CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the CHAP Trial

Table of contents for the trial summary:

• Visual abstract
• Summary
• References
• Credits
• Twitter Archive

April 2^nd, 2022

Treatment for Mild Chronic Hypertension during Pregnancy

A.T. Tita, J.M. Szychowski, K. Boggess, L. Dugoff, B. Sibai, K. Lawrence, B.L. Hughes, J. Bell, K. Aagaard, R.K. Edwards, K. Gibson, D.M. Haas, L. Plante, T. Metz, B. Casey, S. Esplin, S. Longo, M. Hoffman, G.R. Saade, K.K. Hoppe, J. Foroutan, M. Tuuli, M.Y. Owens, H.N. Simhan, H. Frey, T. Rosen, A. Palatnik, S. Baker, P. August, U.M. Reddy, W. Kinzler, E. Su, I. Krishna, N. Nguyen, M.E. Norton, D. Skupski, Y.Y. El‐Sayed, D. Ogunyemi, Z.S. Galis, L. Harper, N. Ambalavanan, N.L. Geller, S. Oparil, G.R. Cutter, and W.W. Andrews, for the Chronic Hypertension and Pregnancy (CHAP) Trial Consortium

https://www.nejm.org/doi/full/10.1056/NEJMoa2201295

Relevant Literature – CHAP Trial

Relevant Guidelines – CHAP Trial

There were several reviews of published guidelines for hypertension disorders of pregnancy; guidelines agreed that severe hypertension (>160/110) in pregnancy should be treated, but there was no consensus between guidelines on the treatment of mild to moderate chronic hypertension or optimal treatment targets for blood pressure during pregnancy. ^7,8 The lack of high-quality evidence was cited as a reason for the lack of consensus between guidelines.

Selected ACOG Guidelines Pertaining to Management of Chronic Hypertension in Pregnancy⁹

2017 AHA/ACC Hypertension Guideline: Section 10.2.2 on Pregnancy¹⁰

Summary of Guidelines for diagnosis and treatment (USA, Europe, Canada, Australia/New Zealand)¹¹

Study Rationale – CHAP Trial

There is a lack of data regarding the benefits and safety of treating mild chronic hypertension (BP <160/100 mmHg) during pregnancy. Chronic hypertension (cHTN) may complicate 2-6% of the US births and is associated with adverse obstetric and maternal outcomes, but current guidelines recommend withholding or discontinuing treatment below a threshold of 160/100 due to prior data potentially linking hypotension with increased perinatal mortality and intrauterine growth restriction, first noted in 1961 by McLure-Brown et al.¹² This treatment threshold directly contradicts treatment recommendations for cHTN in the general population and stems from a lack of clear evidence demonstrating the risk or benefit of cHTN treatment in pregnancy.

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Objective – CHAP Trial

The objective was to demonstrate whether a strategy of targeting BP less than 140/90 when treating cHTN in pregnancy reduces adverse outcomes without affecting fetal growth.

Trial

Open-labeled, pragmatic, multicenter, randomized controlled trial conducted across 70 recruiting sites in the United States.

Intervention

A protocol was established for measuring blood pressure in clinic visits using an automated device (Omron HEM-907). Patients were then randomly assigned to blood pressure goal of <140/90 (active treatment) or standard (control) treatment where only severe hypertension was treated (systolic pressure ≥160 or diastolic pressure ≥105).

In the active treatment group, a single-agent anti-hypertensive was initiated (labetalol, extended-release nifedipine, or alternative therapy such as amlodipine or methyldopa if the patient preferred). The dose was escalated to the maximum recommended dose tolerated before initiation of a second agent (preferably nifedipine or labetalol). 

Enrollment Criteria

• Inclusion criteria:
  • Females with a new diagnosis (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, at least 2 occasions, at least 4 hours apart, before 20 weeks gestation without prior history of hypertension) or known chronic hypertension (confirmed by documented elevated blood pressure and current or previous anti-hypertensive therapy) during pregnancy receiving prenatal care at one of the participating centers
  • Singleton pregnancy
  • Viable pregnancy < 23 weeks of gestation

• Exclusion criteria:
  • Clinic blood pressure confirmed ≥ 160/90 with or without treatment
  • Established history of severe hypertension (e.g.>1 anti-hypertensive agent, diagnosis of severe hypertension by a clinical provider in clinic on review blood pressure)
  • Multifetal pregnancy
  • Known history of or diagnosis of a secondary cause of chronic hypertension
  • High-risk comorbidities for which treatment may be indicated:
    • Diabetes mellitus diagnosed ≤ 10 years of age or diagnosis made ≥ 20 years ago
    • Diabetes mellitus complicated by end-organ damage (retinopathy, nephropathy, heart disease, transplant)
    • Chronic kidney disease
    • Cardiac diseases (cardiomyopathy, angina, coronary artery disease)
    • Prior stroke
    • Sickle cell disease
  • Known major fetal anomaly in current pregnancy
  • Known fetal demise in current pregnancy
  • Suspected intra-uterine growth restriction
  • Membrane rupture or planned termination prior to randomization
  • Plan to deliver outside designated centers or low likelihood of follow up
  • Contraindication for labetalol and nifedipine
  • Current substance abuse or addiction
  • Participation in another trial without prior approval
  • Refusal of patient
  • Refusal of physician or provider

Outcomes

• Primary Outcomes
  • Composite of pre-eclampsia with severe features occurring up to 2 weeks after birth
  • Medically indicated preterm birth before 35 weeks gestation
  • Placental abruption
  • Fetal or neonatal death

• Primary Safety Outcomes
  • Poor fetal growth (birth weight <10^th percentile based on gestational age and sex)
  • Small-for-gestational-age birth weight less than 5^th percentile

• Secondary Outcomes
  • Composite of maternal death or serious complications (stroke, myocardial infarction or angina, heart failure, pulmonary edema, encephalopathy, intubation, renal failure or admission to intensive care unit)
  • Preterm birth (<37 weeks)
  • Composite of serious neonatal complications (necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia or grade 3 or 4 intraventricular hemorrhage)
  • Other maternal outcomes (pre-eclampsia, worsening chronic hypertension, blood transfusion, cesarean delivery)
  • Other newborn outcomes (neonatal intensive care unit admission, length of hospital stay, birth weight <2500 g, bradycardia, hypoglycemia, hypotension, ponderal index, head circumference, placental weight)

Statistical Analysis

• Sample size:  The final sample size was approved by the data and safety monitoring board with 2404 participants (1202 in each group), sufficient to detect a relative reduction of 33% in the incidence of primary-composite outcome (assuming baseline incidence rate of primary outcome was 16% with 10% non-adherence and 5% lost to follow-up) with 85% power and a two-sided alpha of 0.05. Blinded reassessment of sample size after enrollment of 800 patients showed a primary-outcome incidence of 30%, confirming that the above number of participants would be sufficient.
• Analysis: Intention-to-treat model. For cases where the primary-outcome was undetermined, primary analysis used multiple imputations for primary outcome. Log-binomial regression was used to generate adjusted relative risk and 95% confidence interval for primary outcomes. 

Participant Characteristics:

• Of nearly 30,000 patients screened, ultimately, data for only 2419 patients was analyzed. Most patients who were excluded were ineligible due to blood pressure that was too high, too low, or gestational age that was too high.
• Both groups were well balanced in demographic characteristics. Nearly 50% of the enrolled patients identified as Black (compared to ~12% in CHIPS)³.
• Mean BMI at enrollment was 37.5 kg/m²
• Regarding cHTN diagnosis: 56% with known cHTN on medication, 22% with known cHTN not on medication, 22% with newly diagnosed cHTN
• Labetalol and Nidefipine were the two most common anti-hypertensives being used prior to randomization
• Before enrollment, nearly half of the patients in both groups were taking aspirin, it increased to three fourth by the time of delivery
• Primary outcome favoring the active treatment group was influenced largely by pre-eclampsia with severe features and medically indicated preterm birth at <35 weeks however, abruption and fetal/neonatal death are rarer pregnancy outcomes in general

Outcomes

Primary Outcomes:

• The primary outcome of composite of pre-eclampsia with severe features, medically indicated preterm birth <35 weeks, placental abruption and fetal or neonatal death at < 28 days occurred in 30.2% of active treatment group vs 37% of control group (p <0.001)
• Primary safety outcome of small-for-gestational-age birth weight <10^th percentile was similar in both active treatment and control groups, 11.2% and 10.4% respectively (p = 0.56)

Secondary Outcomes:

• Incidence of composite of maternal death or serious complications (heart failure, stroke, or encephalopathy; myocardial infarction or angina; pulmonary edema; admission to an intensive care unit [ICU] or intubation; or renal failure) or any preterm birth (<37 weeks’ gestation) was overall low and did not differ significant between the active treatment and control groups

Adverse Events:

Incidence of composite of serious neonatal complications (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, or intraventricular hemorrhage of grade 3 or 4) did not differ significantly between the active treatment and control groups

Conclusions – CHAP Trial

Treating chronic hypertension in pregnancy using a blood pressure target of less than 140/90 is associated with improved pregnancy outcomes as compared to reserving treatment for severe hypertension alone. In those patients with tighter blood pressure goals, no increase in risk for fetal growth restriction was observed.

Limitations & Considerations

• A large number of secondary outcomes were not adjusted for multiple outcomes and should be interpreted accordingly (i.e. reduction in pre-eclampsia is exciting but more research is needed prior to changing guidelines)
• Open-label trial making it more subject to bias
• Participants were carefully selected for this trial; 12 people were screened for every one participant selected to be enrolled. This brings into question the generalizability of the trial.

1. Sibai BM, Mabie WC, Shamsa F et al. A comparison of no medication versus methyldopa or labetalol in chronic hypertension during pregnancy. Am J Obstet Gynecol. 1990 Apr;162(4):960-6; discussion 966-7. doi: 10.1016/0002-9378(90)91297-p.
2. Nifedipine versus expectant management in mild to moderate hypertension in pregnancy. Gruppo di Studio Ipertensione in Gravidanza. Br J Obstet Gynaecol. 1998 Jul;105(7):718-22. doi: 10.1111/j.1471-0528.1998.tb10201.x.
3. Magee LA, von Dadelszen P, Rey E, et al. Less-tight versus tight control of hypertension in pregnancy. N Engl J Med 2015;372:407-417.
4. Boucheron P, Lailler G, Moutengou E, et al. Hypertensive disorders of pregnancy and onset of chronic hypertension in France: the nationwide CONCEPTION study. Eur Heart J. 2021 Oct 13:ehab686. doi: 10.1093/eurheartj/ehab686
5. Abalos E, Duley L, Steyn DW, et al. Anti-hypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD002252. doi: 10.1002/14651858.CD002252.pub2. Update in: Cochrane Database Syst Rev. 2014;2:CD002252.
6. Webster LM, Conti-Ramsden F, Seed PT, Webb AJ, Nelson-Piercy C, Chappell LC. Impact of Antihypertensive Treatment on Maternal and Perinatal Outcomes in Pregnancy Complicated by Chronic Hypertension: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2017 May 17;6(5):e005526. doi: 10.1161/JAHA.117.005526. PMID: 28515115; PMCID: PMC5524099.
7. Tsakiridis I, Giouleka S, Arvanitaki A, et al. Chronic hypertension in pregnancy: synthesis of influential guidelines. J Perinat Med. 2021 Apr 20;49(7):859-872. doi: 10.1515/jpm-2021-0015.
8. Sinkey RG, Battarbee AN, Bello NA, et al. Prevention, Diagnosis, and Management of Hypertensive Disorders of Pregnancy: a Comparison of International Guidelines. Curr Hypertens Rep. 2020 Aug 27;22(9):66. doi: 10.1007/s11906-020-01082-w.
9. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 203: Chronic Hypertension in Pregnancy. Obstet Gynecol. 2019 Jan;133(1):e26-e50. doi: 10.1097/AOG.0000000000003020.
10. Whelton PK, Carey RM, Aronow WS, 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: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-e248. doi: 10.1016/j.jacc.2017.11.006. Epub 2017 Nov 13. Erratum in: J Am Coll Cardiol. 2018 May 15;71(19):2275-2279.
11. Garovic VD, Dechend R, Easterling T, et al. Hypertension in Pregnancy: Diagnosis, Blood Pressure Goals, and Pharmacotherapy: A Scientific Statement From the American Heart Association. 2021 Dec;79:e21-41.
12. McClure-Brown JC: Survey of eclampsia clinical aspects. Report to the 7th Conference of the International Society of Geographical Pathology, London, 1960. Path Microbiol. 1961, 24: 542-556.

The published archive features curated twitter highlights from the journal club event.