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    1202 "52 990190 wo Kg uo syeunofeyeydny wy popeoquaocr trial Fibrillation: SPRIN Incidence and Implications of Atrial Fibrillation/Flutter in Hypertension Insights From the SPRINT Trial Vibhu Parcha, Nirav Patel, Rajat Kalra, Joonseok Kim, Orlando M. Gutiérrez, Garima Arora, Pankaj Arora See Baitorial, pp 1414-1416 Abstract—We evaluated the impact of intensive blood pressure control onthe incidence of new-onset arial fibrillation/Mutter (AP) and the prognostic implications of preexisting and new-onset AF in SPRINT (Systolic Blood Pressure Intervention Trial) participants. New-onset AF was defined as occurrence of AF in 12-Lead electrocardiograms after randomization in participants free of AF at baseline. Poisson regression modeling was used to calculate incident rates of new-onset AF, Multivariable-adjusted Cox proportional hazard models were used to evaluate the risk of adverse cardiovascular events (composite of myocardial infarction, non-myocardial infarction acute coronary syndrome, stroke, heart failure, or cardiovascular death). In 9327 participants, 845% had preexisting AF, and 1.65% had new-onset AR. The incidence of new-onset AF was 4.53 per 1000-person years, with similar rates in the standard and intensive treatment arms (4.95 versus 4.11 per 1000-person years; adjusted P=0.14), Participants with preexisting AF (adjusted hazard ratio, 1.83 [95% Ci, 1.46-2.31); P<0.001) and new-onset AF (adjusted hazard ratio, 245 [95% Cl, 1.58-3.80]; P<0.001) had a greater risk for development of adverse cardiovascular events compared with those with no AF. Participants with preexisting AF ‘ho achieved blood pressure <120/80 mmHg at 3 months continued have a poor prognosis (adjusted hazard ratio, 1.88 {95% CI, 1.32-2.70}; P=0.001) compared with those with no AF. Intensive blood pressure control does not diminish the incidence of new-onset AF in an older, high-risk, nondiabetic population. Both preexisting and new-onset AF have adverse prognostic implications. In participants with preexisting AF, residual cardiovascular risk is evident even with on- treatment blood pressure <120/80 mmHg. Registration—URL: nips://wwv.clinicaltrials.gov; Unique identifier: NCTO1206062. (Hypertension, 2020; 1490, DOI: 10.1161/HYPERTENSIONAHA.120.14690.) # Data Supplement 83. Key Words: atrial fibrillation blood pressure heart failure ™ hypertension # incidence # myocardial infarction stroke 'ypertension is one ofthe major risk factors associated with {the development of atrial fibrillaion/flutter (AF). Nearly (60% of patients with AF have hypertension, and elevated blood pressure (BP) is associated with an increased incidence of AR.'* Atrial fibrillation and hypertension have similar risk factors, and the cardiovascular hemodynamic changes, cardiac structural, ‘modifications, and renal dysfunction consequent of hyperten- sion are recognized contributors to the development of AF and its associated complications."* Adequate BP management is crucial for AF prevention and the associated adverse cardiovas- cular outcomes, The cardiovascular morphological changes and subclinical pathophysiological changes resulting from elevated BBP serve as a substrate for the development and persistence of AF and the eventual occurrence of poor outcomes." Despite the role of elevated BP in the etiopathogenesis of AR. there i limited data from randomized controlled trials ‘onthe impact of intensive BP control on the incidence of AR” Prior observational data has been conflicting suggesting that both standard (<140 mmHg) and intensive (<120 mmHg) BP control may reduce incident AF***"! The SPRINT (Systolic Blood Pressure Intervention Trial) helped to establish the benefit of intensive BP management for reducing the risk of adverse cardiovascular outcomes. Thus, the SPRINT study population provides a unique opportunity to evalate the role of intensive BP control in educing the incidence of AF. ‘We hypothesized tha (1) intensive BP contol reduces the risk for development of new-onset AF when compared with standard BP control, (2) both new-onset and preexisting AF ‘Received January 7, 202; fist decision January 19, 2020; revision accepted March 10, 2020. From the Division of Cardiovascular Disease (VP, 1K (OMG), and Deparment of Epidemiology (OMG), U “Minnesot, Minneapolis (R.K.); a Section of Cardiology, PA), Department of Medicine (N-P), Division of Nephrology, Department of Medicine ‘of Alshatna at Birmingham, Birmingham; Cardiovascular Division, University of ingham Veterans Affairs Medical Center, AL (PA), ‘The Data Supplement is available with this article at http://w ahajournals.ory/doV/suppV/0.1161/HYPERTENSIONAA.120.14690, Correspondence to Pankaj Arora Division of Cardiovascular Disease, 1670 University Blvd, Volker Hall B140, University of Alabama at Birmingham, Birmingham, AL 35294-0019, Email parora@ uabme.eda (© 2020 American Heart Assocation, Inc “Hypertension is available at htps:/wwwahajournals.oryjournalhyp DOL: 10.1161/HYPERTENSIONAHA.120.14690 120257 290190 wo 6g ao sjeusnoteyey diy wos popeOKUAO 1484 Hypertension —_ June 2020 in hypertensive participants portend poor prognostic implica- tions, and (3) attainment of systolic BP <120/80 mmHg in, individuals with preexisting AF will attenuate the risk of ad- ‘verse cardiovascular outcomes. Methods ‘SPRINT tial data for this study are publicly available at National Heart, Lung, and Blood Institute BioLINCC data repository and can bbe accessed at https/bolince lb ih gov/home!. ‘Study Population and Design ‘The SPRINT trial was a multicenter, open-label, clinica ral that ran domized 9361 hypertensive participants enrolled between November 2010 and March 2013 to intensive and standard BP management.” ‘The local Institutional Review Board at the respective tial sites approved the tal. All participants provided written informed con- sent, and the tial complied with principles in the Declaration of Helsinki. The inclusion and exclusion eriteria and the results ofthe SPRINT tral have been previously described (Methods in the Data Supplement).”° The enrlled participants were randomized to either Standard (systolic BP <140 mmHg) or intensive (systolic BP <120, ‘mm Hg) BP treatment targets ECG Ascertainment Participants with AF present on baseline ECG (within the fist 7 days) ‘oF having & history of AF were defined as having preexisting AF. Detection of AF on ECGs after randomization was defined as now- ‘onset AF, The GE MAC 1200 electrocardiograph (GE, Milwaukee, Wisconsin) was used to obtain the digital ECG data with a 10 mmi ‘my calibration and a speed of 25 mn, Scheduled ECGs took place athaseline, year 2, ear 4, and closcout visits. This was in addition to unscheduled ECGs obtained during suspected cardiovascular event land by the study investigators evaluating participants for safety. All ECG readings were adjudicated centally at the Epidemiological Cardiology Research Center, Wake Forest School of Medicine (Winston-Salem, NC)" All ECGs underwent visual inspection for ‘poor quality and technical errors before automatic processing by GE. 12-SL Marquette version 2001 (GE, Milwaukee, WD." Outcomes ‘The primary study outcome was the incidence of new-onset AF in those frce of preexisting AF, stratified by treatment strategy. Additional study outcome was the risk of development of adverse cardiovascular events (composite of myocardial infartion [MI], non- MI acute coronary syndrome, stroke, hear fuilure, or cardiovascular cause of death) by the status of AF and by achieved BP at 3 months among those with preexisting AF. Secondary outcomes included indi- vidual components of the composite outcome separately. Statistical Amalyses ‘Bascine characteristics were compared by AF status using descrip- tive statistics. Continuous variables were summarized as median and interguarile range (1QR) and compared using Wilcoxon rank- ‘Sum test. Categorical variables were summarized as counts and per centages and compared using 7° test, Poisson regression was used to assess the incidence rates of new-onset AF in overall population and by treatment strategy. The difference in risk of new-onset AF by treatment strategy was assessed using mulvarisbl-ajusted Poisson modeling. The model was adjusted for age, sex, race, body mass index, baseline systolic BP baseline heart rate, lft ventricular hy- pertrphy on ECG (defined using Comell voltage riteia, clinical for subclinical cardiovascular disease, chronic kidney disease, umber ‘of ECGs, total cholesterol levels, aspirin use, statin use, ACE (angio- tensn-converting enzyme) inibitor/angiotensn receptor blockers use, smoking satus, thyroid disease, aleobol abuse, and eatment siraegy.* Kaplan-Meier curves were generated for cumulative inc- dence of ncw-onsct AF by teatment strategy and compared using log- rank test. Relative strength of association between risk of new-onset AP and various clinical and demographic factors was evaluated using ‘multivariable-adjusted Cox models, and compared using likelihood ratio test, as described previously.” ‘Maltivariable-adjusted Cox proportional hazard models were used to evaluate the hazard of adverse cardiovascular events and the sec- ‘ondary outcomes by the status of AF and by achieved BP among those ‘with preexisting AF. Te models were adjusted forthe abovementioned ‘covariates. Potential interaction by treatment strategy was assessed us: ing multiplicative iteration term, All analyses were performed us- ing STATA SE version 16,0 (StatsCorp, College Station, TX), with a Diailed P value of <0.05 considered statistically significant, Results Among 9327 participants with available data, preexisting AF was present in 8.45% of the study population. The incidence ‘of new-onset AF was 4.53 per 1000-person years (95%,3.84- 5.34 per 1000-person year). In comparison to those free of AR, participants with preex- isting AF were older (74 {TOR, 66-79] years) and more likely to be white (76.9%, Pc0.001) and male (71.2%, P<0.001), Patients ‘ith preexisting AF were also more likely to have clinical and subclinical cardiovascular disease (36.1% versus. 18.3%) and greater aspirin use (62.4% versus 49.8; P0.10). In those with new-onset AF on intensive treatment, the hazard for de- velopment of adverse cardiovascular events was 0.84 (95% CL, 0.56-1.26; P=0.39) compared with standard therapy. The hhazard for stroke in those with preexisting AF was 2.20 (95% Cl, 1.40-3.48; P=0.001), and for those with new-onset AF was, 2.92 (95% Cl, 1.16-7.32; P=0.02). Those with preexisting AF hazard ratio, 3.58 [95% CI, 2.46-5.23}; P<0.001) and new- onset AF (hazard ratio, 5.32 (95% Cl, 2.93-9.67); P<0.001), also had a greater risk of developing heart failure compared ‘with those free of AF. The hazard for cardiovascular death was 2,69 (95% Cl, 1.64-4.40; P0.001) for preexisting AF and 1.25, (95% Cl, 0.17-9.22; P=0,82) for those with new-onset AF. Residual Cardiovascular Risk in Participants with Preexisting AF and Intensive BP Control Approximately 35% (n=281) of participants with preexisting AF achieved the BP level of <120/80 mmHg at 3 months ‘Those who achieved the BP level of <120/80 mmHg were clinically and demographically similar to those who did not, except fr being older (75 [IQR, 67-80] years versus 73 [1QR, 665-79} years; P=0.01) and having worse renal function (esti- ‘mated glomerular filtration rate, 63.2 [IQR, 50.6-77.8] versus 68.1 [1QR, $43-81.9]; P-0.007) Participants with preex- isting AF and BP of <120/80 mmHg at 3 months, hada greater risk for adverse cardiovascular events compared with those free of AF (hazard ratio, 1.88 [95% CI, 1.32-2.70}; P=0.001; Figure 4). Among individuals with preexisting AF and BP of <<120/80 mmHg the hazard was 2.43 (95% CI, 1.24476; P=0.01) for stroke, 1.74 (95% Cl, 0.98-3.11; P=0,058) for MI and 3.17 (95% Cl, 1.76-5.69; P<0.001) for heart failure, compared with those free of AF. Discussion In the large, well-phenotyped cohort of relatively older, high- risk, nondiabetic hypertensive participants from the SPRINT trial, we observed a similar incidence of new-onset AF among. individuals in the intensive and standard BP control arms. New ‘onset AF was driven primarily by age, body mass index, rice, ‘smoking status, and presence of clinical or subclinical cardiovas- cular disease. We observed that both preexisting and new-onset, [AF increased the hazard of developing adverse cardiovascular events compared with those free of AF. Aggressive contol of [BP to <120/80 mmHg was not associated with decreased risk of adverse cardiovascular events in those with prevalent AF. This, suggest that residual cardiovascular risk needs to be addressed, after stringent BP control inthis population. ata from multiple prospective studies have established the association of hypertension with incident AF, with em- pirical evidence from observational studies and smaller trials, Implications of AF in Hypertension: SPRINT Trial 1485 specifying the role of BP reduction in decreasing the inci- dence of AF'*'%2 Prior works have focused on evalu- ating the baseline or on-treatment BP with progression of AF or development of new-onset AFS**2"!" Yet, it has been unclear whether intense BP reduction will further de- crease the incidence of atrial fibrillation, Our work provides, knowledge about the lack of incremental benefit of intensive BP control to reduce new-onset AF in this high-risk, older nondiabetic cohort, Structural remodeling, autonomic dys- regulation, increased oxidative stress, interstitial fibrosis and activation of the renin-angiotensin-aldosterone system have ‘been proposed as probable pathophysiological pathways for the development of AF in hypertension.'22" Recent data from the Atherosclerosis Risk in Communities study sug- ‘gests that the retrospective application of the 2017 high BP ‘guidelines does not correspond to a higher incidence of AF attributed to hypertension.» The similar incidence of AF in, both intensive and standard BP control arms of the SPRINT cohort suggests that underlying pathophysiology contributing to the development of AF may not be completely mitigated ‘with more intensive BP control. Additionally, left ventricular hypertrophy resulting from prolonged high BP is associated with the occurrence and progression of AF in hypertensive individuals." We observed that baseline left ventricular hy- pertrophy had a strong to modest association with new-onset, AR. Strict BP control may partially reverse the architectural changes in the heart, but the effects take time to establish, ‘and ongoing subclinical organ damage from various patho- logical pathways may persist. This may contribute to the re- sidual risk and, eventually, a higher adverse cardiovascular ‘event risk despite optimal BP control. High BP may confer a higher risk for incident AF, but due to its association with various comorbidities, its tight control may not attenuate the ‘competing risk of AF arising out of other uncontrolled re~ sidual factors." Thus, although BP control has been convinc- ingly demonstrated to reduce AF burden and incident AF, there may be diminishing returns beyond a moderately strict, threshold.” SPRINT enrolled a relatively older (mean age, 67.9 years) population with a higher baseline cardiovascular disease risk (mean Framingham Risk Score of 24,8%)." This suggested that the population was predisposed to AF regardless of BP control due to ongoing underlying clinical and subclinical pa- thology. A younger, lower-risk population with less comor- bidity burden may be ideal to demonstrate a more significant preventive role for aggressive BP control strategy in reducing, the incidence of AF. Moreover, SPRINT excluded individuals, ‘with diabetes mellitus, which is a known predisposing fac- tor for new-onset AF” Intensive BP control in diabetic indi- ‘viduals has been associated with reduced incidence for the ‘composite of AF or intermediary phenotype (P-wave indices) ‘but not for AF alone.”® Hence, presence of diabetes mellitus ‘may be an important effect modifier for the relationship of intensive BP control with new-onset AF, which requires pro- spective testing in a population inclusive of diabeties. Prior data from epidemiological studies in younger, lower-risk populations, have shown that poor renal function is assoct- ated with incident AF, which is contrasted by chronic kidney disease being a poor clinical correlate for incident AF in the 120257 290190 wo 6g ao sjeusnoteyey diy wos popeOKUAO 1486 Hypertension June 2020 Table. Basie Characters ofthe Stay Patipants | Pale Free ot AF | Pale Free ot AE Characteristics Fee of AF; N=B408Preesting AF; N=778 New-Onset AF, N=141__ vs Preexisting) ‘ws New-Onset) Ctra for increased OV risk ‘Ao275y 2199.6.) 361 (46.4) 71 (604) <0001

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