Impact of seasonal blood pressure changes on visit-to-visit blood pressure variability and related cardiovascular outcomes.

BACKGROUND: Visit-to-visit blood pressure (BP) variability associates with an increased risk of cardiovascular events. We investigated the role of seasonal BP modifications on the magnitude of BP variability and its impact on cardiovascular risk. METHODS: In 25 390 patients included in the ONTARGET and TRANSCEND trials, the on-treatment systolic (S) BP values obtained by five visits during the first two years of the trials were grouped according to the month in which they were obtained. SBP differences between winter and summer months were calculated for BP variability quintiles (Qs), as quantified by the coefficient of variation (CV) of on-treatment mean SBP from the five visits. The relationship of BP variability with the risk of cardiovascular events and mortality was assessed by the Cox regression model. RESULTS: SBP was approximately 4 mmHg lower in summer than in winter regardless of confounders. Winter/summer SBP differences contributed significantly to each SBP-CV quintile. Increase of SBP-CV from Q1 to Q5 was associated with a progressive increase in the adjusted hazard ratio (HR) of the primary endpoint of the trials, i.e. morbid and fatal cardiovascular events. This association was even stronger after removal of the effect of seasonality from the calculation of SBP-CV. A similar trend was observed for secondary endpoints. CONCLUSIONS: Winter/summer SBP differences significantly contribute to visit-to-visit BP variability. However, this contribution does not participate in the adverse prognostic significance of visit-to-visit BP variations, which seems to be more evident after removal of the BP effects of seasonality from visit-to-visit BP variations.

Triglyceride-glucose index, low-density lipoprotein levels, and cardiovascular outcomes in chronic stable cardiovascular disease: results from the ONTARGET and TRANSCEND trials.

AIMS: The triglyceride-glucose index (TyG) has been proposed as an alternative to insulin resistance and as a predictor of cardiovascular outcomes. Little is known on its role in chronic stable cardiovascular disease and its predictive power at controlled low density lipoprotein (LDL) levels. METHODS AND RESULTS: Our study population consisted of 29 960 participants in the ONTARGET and TRANSCEND trials that enrolled patients with known atherosclerotic disease. Triglycerides and glucose were measured at baseline. TyG was calculated as the logarithmized product of fasting triglycerides and glucose divided by 2. The primary endpoint of both trials was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The secondary endpoint was all-cause death and the components of the primary endpoint. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) with extensive covariate adjustment for demographic, medical history, and lifestyle factors. During a mean follow-up of 4.3 years, 4895 primary endpoints and 3571 all-cause deaths occurred. In fully adjusted models, individuals in the highest compared to the lowest quartile of the TyG index were at higher risk for the primary endpoint (HR 1.14; 95% CI 1.05-1.25) and for myocardial infarction (HR 1.30; 95% CI 1.11-1.53). A higher TyG index did not associate with the primary endpoint in individuals with LDL levels < 100 mg/dL. CONCLUSION: A higher TyG index is associated with a modestly increased cardiovascular risk in chronic stable cardiovascular disease. This association is largely attenuated when LDL levels are controlled. REGISTRATION: www.clinicaltrials.gov: NCT00153101.

The association of triglyceride-glucose index (TyG) with cardiovascular disease in chronic stable cardiovascular disease and its predictive power at controlled low density lipoprotein (LDL) levels is unclear. Using a study population of 29 960 participants with chronic stable cardiovascular disease, we found that higher TyG levels were associated with a modestly increased risk for incident cardiovascular events and low LDL levels largely attenuated the association of TyG with cardiovascular risk.

Association between exercise frequency with renal and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk.

BACKGROUND: Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. METHODS: Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ2-test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. RESULTS: Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p < 0.0001 for both) compared to lower exercise levels. Similar results were observed for those with and without diabetes without interaction for renal outcomes (p = 0.097-0.27). Physical activity was associated with reduced eGFR decline with a moderate association between activity and diabetes status (p = 0.05). CONCLUSIONS: Moderate physical activity was associated with improved kidney outcomes with a threshold at two sessions per week. The association of physical activity with renal outcomes did not meaningfully differ with or without diabetes but absolute benefit of activity was even greater in people with diabetes. Thus, risks were similar between those with diabetes undertaking high physical activity and those without diabetes but low physical activity. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov.uniqueidentifier :NCT00153101.

Detection of Fraud in a Clinical Trial Using Unsupervised Statistical Monitoring.

BACKGROUND: A central statistical assessment of the quality of data collected in clinical trials can improve the quality and efficiency of sponsor oversight of clinical investigations. MATERIAL AND METHODS: The database of a large randomized clinical trial with known fraud was reanalyzed with a view to identifying, using only statistical monitoring techniques, the center where fraud had been confirmed. The analysis was conducted with an unsupervised statistical monitoring software using mixed-effects statistical models. The statistical analyst was unaware of the location, nature, and extent of the fraud. RESULTS: Five centers were detected as atypical, including the center with known fraud (which was ranked 2). An incremental analysis showed that the center with known fraud could have been detected after only 25% of its data had been reported. CONCLUSION: An unsupervised approach to central monitoring, using mixed-effects statistical models, is effective at detecting centers with fraud or other data anomalies in clinical trials.

Cardiovascular outcomes in patients at high cardiovascular risk with previous myocardial infarction or stroke.

BACKGROUND: Guidelines recommend to start blood pressure (BP)-lowering drugs also according to cardiovascular risk including history of cardiovascular events. We hypothesized that in patients with a history of myocardial infarction (MI), stroke, both or none of those, the index events predict the next event and have different SBP risk associations to different cardiovascular outcomes. DESIGN AND MEASUREMENTS: In this pooled posthoc, nonprespecified analysis, we assessed outcome data from high-risk patients aged 55 years or older with a history of cardiovascular events or proven cardiovascular disease, randomized to the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and to Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease Trial investigating telmisartan, ramipril and their combination with a median follow-up of 56 months. Standardized office BP was measured every 6 months. Associations of mean achieved BP on treatment were investigated on MI, stroke and cardiovascular death. We identified patients with previous MI (N = 13 487), stroke (N = 4985), both (N = 1509) or none (N = 10 956) of these index events. Analyses were done by Cox regression, analysis of variance and Chi2-test. 30 937 patients with complete data were enrolled between 1 December 2001 and 31 July 2003, and followed until 31 July 2008. Data of both trials were pooled as the outcomes were similar. RESULTS: Patients with MI as index event had a higher risk to experience a second MI [hazard ratio 1.42 (confidence interval (CI) 1.20-1.69), P < 0.0001] compared with patients with no events but no increased risk for a stroke as a next event [hazard ratio 0.95 (CI 0.73-1.23), n.s.]. The risk was roughly doubled when they had both, MI and stroke before [hazard ratio 2.07 (CI 1.58-2.71), P < 0.0001]. Patients with a stroke history had a roughly three-fold higher likelihood to experience a second stroke [hazard ratio 2.89 (CI 2.37-3.53) P < 0.0001] but not MI [hazard ratio 1.07 (CI 0.88-1.32), n.s.]. Both types of index events increased roughly three-fold the risk of a second stroke compared with no previous events. The SBP-risk relationship was not meaningfully altered by the event history. After MI and stroke the risk for subsequent events and cardiovascular death was increased over the whole SBP spectrum. A J-shape relationship between BP and outcome was only observed for cardiovascular death. CONCLUSION: Previous MI and previous stroke are associated with increased risk for the same event in the future, independent of achieved SBP. Thus, secondary prevention may also be chosen according to the event history of patients. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov. Unique identifier: NCT00153101.

Cardiovascular Outcomes According to Polypharmacy and Drug Adherence in Patients with Atrial Fibrillation on Long-Term Anticoagulation (from the RE-LY Trial).

Prevalence of atrial fibrillation (AF) increases with age, along with comorbidities and, thus, polypharmacy. Non-adherence is associated with polypharmacy. This study aimed to identify patients at risk for cardiovascular events according to their pharmacological treatment intensity and adherence. Patients (n = 18,113) with a mean age of 71.5 ± 8.7 years, at high cardiovascular risk were followed between December 2005 until December 2007 for a median time of 2 years. The association between polypharmacy and adherence and their impact on cardiovascular and bleeding events were explored. Adherence was defined as a study drug intake of ≥80%. Patients with more co-medications had a higher body mass index, higher prevalence of hypertension, coronary heart disease, heart failure, and diabetes mellitus (all p < 0.0001) compared to ≤4 or 5-8 co-medications, but no differences in history of stroke (p = 0.68) or transient ischemic attack (p = 0.065). Across all treatments, the adjusted hazard ratios (HRs) increased in patients with more co-medications (≥9 vs ≤4) for all-cause death (HR 1.30; 1.06-1.59), major bleeding (HR 1.65; 1.33-2.05), and all bleeding events (HR 1.44; 1.31-1.59). Yearly event rates were higher in non-adherent than adherent patients for stroke and systemic embolism (SSE) (3.14 vs 1.00), all-cause death (7.76 vs 2.66), major bleeding (6.21 vs 2.65), and all bleeding (28.71 vs 19.05; all p < 0.0001). After an event the patients were more likely to become non-adherent (adherence after SSE 30.3%, after major bleeding 33.4%, after all bleeding 66.7%; all p < 0.0001). The treatment effects were consistent to the overall group in the different polypharmacy groups. In conclusion, polypharmacy and non-adherence are risk indicators for increased adverse cardiovascular and bleeding events. Dabigatran is safe to use across the full spectrum of AF patients, independent of the number of co-medications and adherence. Patients with co-medications and comorbidities require special attention and encouragement to adhere to oral anticoagulation.

Renal outcomes and blood pressure patterns in diabetic and nondiabetic individuals at high cardiovascular risk.

BACKGROUND: Diabetes and hypertension are risk factors for renal and cardiovascular outcomes. Data on the association of achieved blood pressure (BP) with renal outcomes in patients with and without diabetes are sparse. We investigated the association of achieved SBP, DBP with renal outcomes and urinary albumin excretion (UAE) in people with vascular disease. METHODS: In this pooled analysis, we assessed renal outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, randomized to The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and to Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease trials investigating telmisartan, ramipril and their combination with a median follow-up of 56 months. Standardized office BP was measured every 6 months, estimated glomerular filtration rate (eGFR) and UAE at baseline, 2 years and study end. Associations of mean achieved BP on treatment were investigated on major renal outcomes including end-stage renal disease (ESRD), decline of eGFR by at least 40%, doubling of creatinine and the composites thereof and on UAE. Analyses were by Cox regression analysis, analysis of variance and Chi2-test. Of 30 937 patients with complete data, 19 450 patients without and 11 487 with diabetes were enrolled between 1 December 2001 and 31 July 2003 and followed until 31 July 2008. Data were pooled as the outcomes for telmisartan 80 mg/day (n = 2903) or placebo (n = 2907) for Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease and ramipril 10 mg/day (n = 8407), telmisartan 80 mg/day (n = 8386) or the combination of both (n = 8334) were similar. RESULTS: For both those with and without diabetes, the hazard ratios for the composites ESRD or doubling of serum creatinine (707 events overall) and ESRD or 40% eGFR loss (2371 events overall) reached a nadir at achieved SBP of 120 to less than 140 mmHg, and increased with higher and lower SBP with similar relative risk with or without diabetes. For example, risk for the former composite reached a hazard ratios 3.06 (confidence interval 1.90-4.92) with a mean achieved SBP more than 160 mmHg compared with 120 to less than 130 mmHg with diabetes and hazard ratios 2.14 (1.09-4.26) without diabetes. In contrast, the development of new microalbuminuria and macroalbuminuria (3002 and 846 events overall) associated linearly over the whole range of achieved SBP (apart from a slight increase in risk at SBP less than 120 mmHg only in those without diabetes). Absolute risks for the composite and albuminuria outcomes were consistently greater in those with diabetes as compared with without diabetes with high event rates over the whole SBP spectrum. The increased renal risk at low SBP was not related to a meaningful reduction of mandated study drugs or open label renin-angiotensin-aldosterone system inhibition. CONCLUSION: In patients at high cardiovascular risk, SBP levels more than 140 mmHg and less than 120 are associated with increased risk for renal outcomes. Renal risk was greater in diabetes across the whole range of achieved SBP and DBP. These data suggest similar target BP range in patients with and without diabetes to prevent renal outcomes, a frequent complication in high-risk vascular patients. CLINICAL TRIAL REGISTRATION: Clinical Trial registration: http://clinicaltrials.gov.Unique identifier: NCT00153101.

Visit-to-visit blood pressure variability and renal outcomes: results from ONTARGET and TRANSCEND trials.

AIMS: There is conflicting evidence on whether in treated hypertensive patients the risk of renal outcomes is associated with visit-to-visit SBP variability. Furthermore, limited evidence is available on how important is SBP variability for prediction of renal outcomes compared with on-treatment mean SBP. We addressed these issues in 28 790 participants of the Ongoing Treatment Alone and in combination with Ramipril Global End point Trial and Telmisartan Randomized AssessmeNt Study in ACE iNtolerant Subjects with Cardiovascular Disease trials. METHODS AND RESULTS: SBP variability was expressed as the coefficient of variation of the mean with which it showed no relationship. SBP variability and mean values were obtained from five visits during the first 2 years of treatment after the end of the titration phase. Incidence of several renal outcomes (end-stage renal disease, doubling of serum creatinine, new microalbuminuria, new macroalbuminuria and their composite) was calculated from the third year of treatment onward. Patients were divided in quintiles of SBP-coefficient of variation (SBP-CV) or mean SBP, which exhibited superimposable mean blood pressure and SBP-CV values, respectively. A progressive increase of SBP-CV was not accompanied by a parallel increase in a widely adjusted (baseline and on-treatment confounders) risk of most renal outcomes (end-stage renal disease, new macroalbuminuria, new microalbuminuria and their composite) in the subsequent on-treatment years. In contrast, the adjusted risk of most renal outcomes increased progressively from the lowest to the highest quintile of on-treatment mean SBP. Progression from lowest to highest mean on-treatment SBP, but not SBP-CV, was also associated with a less frequent return to normoalbuminuria in patients with initial micro or macroalbuminuria. Renal outcome prediction was slightly improved by the combined use of SBP-CV and mean SBP quintiles. CONCLUSION: Visit-to-visit SBP variability had no major predictive value for the risk of renal outcomes, which, in contrast, was sensitively predicted by mean on-treatment SBP. A further slight increase in prediction of renal outcomes was seen by combining on-treatment mean SBP and variability.

Factors Associated With Nocturia-Related Quality of Life in Men With Lower Urinary Tract Symptoms and Treated With Tamsulosin Oral Controlled Absorption System in a Non-Interventional Study.

Nocturia impairs quality of life (QoL). We have performed a non-interventional study in which men with lower urinary tract symptoms (LUTS) were treated for at least 3 months with tamsulosin oral controlled absorption system (0.4 mg q.d.). Other than observing efficacy and tolerability of this drug formulation, the study was designed to explore the relative roles of number of nocturia episodes and of non-urological causes of nocturia on nocturia-related QoL at baseline and treatment-associated changes thereof. The study enrolled 5775 men seeking treatment of their LUTS. Tamsulosin improved LUTS, e.g. International Prostate Symptom Score from 19.5 ± 5.9 to 10.1 ± 4.9 (means ± SD). This was associated by clinically meaningful improvements in the Nocturia QoL score (from 45 ± 19 to 73 ± 17 points) and other QoL scores. Number of nocturnal voids was the key driver of all QoL scores at baseline; change of number of nocturia episodes that of improvement of all QoL scores upon treatment. In contrast, non-urological causes of nocturia such as heart failure, diabetes, sleep apnea, fluid or alcohol intake or use of diuretics or hypnotics had only small if any effects on baseline QoL or treatment-associated improvements thereof. The observed effects of non-urological causes on QoL apparently were largely driven by their effect on number of nocturnal voids. These data further support the idea that improvement of nocturia may be an important treatment goal in male LUTS.

Cardiovascular outcomes, bleeding risk, and achieved blood pressure in patients on long-term anticoagulation with the thrombin antagonist dabigatran or warfarin: data from the RE-LY trial.

AIMS: A J-shaped association of cardiovascular events to achieved systolic (SBP) and diastolic (DBP) blood pressure was shown in high-risk patients. This association on oral anticoagulation is unknown. This analysis from RELY assessed the risks of death, stroke or systemic emboli, and bleeding according to mean achieved SBP and DBP in atrial fibrillation on oral anticoagulation. METHODS AND RESULTS: RE-LY patients were followed for 2 years and recruited between 22 December 2005 until 15 December 2007. 18.113 patients were randomized in 951 centres in 54 countries and 18,107 patients with complete blood pressure (BP) data were analysed with a median follow-up of 2.0 years and a complete follow-up in 99.9%. The association between achieved mean SBP and DBP on all-cause death, stroke and systemic embolic events (SSE), major, and any bleeding were explored. On treatment, SBP >140 mmHg and <120 mmHg was associated with all-cause death compared with SBP 120-130 mmHg (reference). For SSE, risk was unchanged at SBP <110 mmHg but increased at 140-160 mmHg (adjusted hazard ratio (HR) 1.81; 1.40-2.33) and SBP ≥160 mmHg (HR 3.35; 2.09-5.36). Major bleeding events were also increased at <110 mmHg and at 110 to <120 mmHg. Interestingly, there was no increased risk of major bleeding at SBP >130 mmHg. Similar patterns were observed for DBP with an increased risk at <70 mmHg (HR 1.55; 1.35-1.78) and >90 mmHg (HR 1.88; 1.43-2.46) for all-cause death compared to 70 to <80 mmHg (reference). Risk for any bleeding was increased at low DBP <70 mmHg (HR 1.46; 1.37-1.56) at DBP 80 to <90 mmHg (HR 1.13; 1.06-1.31) without increased risk at higher achieved DBP. Dabigatran 150 mg twice daily showed an advantage in all patients for all-cause death and SSE and there was an advantage for 110 mg dabigatran twice daily for major bleeding and any bleeding irrespective of SBP or DBP achieved. Similar results were obtained for baseline BP, time-updated BP, and BP as time-varying covariate. CONCLUSION: Low achieved SBP associates with increased risk of death, SSE, and bleeding in patients with atrial fibrillation on oral anticoagulation. Major bleeding events did not occur at higher BP. Low BP might identify high-risk patients not only for death but also for high bleeding risks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov-Identifier: NCT00262600.

Resting heart rate and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk analysis from the ONTARGET/TRANSCEND trials.

AIMS: Resting heart rate (RHR) has been shown to be associated with cardiovascular outcomes in various conditions. It is unknown whether different levels of RHR and different associations with cardiovascular outcomes occur in patients with or without diabetes, because the impact of autonomic neuropathy on vascular vulnerability might be stronger in diabetes. METHODS AND RESULTS: We examined 30 937 patients aged 55 years or older with a history of or at high risk for cardiovascular disease and after myocardial infarction, stroke, or with proven peripheral vascular disease from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination followed for a median of 56 months. We analysed the association of mean achieved RHR on-treatment with the primary composite outcome of cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, the components of the composite primary outcome, and all-cause death as continuous and categorical variables. Data were analysed by Cox regression analysis, ANOVA, and χ2 test. These trials were registered with ClinicalTrials.gov.number NCT00153101. Patients were recruited from 733 centres in 40 countries between 1 December 2001 and 31 July 2008 (ONTARGET) and 1 November 2001 until 30 May 2004 (TRANSCEND). In total, 19 450 patients without diabetes and 11 487 patients with diabetes were stratified by mean RHR. Patients with diabetes compared to no diabetes had higher RHRs (71.8 ± 9.0 vs. 67.9 ± 8.8, P < 0.0001). In the categories of <60 bpm, 60 ≤ 65 bpm, 65 ≤ 70 bpm, 70 ≤ 75 bpm, 75 ≤ 80 bpm and ≥80 bpm, non-diabetic patients had an increased hazard of the primary outcome with mean RHR of 75 ≤ 80 bpm (adjusted hazard ratio [HR] 1.17 (1.01-1.36)) compared to RHR 60 ≤ 65 bpm. For patients with in-trial RHR ≥80 bpm the hazard ratios were highest (diabetes: 1.96 (1.64-2.34), no diabetes: 1.73 (1.49-2.00), For cardiovascular death hazards were also clearly increased at RHR ≥80 bpm (diabetes [1.99, (1.53-2.58)], no diabetes [1.73 (1.38-2.16)]. Similar results were obtained for hospitalization for heart failure and all-cause death while the effect of RHR on myocardial infarction and stroke was less pronounced. Results were robust after adjusting for various risk indicators including beta-blocker use and atrial fibrillation. No significant association to harm was observed at lower RHR. CONCLUSION: Mean RHR above 75-80 b.p.m. was associated with increased risk for cardiovascular outcomes except for stroke. Since in diabetes, high RHR is associated with higher absolute event numbers and patients have higher RHRs, this association might be of particular clinical importance in diabetes. These data suggest that RHR lowering in patients with RHRs above 75-80 b.p.m. needs to be studied in prospective trials to determine if it will reduce outcomes in diabetic and non-diabetic patients at high cardiovascular risk. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov.Unique identifier: NCT00153101.

Prehospital Stroke Management Optimized by Use of Clinical Scoring vs Mobile Stroke Unit for Triage of Patients With Stroke: A Randomized Clinical Trial.

Importance: Transferring patients with large-vessel occlusion (LVO) or intracranial hemorrhage (ICH) to hospitals not providing interventional treatment options is an unresolved medical problem. Objective: To determine how optimized prehospital management (OPM) based on use of the Los Angeles Motor Scale (LAMS) compares with management in a Mobile Stroke Unit (MSU) in accurately triaging patients to the appropriate hospital with (comprehensive stroke center [CSC]) or without (primary stroke center [PSC]) interventional treatment. Design, Setting, and Participants: In this randomized multicenter trial with 3-month follow-up, patients were assigned week-wise to one of the pathways between June 15, 2015, and November 15, 2017, in 2 regions of Saarland, Germany; 708 of 824 suspected stroke patients did not meet inclusion criteria, resulting in a study population of 116 adult patients. Interventions: Patients received either OPM based on a standard operating procedure that included the use of the LAMS (cut point ≥4) or management in an MSU (an ambulance with vascular imaging, point-of-care laboratory, and telecommunication capabilities). Main Outcomes and Measures: The primary end point was the proportion of patients accurately triaged to either CSCs (LVO, ICH) or PSCs (others). Results: A predefined interim analysis was performed after 116 patients of the planned 232 patients had been enrolled. Of these, 53 were included in the OPM group (67.9% women; mean [SD] age, 74 [11] years) and 63 in the MSU group (57.1% women; mean [SD] age, 75 [11] years). The primary end point, an accurate triage decision, was reached for 37 of 53 patients (69.8%) in the OPM group and for 63 of 63 patients (100%) in the MSU group (difference, 30.2%; 95% CI, 17.8%-42.5%; P < .001). Whereas 7 of 17 OPM patients (41.2%) with LVO or ICH required secondary transfers from a PSC to a CSC, none of the 11 MSU patients (0%) required such transfers (difference, 41.2%; 95% CI, 17.8%-64.6%; P = .02). The LAMS at a cut point of 4 or higher led to an accurate diagnosis of LVO or ICH for 13 of 17 patients (76.5%; 6 triaged to a CSC) and of LVO selectively for 7 of 9 patients (77.8%; 2 triaged to a CSC). Stroke management metrics were better in the MSU group, although patient outcomes were not significantly different. Conclusions and Relevance: Whereas prehospital management optimized by LAMS allows accurate triage decisions for approximately 70% of patients, MSU-based management enables accurate triage decisions for 100%. Depending on the specific health care environment considered, both approaches are potentially valuable in triaging stroke patients. Trial Registration: ClinicalTrials.gov identifier: NCT02465346.

Cardiovascular outcomes and achieved blood pressure in patients with and without diabetes at high cardiovascular risk.

AIMS: Studies have shown a non-linear relationship between systolic blood pressure (SBP) and diastolic blood pressure (DBP) and outcomes, with increased risk observed at both low and high blood pressure (BP) levels. We hypothesized that the BP-risk association is different in individuals with and without diabetes at high cardiovascular risk. METHODS AND RESULTS: We identified patients with (N = 11 487) or without diabetes (N = 19 450), from 30 937 patients, from 133 centres in 44 countries with a median follow-up of 56 months in the ONTARGET/TRANSCEND studies. Patients had a prior history of stroke, myocardial infarction (MI), peripheral artery disease, or were high-risk diabetics. Patients in ONTARGET had been randomized to ramipril 10 mg daily, telmisartan 80 mg daily, or the combination of both. Patients in TRANSCEND were ACE intolerant and randomized to telmisartan 80 mg daily or matching placebo. We analysed the association of mean achieved in-trial SBP and DBP with the composite outcome of cardiovascular death, MI, stroke and hospitalization for congestive heart failure (CHF), the components of the composite, and all-cause death. Data were analysed by Cox regression and restricted cubic splines, adjusting for risk markers including treatment allocation and accompanying cardiovascular treatments. In patients with diabetes, event rates were higher across the whole spectrum of SBP and DBP compared with those without diabetes (P < 0.0001 for the primary composite outcome, P < 0.01 for all other endpoints). Mean achieved in-trial SBP ≥160 mmHg was associated with increased risk for the primary outcome [diabetes/no diabetes: adjusted hazard ratio (HR) 2.31 (1.93-2.76)/1.66 (1.36-2.02) compared with non-diabetics with SBP 120 to <140 mmHg], with similar findings for all other endpoints in patients with diabetes, and for MI and stroke in patients without diabetes. In-trial SBP <120 mmHg was associated with increased risk for the combined outcome in patients with diabetes [HR 1.53 (1.27-1.85)], and for cardiovascular death and all-cause death in all patients. In-trial DBP ≥90 mmHg was associated with increased risk for the primary outcome [diabetes/no diabetes: HR 2.32 (1.91-2.82)/1.61 (1.35-1.93) compared with non-diabetics with DBP 70 to <80 mmHg], with similar findings for all other endpoints, but not for CHF hospitalizations in patients without diabetes. In-trial DBP <70 mmHg was associated with increased risk for the combined outcome in all patients [diabetes/no diabetes: HR 1.77 (1.51-2.06)/1.30 (1.16-1.46)], and also for all other endpoints except stroke. CONCLUSION: High on treatment BP levels (≥160 or ≥90 mmHg) are associated with increased risk of cardiovascular outcomes and death. Also low levels (<120 or <70 mmHg) are associated with increased cardiovascular outcomes (except stroke) and death. Patients with diabetes have consistently higher risks over the whole BP range, indicating that achieving optimal BP goals is most impactful in this group. These data favour guidelines taking lower BP boundaries into consideration, in particular in diabetes. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov.Unique identifier: NCT00153101.

Achieved diastolic blood pressure and pulse pressure at target systolic blood pressure (120-140 mmHg) and cardiovascular outcomes in high-risk patients: results from ONTARGET and TRANSCEND trials.

Aims: Current guidelines of hypertensive management recommend upper limits for systolic (SBP) and diastolic blood pressure (DBP). J-curve associations of BP with risk exist for some outcomes suggesting that lower limits of DBP goals may also apply. We examined the association between mean attained DBP and cardiovascular (CV) outcomes in patients who achieved an on-treatment SBP in the range of 120 to <140 mmHg in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND) trials on patients with high CV risk. This SBP range was associated with the lowest CV risk. Methods: We analysed the outcome data from patients age 55 years or older with CV disease from the ONTARGET and TRANSCEND trials that randomized high-risk patients to ramipril, telmisartan, and the combination. In patients with controlled SBP (on-treatment 120 to <140 mmHg), the composite outcome of CV death, myocardial infarction, stroke and hospital admission for heart failure, the components thereof, and all-cause mortality were analysed according to mean on-treatment DBP as categorical (<70, 70 to <80, 80 to <90, and ≥90 mmHg) and continuous variable as well as the change of DBP according to baseline DBP. Pulse pressure (PP) was related to outcomes as a continuous variable. Results: In 16 099 of 31 546 patients, mean achieved SBP was 120 to <140 mmHg. The nominally lowest risk for all outcomes was observed at an achieved DBP of 70 to <80 mmHg. A higher achieved DBP was associated with a higher risk for the outcomes of stroke and of hospitalization for heart failure (≥80 mmHg) and myocardial infarction (≥90 mmHg). A lower achieved DBP (<70 mmHg) was associated with a higher risk for the primary outcome [hazard ratio (HR) 1.29, 95% confidence interval (95% CI) 1.15-1.45; P < 0.0001], myocardial infarction HR 1.54 (95% CI 1.26-1.88, P < 0.0001) and hospitalization for heart failure HR 1.81 (95% CI 1.47-2.24, P < 0.0001) and all-cause death (HR 1.19, 95% CI 1.04-1.35; P < 0.0001) while there was no signal for stroke and CV death compared to DBP 70 to <80 mmHg. A decrease of DBP was associated with lower risk when baseline DBP was >80 mmHg. The associations to outcomes were similar when patients were divided to SBP 120 to <130 mmHg or 130 to <140 mmHg for DBP or PP. Conclusion: Compared to a DBP of 70 to <80 mmHg, lower and higher DBP was associated with a higher risk in patients achieving a SBP of 120 to <140 mmHg. Associations of DBP and PP to risk were similar notably at controlled SBP. These data suggest at optimal achieved SBP, risk is still defined by low or high DBP. These findings support guidelines which take DBP at optimal SBP control into consideration.

Relative and Combined Prognostic Importance of On-Treatment Mean and Visit-to-Visit Blood Pressure Variability in ONTARGET and TRANSCEND Patients.

In 28 790 patients recruited for the ONTARGET (Ongoing Treatment Alone and in Combination With Ramipril Global End Point Trials) and TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease) trials, we investigated the prognostic value for cardiovascular events (primary outcome) of (1)on-treatment visit-to-visit systolic blood pressure (SBP) variability versus mean SBP and (2) the 2 measures together. SBP variability was measured by the coefficient of variation (CV) of mean SBP to which it was unrelated. Confounders such as variable time and number of visits from which to calculate SBP-CV were avoided by using the same number of visits at identical times in all patients. The covariate-adjusted risk of the primary outcome (Cox models) increased as SBP-CV or mean on-treatment quintile SBP increased, but only for mean on-treatment SBP, the relationship achieved statistical significance: global test for trend, P=0.12 versus P<0.0001. SBP-CV showed a relationship with fatal events, but it was unrelated to the risk of myocardial infarction and stroke, which were predicted by on-treatment mean SBP. Prediction of the primary outcome improved by the combined use of both measures: global test for trend, P<0.0001; hazard ratio for combined fifth versus first quintile, 1.42 (1.20-1.68) compared with 1.13 (1.01-1.27) for SBP-CV and 1.24 (1.11-1.40) for mean SBP. Thus, in the present study, on-treatment mean SBP provided an overall better prediction of cardiovascular risk than visit-to-visit SBP-CV. Prediction improved by their combined use, which may thus offer a more precise estimate of the protective effect of treatment. CLINICAL TRIAL REGISTRATION: URL: http//www.clinicaltrial.gov. Unique identifier: NCT00153101

Circulating Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 predict Three-months Outcome after Ischemic Stroke.

Reports on neuroprotective effects of Insulin-like growth factor-1 (IGF-1) and Insulin-like growth factor binding protein-3 (IGFBP-3) in ischemic brain tissue are inconsistent. The aim of this study was to determine if plasma levels of IGF-1 and IGFBP-3 in acute stroke patients are indicative of 3 months functional outcome. Plasma levels were measured via chemiluminescence immunoassay in heparin blood samples of patients included in the EARLY trial (NCT00562588). Plasma samples were drawn on admission and 8 days post-stroke. Neurological deficits were assessed via modified Rankin Scale (mRS) 3 months post-stroke, resulting in favorable (mRS=0-2) or unfavorable (mRS=3-6) outcome. A multiple binary logistic regression including IGF-1 and IGFBP-3 levels and confounders was conducted. Out of 404 included patients, 89 patients had an unfavorable outcome. Mean mRS on admission as well as 3 months post-stroke was 2 (±1). Low IGF-1 levels (day 8) were independently associated with a decreased risk of an unfavorable outcome (OR 0.61; 95%CI 0.37-0.99; p=0.044). Low IGFBP-3 levels (day 8) were independently associated with an unfavorable outcome (OR 2.75; 95%CI 1.56-4.84; p<0.001). Low IGFBP-3 levels and high IGF-1 levels in the subacute phase are predictive of unfavorable outcome 3 months after stroke.

Achieved blood pressure and cardiovascular outcomes in high-risk patients: results from ONTARGET and TRANSCEND trials.

BACKGROUND: Studies have challenged the appropriateness of accepted blood pressure targets. We hypothesised that different levels of low blood pressure are associated with benefit for some, but harm for other outcomes. METHODS: In this analysis, we assessed the previously reported outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination, with a median follow-up of 56 months. Detailed descriptions of randomisation and intervention have already been reported. We analysed the associations between mean blood pressure achieved on treatment; prerandomisation baseline blood pressure; or time-updated blood pressure (last on treatment value before an event) on the composite outcome of cardiovascular death, myocardial infarction, stroke, and hospital admission for heart failure; the components of the composite outcome; and all-cause death. Analysis was done by Cox regression analysis, ANOVA, and χ2. These trials were registered with ClinicalTrials.gov, number NCT00153101. FINDINGS: Recruitment for ONTARGET took place between Dec 1, 2001, and July 31, 2008. TRANSCEND took place between Nov 1, 2001, and May 30, 2004. 30 937 patients were recruited from 733 centres in 40 countries and followed up for a median of 56 months. In ONTARGET, 25 127 patients known to be tolerant to angiotensin-converting-enzyme (ACE)-inhibitors were randomly assigned after a run-in period to oral ramipril 10 mg/day (n=8407), telmisartan 80 mg/day (n=8386), or the combination of both (n=8334). In TRANSCEND, 5810 patients who were intolerant to ACE-inhibitors were randomly assigned to oral telmisartan 80 mg/day (n=2903) or placebo (n=2907). Baseline systolic blood pressure (SBP) 140 mm Hg or higher was associated with greater incidence of all outcomes compared with 120 mm Hg to less than 140 mm Hg. By contrast, a baseline diastolic blood pressure (DBP) less than 70 mm Hg was associated with the highest risk for most outcomes compared with all DBP categories 70 mm Hg or more. In 4052 patients with SBP less than 120 mm Hg on treatment, the risk of the composite cardiovascular outcome (adjusted hazard ratio [HR] 1·14, 95% CI 1·03-1·26), cardiovascular death (1·29, 1·12-1·49), and all deaths (1·28, 1·15-1·42) were increased compared with those in whom SBP was 120-140 mm Hg during treatment (HR 1 for all outcomes, n=16099). No harm or benefit was observed for myocardial infarction, stroke, or hospital admission for heart failure. Mean achieved SBP more accurately predicted outcomes than baseline or time-updated SBP, and was associated with the lowest risk at approximately 130 mm Hg, and at 110-120 mm Hg risk increased for the combined outcome, cardiovascular death, and all-cause death except stroke. A mean DBP less than 70 mm Hg (n=5352) during treatment was associated with greater risk of the composite primary outcome (HR 1·31, 95% CI 1·20-1·42), myocardial infarction (1·55, 1·33-1·80), hospital admission for heart failure (1·59, 1·36-1·86) and all-cause death (1·16, 1·06-1·28) than a DBP 70-80 mm Hg (14 305). A pretreatment and mean on-treatment DBP of about 75 mm Hg was associated with the lowest risk. INTERPRETATION: Mean achieved SBP less than 120 mm Hg during treatment was associated with increased risk of cardiovascular outcomes except for myocardial infarction and stroke. Similar patterns were observed for DBP less than 70 mm Hg, plus increased risk for myocardial infarction and hospital admission for heart failure. Very low blood pressure achieved on treatment was associated with increased risks of several cardiovascular disease events. These data suggest that the lowest blood pressure possible is not necessarily the optimal target for high-risk patients, although it is not possible to rule out some effect of reverse causality. FUNDING: Boehringer Ingelheim.

Factors associated with efficacy of an ibuprofen/pseudoephedrine combination drug in pharmacy customers with common cold symptoms.

AIM: The aim of this study was to explore factors affecting efficacy of treatment of common cold symptoms with an over-the-counter ibuprofen/pseudoephedrine combination product. METHODS: Data from an anonymous survey among 1770 pharmacy customers purchasing the combination product for treatment of own common cold symptoms underwent post-hoc descriptive analysis. Scores of symptoms typically responsive to ibuprofen (headache, pharyngeal pain, joint pain and fever), typically responsive to pseudoephedrine (congested nose, congested sinus and runny nose), considered non-specific (sneezing, fatigue, dry cough, cough with expectoration) and comprising all 11 symptoms were analysed. Multiple regression analysis was applied to explore factors associated with greater reduction in symptom intensity or greater probability of experiencing a symptom reduction of at least 50%. RESULTS: After intake of first dose of medication, typically ibuprofen-sensitive, pseudoephedrine-responsive, non-specific and total symptoms were reduced by 60.0%, 46.3%, 45.4% and 52.8%, respectively. A symptom reduction of at least 50% was reported by 73.6%, 55.1%, 50.9% and 61.6% of participants, respectively. A high baseline score was associated with greater reductions in symptom scores but smaller probability of achieving an improvement of at least 50%. Across both multiple regression approaches, two tablets at first dosing were more effective than one and (except for ibuprofen-sensitive symptoms) starting treatment later than day 2 of the cold was generally less effective. DISCUSSION AND CONCLUSIONS: Efficacy of an ibuprofen/pseudoephedrine combination in the treatment of common cold symptoms was dose-dependent and greatest when treatment started within the first 2 days after onset of symptoms.

Pathophysiological Factors in the Relationship between Chronological Age and Calculated Lung Age as Detected in a Screening Setting in Community-Dwelling Subjects.

AIM: To explore the relationship between pathophysiological factors and premature lung aging in a cohort of community-dwelling subjects in a health-screening setting. METHODS: 16,107 pharmacy customers in Germany (5954 males, 10,153 females; mean age 59.7 years) participated in a lung function screening project by providing demographic data, including smoking status and known airway conditions and performing spirometry with a Vitalograph, a spirometry screening device. Lung age was calculated from the spirometric findings, and the difference between chronological age and calculated lung age was analyzed in its relationship to the demographic data in general linear models. RESULTS: In the overall cohort, calculated lung age exceeded chronological age by 10.0 years. Based on the subset of non-smokers not reporting any airway conditions, Vitalograph data in this setting may underestimate FEV1 to some degree, but this apparently had little impact on the detection of association of lung age with pathophysiological factors or the corresponding effect sizes. The most important factors associated with greater lung age based on strength of association were presence of dyspnea, being a smoker, and reporting a history of COPD or asthma. Corresponding effect sizes for the difference between age and lung age were 6.5, 5.7, 13.9, and 8.3 years over the chronological age. DISCUSSION AND CONCLUSION: These data confirm the usefulness of screening devices of lung function testing for epidemiological but potentially also for pharmaco-epidemiological studies.