general population. These risk factors for atherosclerosis and organ dysfunction may be ameliorated by statins. We retrospectively analyzed 438 cART treated PLWH from the Nutrition For Healthy Living (NFHL) cohort to determine the association between statins and myocardial infarction (MI), stroke, and all-cause mortality as a composite. We used Cox proportional hazards regression as our main analysis. The average age was 44 years, 32% were women, and 67 of the 438 subjects used statins. There was no association between statins and our composite endpoint in two separate models [1.26 (0.57–2.79) in statin history model and 0.93 (0.65–1.32) per year in statin duration model]. The composite outcome was significantly associated with CD4 count, age, and smoking status in both models. CD4 count remained significant even after exclusion of mortality from the composite (HR=0.88, p=0.02). Confounding control via propensity scoring and multiple imputations did not change the results. Statins did not have an effect on MI, stroke, and mortality. Interestingly, CD4 count appears to be an important predictor of these outcomes, even after exclusion of death from the composite.
Cryptogenic stroke; Patent foramen ovale; Ischemic stroke; Echocardiography; Secondary prevention
Guidelines for stroke prevention recommend development of sex‐specific stroke risk scores. Incorporating sex in Clinical Prediction Models (CPMs) may support sex‐specific clinical decision making. To better understand their potential to guide sex‐specific care, we conducted a field synopsis of the role of sex in stroke‐related CPMs.
Methods and Results
We identified stroke‐related CPMs in the Tufts Predictive Analytics and Comparative Effectiveness CPM Database, a systematic summary of cardiovascular CPMs published from January 1990 to May 2012. We report the proportion of models including the effect of sex on stroke incidence or prognosis, summarize the directionality of the predictive effects of sex, and explore factors influencing the inclusion of sex. Of 92 stroke‐related CPMs, 30 (33%) contained a coefficient for sex or presented sex‐stratified models. Only 12/58 (21%) CPMs predicting outcomes in patients included sex, compared to 18/30 (60%) models predicting first stroke (P<0.0001). Sex was most commonly included in models predicting stroke among a general population (69%). Female sex was consistently associated with reduced mortality after ischemic stroke (n=4) and higher risk of stroke from arrhythmias or coronary revascularization (n=5). Models predicting first stroke versus outcomes among patients with stroke (odds ratio=5.75, 95% CI 2.18–15.14, P<0.001) and those developed from larger versus smaller sample sizes (odds ratio=4.58, 95% CI 1.73–12.13, P=0.002) were significantly more likely to include sex.
Sex is included in a minority of published CPMs, but more frequently in models predicting incidence of first stroke. The importance of sex‐specific care may be especially well established for primary prevention.
prevention; prognosis; risk factor; risk model; sex; stroke; Risk Factors; Women; Primary Prevention; Secondary Prevention; Health Services
The IMMEDIATE Trial of emergency medical service use of intravenous glucose–insulin–potassium (GIK) very early in acute coronary syndromes (ACS) showed benefit for the composite outcome of cardiac arrest or in-hospital mortality.
This analysis of IMMEDIATE Trial data sought to develop a predictive model to help clinicians identify patients at highest risk for this outcome and most likely to benefit from GIK.
Multivariable logistic regression was used to develop a predictive model for the composite endpoint cardiac arrest or in-hospital mortality using the 460 participants in the placebo arm of the IMMEDIATE Trial.
The final model had four variables: advanced age, low systolic blood pressure, ST elevation in the presenting electrocardiogram, and duration of time since ischemic symptom onset. Predictive performance was good, with a C statistic of 0.75, as was its calibration. Stratifying patients into three risk categories based on the model's predictions, there was an absolute risk reduction of 8.6% with GIK in the high-risk tertile, corresponding to 12 patients needed to treat to prevent one bad outcome. The corresponding values for the low-risk tertile were 0.8% and 125, respectively.
The multivariable predictive model developed identified patients with very early ACS at high risk of cardiac arrest or death. Using this model could assist treating those with greatest potential benefit from GIK.
Acute coronary syndrome; Glucose–insulin–potassium (GIK); Predictive model; Cardiac arrest; Mortality; Emergency medical service
Patent foramen ovale (PFO) is associated with cryptogenic stroke (CS), though the pathogenicity of a discovered PFO in the setting of CS is typically unclear. Transesophageal echocardiography (TEE) features such as PFO size, an associated hypermobile septum, and presence of a right-to-left shunt at rest have all been proposed as markers of risk. The association of these TEE features with other markers of pathogenicity has not been examined.
Methods and Results
We used a recently derived score based on clinical and neuroimaging features to stratify patients with PFO and CS by the probability that their stroke is PFO-attributable. We examined whether high risk TEE features are seen more frequently in patients more likely to have had a PFO-attributable stroke (n = 637) compared to those less likely to have a PFO attributable stroke (n = 657). Large physiologic shunt size was not more frequently seen among those with probable PFO-attributable strokes (OR=0.92; p = 0.53). Neither the presence of a hypermobile septum nor a right-to-left shunt at rest were detected more often in those with a probable PFO-attributable stroke (OR=0.80; p = 0.45 and OR=1.15; 0.11 respectively).
We found no evidence that the proposed TEE risk markers of large PFO size, hypermobile septum, and presence of right-to-left shunt at rest are associated with clinical features suggesting that a CS is PFO-attributable. Additional tools to describe PFOs may be useful in helping to determine whether an observed PFO is incidental or pathogenically related to CS.
cerebrovascular disease/stroke; echocardiography; cardiovascular imaging; risk factor; congenital heart disease
Patent Foramen Ovale; Patent Foramen Ovale Closure; Stroke; Secondary Prevention; Meta-analysis
Cardioembolic (CE) stroke mechanisms account for a significant number of ischemic strokes however the true burden is likely underestimated. It is critically important to identify patients with CE strokes since these individuals have high recurrence rates and represent a subgroup of patients who may benefit from targeted therapy in the form of anticoagulation or device based treatments. Current guidelines offer recommendations for diagnosis and treatment of these patients however important questions remain. Appropriate cardiac testing in the setting of CE must be individualized and the optimal duration of electrocardiographic monitoring to rule out atrial fibrillation (AF) is unclear. So too, risk stratification tools for AF remain understudied and there is controversy about which anticoagulant agents are most appropriate. Lastly, important potential CE sources of stroke such as PFO have garnered significant attention recently and debate regarding how to treat these patients remains. In this review we discuss some of the important controversies in diagnosing and treating patients with possible CE stroke, pointing to areas where future research might be particularly valuable.
cardioembolic stroke; ischemic stroke; atrial fibrillation; patent foramen ovale; cryptogenic stroke; anticoagulation
We examined the influence of clinical, radiologic, and echocardiographic characteristics on antithrombotic choice in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO), hypothesizing that features suggestive of paradoxical embolism might lead to greater use of anticoagulation.
The Risk of Paradoxical Embolism Study combined 12 databases to create the largest dataset of patients with CS and known PFO status. We used generalized linear mixed models with a random effect of component study to explore whether anticoagulation was preferentially selected based on the following: (1) younger age and absence of vascular risk factors, (2) “high-risk” echocardiographic features, and (3) neuroradiologic findings.
A total of 1,132 patients with CS and PFO treated with anticoagulation or antiplatelets were included. Overall, 438 participants (39%) were treated with anticoagulation with a range (by database) of 22% to 54%. Treatment choice was not influenced by age or vascular risk factors. However, neuroradiologic findings (superficial or multiple infarcts) and high-risk echocardiographic features (large shunts, shunt at rest, and septal hypermobility) were predictors of anticoagulation use.
Both antithrombotic regimens are widely used for secondary stroke prevention in patients with CS and PFO. Radiologic and echocardiographic features were strongly associated with treatment choice, whereas conventional vascular risk factors were not. Prior observational studies are likely to be biased by confounding by indication.
Background and Purpose
Despite widespread clinical use, the efficacy of percutaneous closure of patent foramen ovale (PFO) for secondary prevention in patients with cryptogenic stroke has been formally tested only recently by 3 randomized clinical trials (RCTs) with null results in their primary analyses. We aimed to draw more precise conclusions from these RCTs via meta-analysis.
Meta-analysis of incidence rates (IRs) of stroke in treatment arms and hazard ratios (HRs) for the efficacy of closure with random-effects model. Sensitivity analyses were explored for additional outcomes and types of analyses.
Two different types of closure devices were used (StarFLEX in CLOSURE-I trial and Amplatzer PFO occluder in RESPECT and PC-trial). Summary IRs of stroke were low in both arms: 0.76 (95% confidence interval, 0.30-1.96) per 100 person-years in the device group and 1.30 (95%CI, 0.94-1.81) in the medical group. Meta-analysis for HR of stroke showed a non-significant 45% risk reduction (summary HR=0.55 (0.26-1.18)) and results remained non-significant when the two Amplatzer-device trials were combined. However, statistically significant and stronger results were obtained in sensitivity analyses, when composite outcomes or fixed-effects models were considered. Subgroup meta-analyses failed to show any detectable closure-effect modifiers.
Meta-analysis of 3 RCTs for PFO closure does not remedy the uncertainty of individual RCTs. Different inclusion and analysis criteria can lead to mutually conflicting summary conclusions on the benefits of closure. Our findings underscore the importance of generating more randomized evidence for informed decisionmaking on the risks and benefits of closure versus medical therapy.
Patent Foramen Ovale; Patent Foramen Ovale Closure; Stroke; Secondary Prevention; Meta-analysis
The limitations of subgroup analyses are well established—false positives due to multiple comparisons, false negatives due to inadequate power, and limited ability to inform individual treatment decisions because patients have multiple characteristics that vary simultaneously. In this article, we apply Bayes’s rule to determine the probability that a positive subgroup analysis is a true positive. From this framework, we derive simple rules to determine when subgroup analyses can be performed as hypothesis testing analyses and thus inform when subgroup analyses should influence how we practice medicine.
cryptogenic stroke; patent foramen ovale; paradoxical embolism
The purpose of this study was to quantitatively assess the relationship between therapy-induced changes in left ventricular (LV) remodeling and longer-term outcomes in patients with left ventricular dysfunction (LVD).
Whether therapy-induced changes in left ventricular ejection fraction (LVEF), end-diastolic volume (EDV), and end-systolic volume (ESV) are predictors of mortality in patients with LVD is not established.
Searches for randomized controlled trials (RCTs) were conducted to identify drug or device therapies for which an effect on mortality in patients with LVD was studied in at least 1 RCT of ≥500 patients (mortality trials). Then, all RCTs involving those therapies were identified in patients with LVD that described changes in LVEF and/or volumes over time (remodeling trials). We examined whether the magnitude of remodeling effects is associated with the odds ratios for death across all therapies or associated with whether the odds ratio for mortality was favorable, neutral, or adverse (i.e., statistically significantly decreased, nonsignificant, or statistically significantly increased odds for mortality, respectively).
Included were 30 mortality trials of 25 drug/device therapies (n = 69,766 patients; median follow-up 17 months) and 88 remodeling trials of the same therapies (n = 19,921 patients; median follow-up 6 months). The odds ratio for death in the mortality trials was correlated with drug/device effects on LVEF (r = −0.51, p < 0.001), EDV (r = 0.44, p = 0.002), and ESV (r = 0.48, p = 0.002). In (ordinal) logistic regressions, the odds for neutral or favorable effects in the mortality RCTs increased with mean increases in LVEF and with mean decreases in EDV and ESV in the remodeling trials.
In patients with LVD, short-term trial-level therapeutic effects of a drug or device on LV remodeling are associated with longer-term trial-level effects on mortality.