Aspirin for the Prevention of Preeclampsia in Women With Stage 1 Hypertension

Pre-Eclampsia Clinical Trial

Official title:

Aspirin for the Prevention of Preeclampsia in Women With Stage 1 Hypertension: A Pilot Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04908982
• Other study ID #: AS1H
• Status: Recruiting
• Phase: Phase 4
• Start date: May 28, 2021
• Est. completion date: May 31, 2023

Study information

• Verified date: May 2021
• Source: Eastern Virginia Medical School
• Contact: Tetsuya Kawakita, MD
• Phone: 7574467900
• Email: kawakit[@]evms.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In 2017, the American College of Cardiology and the American Heart Association changed the diagnostic criteria for hypertension in non-pregnant adults. The parameters for the diagnosis of stage 1 hypertension were revised from a systolic blood pressure (BP) of 140 to 130 mm Hg and a diastolic BP of 90 to 80 mm Hg. Based on new criteria, stage 1 hypertension is associated with a 2-3 fold increased risk of preeclampsia. There are no data regarding prevention of preeclampsia in women with stage 1 hypertension. Low-dose aspirin has been used during pregnancy to prevent preeclampsia for women at high-risk for preeclampsia. Although the precise mechanism remains uncertain, it is possible that low-dose aspirin improves placental perfusion, which results in a decreased rate of preeclampsia. A study that examines the effect of low-dose aspirin on placenta vasculature and tissue elastography by using novel ultrasound tools would be useful. The 2017 Aspirin for Evidence-Based Preeclampsia Prevention trial compared 150 mg aspirin with placebo in women at high-risk of preeclampsia based on a first-trimester screening. They found a significant decrease in the rate of preterm preeclampsia (4.3% vs. 1.6%; P <0.01). Since this study used the screening algorithm including first-trimester serum markers and uterine artery Doppler, the generalizability in the U.S. women with stage 1 hypertension is limited. Our pilot study will examine 1) the effect of low-dose aspirin 81 mg in women with stage 1 hypertension on placental vasculature and shear-wave elastography; 2) the rate of preterm preeclampsia in women with stage 1 hypertension in a control group and in pregnancies treated with low-dose aspirin 81 mg; 3) feasibility of conducting a larger multicenter randomized controlled trial on this subject.

Description:

In 2017, the American College of Cardiology (ACC) and the American Heart Association (AHA) changed the diagnostic criteria for hypertension in non-pregnant adults.1 The parameters for the diagnosis of stage 1 hypertension were revised from a systolic blood pressure (BP) of 140 to 130 mm Hg and a diastolic BP of 90 to 80 mm Hg.2 Stage 1 hypertension based on the new criteria is associated with an increased risk of preeclampsia compared to normal BP (15-16% vs. 5-7%).3, 4 However, the American College of Obstetricians and Gynecologists (ACOG) continues to diagnose chronic hypertension in pregnancy as a systolic BP above 140 mm Hg and a diastolic BP of 90 mm Hg since there are no data regarding prevention of preeclampsia in women with stage 1 hypertension.5

Preeclampsia is a multi-organ, progressive disorder characterized by the new onset of hypertension with proteinuria or end-organ dysfunction.6 Preeclampsia is a major cause of morbidity such as eclampsia, pulmonary edema, myocardial infarction, stroke, coagulopathy, and renal failure and a leading cause of iatrogenic preterm birth and maternal mortality.7 Preeclampsia is also an economic burden to the health care system. The mean combined maternal and infant medical care costs for women with preeclampsia are significantly higher than those of uncomplicated women ($41,790 vs. $13,187 in 2015 dollars) with the main cost drivers being infant health care costs due to prematurity.8

It is hypothesized that preeclampsia is caused by an imbalance in prostacyclin and thromboxane A2 (TXA2) resulting in vascular disturbances and coagulation defects. Low-dose aspirin (60-150 mg/day) irreversibly acetylates cyclooxygenase (COX)-1, which results in decreased platelet synthesis of TXA2 without affecting vascular wall production of prostacyclin.9. 10 However, it is likely that preeclampsia is a result of poor placentation. In this pilot study, we will examine the effect of low-dose aspirin on placental perfusion by using novel ultrasound tools (Superb Micro-Vascular Imaging [SMI], Shear Wave Elastography [SWE], intensity analysis [IA], and Attenuation Imaging [ATI]). Superb Micro-Vascular Imaging (SMI) is a novel Doppler technique designed to improve the visualization of microscopic vessels, through a new adaptive algorithm, which dramatically enhances microvascular flow and removes artifacts. Shear Wave Elastography (SWE) is a new noninvasive ultrasound-based technology for the evaluation of soft tissue stiffness. Intensity Analysis (IA) is a technique that analyzes tissue homogeneity. Attenuation Imagining (ATI) measures beam attenuation by quantifying an attenuation coefficient (AC db/cm/MHz). Our group has developed longitudinal nomograms on placental vasculature to include uterine and spiral arteries on the maternal side and fetal placental arterioles and umbilical artery on the fetal side.11 Furthermore, longitudinal nomograms related to placental tissue structure, including shear wave elastography has been developed.12

Although the precise mechanism is uncertain, low-dose aspirin has been used during pregnancy to prevent or delay the onset of preeclampsia for women at high-risk for preeclampsia.13 The 2017 Aspirin for Evidence-Based Preeclampsia Prevention trial compared 150 mg aspirin with placebo in women at high-risk of preeclampsia based on a first-trimester screening.14 They found a significant decrease in the rate of preterm preeclampsia less than 37 weeks of gestation (4.3% vs. 1.6%; P <0.01). Since this study used the screening algorithm including first-trimester serum markers and uterine artery Doppler, the generalizability of aspirin preeclampsia prevention in the U.S. women with stage 1 hypertension is limited.

Our long-term goal is to reduce preterm preeclampsia in women with stage 1 hypertension. We hypothesize that 1) spiral artery Pulsatility Index (PI) and Peak Systolic Velocity (PSV) and SWE is lower in women with stage 1 hypertension who receive low-dose aspirin 81 mg compared to those who do not receive low-dose aspirin; 2) Women with stage 1 hypertension who receive low-dose aspirin 81 mg have a lower rate of preterm preeclampsia compared to those who do not receive low-dose aspirin. To examine these hypotheses in a future, large randomized, controlled trial, our aims for this pilot study include the following:

Aim 1. To examine the change in placental vasculature and tissue elastography in women with stage 1 hypertension who receive low-dose aspirin 81 mg and those who do not receive low-dose aspirin.

Aim 2. To examine rates of preterm preeclampsia in women with stage 1 hypertension who receive low-dose aspirin 81 mg and those who do not receive low-dose aspirin.

Aim 3. To examine eligibility rate, recruitment rate, study compliance, and loss of follow-up rate. This information will be useful to assess feasibility of a future multicenter randomized controlled trial.

In summary, women with stage 1 hypertension are at an increased risk of preeclampsia. Low-dose aspirin may reduce the rate of preterm preeclampsia in women with stage 1 hypertension. In this pilot study, we will conduct an open label randomized controlled trial and obtain necessary information for a future multicenter randomized controlled trial.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: May 31, 2023
• Est. primary completion date: May 31, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• Pregnant women from 6 0/7 to 13 6/7 weeks gestation

• 18-50 years old

• Systolic blood pressure of 130-139 mmHg or Diastolic blood pressure of 80-89 mmHg

Exclusion Criteria:

• History of preeclampsia

• Multifetal gestation

• Chronic hypertension

• Pre-gestational diabetes

• Renal disease

• Autoimmune disease

• Aspirin allergy or hypersensitivity

• Presence of nasal polyps

• History of aspirin-induced bronchospasm

Related Conditions & MeSH terms

• Eclampsia
• Hypertension
• Pre-Eclampsia

Intervention

Drug:
• Aspirin 81mg
81mg aspirin daily beginning between 12 and 16 weeks of pregnancy and continuing until delivery.

Locations

Country	Name	City	State
United States	Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Eastern Virginia Medical School	Norfolk	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
Eastern Virginia Medical School	AMAG Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (24)

Abuhamad A, Sinkovskaya E, Heeze A, et al. Longitudinal assessment of placental shear-wave elastography and correlation with placental circulation in normal pregnancies. Am J Obstet Gynecol. 2020;222(1)S67

Abuhamad A, Sinkovskaya E, Heeze A, et al. Noninvasive longitudinal assessment of spiral and uterine arteries in normal pregnancies using novel ultrasound tools. Am J Obstet Gynecol. 2020;222(1)S588-S589

ACOG Committee Opinion No. 743: Low-Dose Aspirin Use During Pregnancy. Obstet Gynecol. 2018 Jul;132(1):e44-e52. doi: 10.1097/AOG.0000000000002708. — View Citation

ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2019 Jan;133(1):1. doi: 10.1097/AOG.0000000000003018. — View Citation

Ahrens KA, Silver RM, Mumford SL, Sjaarda LA, Perkins NJ, Wactawski-Wende J, Galai N, Townsend JM, Lynch AM, Lesher LL, Faraggi D, Zarek S, Schisterman EF. Complications and Safety of Preconception Low-Dose Aspirin Among Women With Prior Pregnancy Losses. Obstet Gynecol. 2016 Apr;127(4):689-698. doi: 10.1097/AOG.0000000000001301. — View Citation

Askie LM, Duley L, Henderson-Smart DJ, Stewart LA; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007 May 26;369(9575):1791-1798. doi: 10.1016/S0140-6736(07)60712-0. Review. — View Citation

Battarbee AN, Sinkey RG, Harper LM, Oparil S, Tita ATN. Chronic hypertension in pregnancy. Am J Obstet Gynecol. 2020 Jun;222(6):532-541. doi: 10.1016/j.ajog.2019.11.1243. Epub 2019 Nov 9. Review. — View Citation

Clarke RJ, Mayo G, Price P, FitzGerald GA. Suppression of thromboxane A2 but not of systemic prostacyclin by controlled-release aspirin. N Engl J Med. 1991 Oct 17;325(16):1137-41. — View Citation

CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet. 1994 Mar 12;343(8898):619-29. — View Citation

Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD004659. Review. Update in: Cochrane Database Syst Rev. 2019 Oct 30;2019(10):. — View Citation

Hao J, Hassen D, Hao Q, Graham J, Paglia MJ, Brown J, Cooper M, Schlieder V, Snyder SR. Maternal and Infant Health Care Costs Related to Preeclampsia. Obstet Gynecol. 2019 Dec;134(6):1227-1233. doi: 10.1097/AOG.0000000000003581. — View Citation

Hauspurg A, Parry S, Mercer BM, Grobman W, Hatfield T, Silver RM, Parker CB, Haas DM, Iams JD, Saade GR, Wapner RJ, Reddy UM, Simhan H. Blood pressure trajectory and category and risk of hypertensive disorders of pregnancy in nulliparous women. Am J Obstet Gynecol. 2019 Sep;221(3):277.e1-277.e8. doi: 10.1016/j.ajog.2019.06.031. Epub 2019 Jun 27. — View Citation

Henderson JT, Whitlock EP, O'Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014 May 20;160(10):695-703. doi: 10.7326/M13-2844. Review. — View Citation

Kozer E, Nikfar S, Costei A, Boskovic R, Nulman I, Koren G. Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis. Am J Obstet Gynecol. 2002 Dec;187(6):1623-30. — View Citation

Muntner P, Carey RM, Gidding S, Jones DW, Taler SJ, Wright JT Jr, Whelton PK. Potential US Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline. Circulation. 2018 Jan 9;137(2):109-118. doi: 10.1161/CIRCULATIONAHA.117.032582. Epub 2017 Nov 13. — View Citation

Patrono C. Aspirin as an antiplatelet drug. N Engl J Med. 1994 May 5;330(18):1287-94. Review. — View Citation

Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation. 2005 Feb 8;111(5):697-716. — View Citation

Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K, Nicolaides KH. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017 Aug 17;377(7):613-622. doi: 10.1056/NEJMoa1704559. Epub 2017 Jun 28. — View Citation

Slone D, Siskind V, Heinonen OP, Monson RR, Kaufman DW, Shapiro S. Aspirin and congenital malformations. Lancet. 1976 Jun 26;1(7974):1373-5. — View Citation

Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010 Aug 21;376(9741):631-44. doi: 10.1016/S0140-6736(10)60279-6. Epub 2010 Jul 2. Review. — View Citation

Sutton EF, Hauspurg A, Caritis SN, Powers RW, Catov JM. Maternal Outcomes Associated With Lower Range Stage 1 Hypertension. Obstet Gynecol. 2018 Oct;132(4):843-849. doi: 10.1097/AOG.0000000000002870. — View Citation

Topel ML, Duncan EM, Krishna I, Badell ML, Vaccarino V, Quyyumi AA. Estimated Impact of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines on Reproductive-Aged Women. Hypertension. 2018 Oct;72(4):e39-e42. doi: 10.1161/HYPERTENSIONAHA.118.11660. — View Citation

Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. 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 Jun;71(6):1269-1324. doi: 10.1161/HYP.0000000000000066. Epub 2017 Nov 13. Review. Erratum in: Hypertension. 2018 Jun;71(6):e136-e139. Hypertension. 2018 Sep;72(3):e33. — View Citation

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* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Preterm Preeclampsia	Preeclampsia developed before 37 weeks	Prior to 37 weeks
Secondary	Preeclampsia	Systolic blood pressure of 140 mmHg or more or diastolic blood pressure of 90 mmHg or more on two occasions at least four hours apart or a systolic blood pressure of 160 mmHg or more or diastolic blood pressure of 110 mmHg or more; and Proteinuria of 300mg or more per 24-hour urine collection or protein/creatinine ratio of 0.3 or more; or in the absence of proteinuria, new-onset hypertension with the new onset of any of the following severe features: thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, new-onset headache unresponsive to medication.	After 37 weeks
Secondary	Gestational Hypertension	Systolic blood pressure of 140 mmHg or more or diastolic blood pressure of 90 mmHg or more on two occasions at least four hours apart with no proteinuria or severe features.	After 20 weeks gestation
Secondary	HELLP Syndrome	Hemolysis, elevated liver enzymes, and low platelet count syndrome	After 20 weeks gestation
Secondary	Eclampsia	New-onset tonic-clonic, focal, or multifocal seizure in the absence of other causative conditions	After 20 weeks gestation