Worse Blood Pressure Levels and Control During Nonsummer Months in Rigorously Treated Patients With Hypertension: The ACCOMPLISH Trial

HomeJournal of the American Heart AssociationAhead of PrintWorse Blood Pressure Levels and Control During Nonsummer Months in Rigorously Treated Patients With Hypertension: The ACCOMPLISH Trial Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessLetterPDF/EPUBWorse Blood Pressure Levels and Control During Nonsummer Months in Rigorously Treated Patients With Hypertension: The ACCOMPLISH Trial Robert D. Brook, Alec J. Brook, Kenneth Jamerson, Phillip D. Levy and Niko Kaciroti Robert D. BrookRobert D. Brook *Correspondence to: Robert D. Brook, MD, Division of Cardiovascular Diseases, Department of Internal Medicine, Wayne State University, 6135 Woodward Ave, Detroit, MI 48202. Email: E-mail Address: [email protected] https://orcid.org/0000-0002-8521-7262 , Division of Cardiovascular Diseases, Department of Internal Medicine, , Wayne State University, , Detroit, , MI, , USA, Search for more papers by this author , Alec J. BrookAlec J. Brook , Wayne Health Physician Group, , Detroit, , MI, , USA, Search for more papers by this author , Kenneth JamersonKenneth Jamerson , Division of Cardiovascular Medicine, , University of Michigan, , Ann Arbor, , MI, , USA, Search for more papers by this author , Phillip D. LevyPhillip D. Levy https://orcid.org/0000-0001-7306-5620 , Department of Emergency Medicine and Integrative Biosciences Center, , Wayne State University, , Detroit, , MI, , USA, Search for more papers by this author and Niko KacirotiNiko Kaciroti , Departments of Pediatrics and Biostatistics, , University of Michigan, , Ann Arbor, , MI, , USA, Search for more papers by this author Originally published8 Jul 2023https://doi.org/10.1161/JAHA.123.030696Journal of the American Heart Association. 2023;0:e030696It is well established that blood pressure (BP) levels increase during winter (5.6/3.3 mm Hg higher than summer).1, 2 Nonetheless, a number of issues require clarification to better inform clinical practice including if treatment aspects (eg, number of drugs, tighter BP control, specific regimens) or patient characteristics modify winter‐induced BP elevations.1 Clinical trial data offer advantages to address these questions compared with observational studies. We therefore assessed the determinants of seasonal BP variations within the ACCOMPLISH (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension) trial.3We are unable to make the data available to other researchers due to contractual ownership. Institutional Review Board approval and patient consent for the analyses of these deidentified data were not required. Monthly variations in BP levels and control rates (<140/90 mm Hg per study criteria) were evaluated in the US trial population (n=8150; 400 sites).3 The Nordic population (n=3353) was excluded because of different entry criteria, higher in‐trial BP levels, and smaller seasonal temperature variations. Each participant had clinic BP measurements repeated up to 12 times across different months over a maximum of 3.5 years according to the trial schedule: 2 weeks before randomization and then at day 1; months 1, 2, 3, 6, and 12; plus every 6 months thereafter (totaling 79 082 readings). We assessed the effects of the months of measurement on BP levels, and control rates using mixed models controlling for relevant factors (Figure). Effect modification of “winter‐induced BP elevations,” the difference in BP levels between winter (December–February) versus summer (June–August), was evaluated by adding interaction terms into the models. Prespecified factors included sex, age (above versus below the mean of 68 years), race (Black [n=1371] versus White and other), obesity (body mass index above versus below 30 kg/m2), drug treatment intensity (2 versus >2 BP‐lowering medications), drug regimen (randomized to benazepril plus hydrochlorothiazide versus amlodipine), and achieved in‐trial systolic BP (<130 versus ≥130 mm Hg averaged over months 6–42).Download figureDownload PowerPointFigure 1. Monthly blood pressure levels and control in the ACCOMPLISH trial.A, Systolic BP. Points (with 95% CIs) represent the differences in systolic levels at each month compared with July (comparator). B, Diastolic BP. Points (with 95% CIs) represent the differences in diastolic BP levels at each month compared with July (comparator). All BP values were highly significantly (P<0.0001) elevated compared with July except for June and August and remained significant after adjusting for multiple testing (Bonferroni correction). The P value for September was P=0.002. The number of BP readings and monthly mean levels for systolic and diastolic BPs are presented at the bottom of the figure. In the mixed models, the outcome is the absolute systolic and diastolic BPs during each month, with the main predictor being month of measurement, controlling for study treatment allocation, visit number (as a discrete factor), Black race versus White and other races, number of add‐on medications, percutaneous coronary intervention, dyslipidemia, myocardial infarction, left ventricular hypertrophy, atrial fibrillation, renal disease, diabetes, and glucose and potassium levels at baseline. By controlling for treatment effect and visit number and their interaction, we remove any potential confounding due to treatment or time in the study (earlier BP measurements in the trial are higher than later readings after treatment intensifcations). A random intercept for each subject was also included in the model. The model was fitted using restricted maximum likelihood. The residual variance used Gaussian covariance for the repeated‐measure structure, accounting for the time between BP measurements. Under this model, the covariances between pairs of observations decays with the exponential of the square of the duration of time between them. While BP varies by visit and month of measurement, there was no interaction between visit and the month of BP measurement, which indicates the month effect per se is not affected by visit (ie, time in study treatment). Thus, we report the monthly BP differences from July averaged across all visits in the curve. C, BP control. Points (with 95% CIs) represent the difference in BP control at each month compared with July. All values are significantly lower except for June and August. ACCOMPLISH indicates Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension; BP, blood pressure; DBP, diastolic blood pressure; and SBP, systolic blood pressure.Participants were taking 3.3±1.05 medications with 77.1% prescribed additional medication(s) beyond initial randomized 2‐drug treatment. Over months 6 to 42, patients achieved an average BP of 129.7/72.3 mm Hg and a control rate of 88.7%. Systolic and diastolic BP levels were significantly higher during all months compared with July (except in June and August) (Figure [A and B]). Accordingly, BP control rates were significantly lower compared with July in all months except August (Figure [C]). Systolic BP levels were the highest (+2.6 mm Hg) and control rates (−7.2%) were the lowest in December). Diastolic BP levels were highest during February (+1.3 mm Hg). Heart rate followed a similar seasonal pattern—highest during February (+0.93 beats/min). None of the factors evaluated showed significant effect modification of winter‐induced BP elevations (P values for interaction terms>0.05).We show for the first time that the BP‐raising effects of winter persist among rigorously treated patients in a clinical trial. There was no evidence that the magnitude of winter‐induced BP elevations differs by personal characteristics. This suggests that most patients may be at risk. Neither greater drug treatment intensity nor use of the combination drug regimen benazepril plus amlodipine, shown to be 20% more effective for cardiovascular protection in ACCOMPLISH,3 proved capable of mitigating seasonal BP elevations. Even tight systolic BP control to <130 mm Hg (current goal)3 failed to protect patients. As such, these core aspects of medical treatment are unlikely effective preventative measures. It has been suggested that scrupulous BP monitoring and up‐titration of drug therapy during winter may be a rational management strategy.1, 2 Our results support this recommendation.Our findings are of high relevance to present‐day medicine, as the ACCOMPLISH cohort is a large and diverse population.3 Clinic BP was meticulously measured per standardized protocol and repeated over several years. Patients were scrupulously managed using contemporary multidrug regimens while achieving tight BP control. Nevertheless, BP remained significantly higher during most months compared with July. However, our analysis cannot prove causation or identify the responsible factors, as it was not designed to investigate mechanisms (eg, thermoregulatory vasoconstriction, neurohormonal activation).2 We also could not account for (or evaluate the causal mediating actions of) time‐varying lifestyle factors (eg, diet, weight) or the direct actions of ambient (or indoor) temperatures because the location of patients' residences or study sites were unavailable due to privacy.3 Given that there were 400 sites scattered across the continental United States, seasonal temperature changes were likely large on average but also highly variable among patients. There was no significant effect modification by any factor evaluated; nonetheless, we cannot exclude the possibility that small effects (of questionable clinical relevance) went undetected despite the enormous number of BP readings included in our models. While the magnitude of winter‐induced BP elevation was relatively modest (<3 mm Hg), it likely impacts >100 million patients with hypertension in the United States alone.4 It may also contribute to visit‐to‐visit BP variability, which is linked to worse cardiovascular outcomes.5 Therefore, our findings support prior calls for future hypertension guidelines to address this important topic.2Sources of FundingDr Brook receives relevant funding from the National Institutes of Environmental Health (1R35ES031702‐01A1).DisclosuresNone.Footnotes*Correspondence to: Robert D. Brook, MD, Division of Cardiovascular Diseases, Department of Internal Medicine, Wayne State University, 6135 Woodward Ave, Detroit, MI 48202. Email: [email protected]eduThis manuscript was sent to Yen‐Hung Lin, MD, PhD, Associate Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 3.References1 Kollias A, Kyriakoulis KG, Stanmbolliu E, Ntineri A, Anagnostopoulos I, Stergiou GS. Seasonal blood pressure variation assessed by different measurement methods: systemic review and meta‐analysis. J Hypertens. 2020; 38:791–798. doi: 10.1097/HJH.0000000000002355CrossrefMedlineGoogle Scholar2 Stergiou GS, Palatini P, Modesti PA, Asayama K, Asmar R, Bilo G, de la Sierra A, Dolan E, Head G, Kario K, et al. Seasonal variation in blood pressure: evidence, consensus and recommendations for clinical practice. Consensus statement by the European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability. J Hypertens. 2020; 38:1235–1243. doi: 10.1097/HJH.0000000000002341CrossrefMedlineGoogle Scholar3 Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez EJ. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high‐risk patients. N Engl J Med.2008; 359:2417–2428. doi: 10.1056/NEJMoa0806182CrossrefMedlineGoogle Scholar4 Whelton PK, Carey RM, Aronow WS, Casey DE, Collin KJ, Himmelfarb CD, DePalma SM, Gidding S, Jamerson KA, Jones DW, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018; 71:1269–1324. doi: 10.1161/HYP.0000000000000066LinkGoogle Scholar5 Clark D, Nicholls SJ, St John J, Elshazly MB, Ahmed HM, Khraishah H, Nissen SE, Puri R. Visit‐to‐visit blood pressure variability, coronary atheroma progression, and clinical outcomes. JAMA Cardiol. 2019; 4:437–443. doi: 10.1001/jamacardio.2019.0751CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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Published on behalf of the American Heart Association, Inc., by Wiley BlackwellThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.https://doi.org/10.1161/JAHA.123.030696PMID: 37421293 Manuscript receivedApril 20, 2023Manuscript acceptedJune 14, 2023Originally publishedJuly 8, 2023 Keywordshypertensiontemperatureclinical trialenvironmentblood pressure controlcardiovascular riskPDF download SubjectsHigh Blood PressureHypertension