The CHIPS Trial

The CHIPS Trial: The Control of Hypertension In Pregnancy Study

Formal Publication Title: Less-Tight versus Tight Control of Hypertension in Pregnancy

https://www.nejm.org/doi/full/10.1056/nejmoa1404595

Some general background information

• Who did the study and who published it?

  • An open, multicenter, international, randomized controlled trial. 

    • Coordinating center: University of British Columbia (go Canada again!)

  • Where was it published? The New England Journal of Medicine in 2015 

• Why was the study done? 

  • Hypertension is common – at the time of this publication, it was estimated to affect 10% of pregnancies, with 1% being cHTN, 5-6% being gHTN, and 2-3% being preeclampsia.

  • Treatment of blood pressure at specific thresholds had not really been well defined.

    • On one hand – using antihypertensives liberally and early might help prevent maternal / fetal complications related to uncontrolled HTN.

    • On the other hand – antihypertensives might have their own consequences, as shown in other smaller studies (i.e., FGR).

• What was the research question?

  • To compare tight versus less-tight control of non-proteinuric, non-severe hypertension in pregnancy

Methods

• Who participated and when?

  • Subjects were recruited from March 2009 to August 2012 - 95 sites in 16 countries enrolled at least one patient.

  • Eligibility: 

    • Had non-severe, non-proteinuric preexisting hypertension or gestational hypertension

      • That’s right – they treated gHTN too! More on that later

      • Preexisting HTN defined as diagnosis pre-20 wks, gestational HTN defined as diagnosis after 20wks

    • A DBP of 90-105 if not receiving therapy, or 85-105 if already on treatment

      • BP were obtained at least 4 hours apart or at two consecutive outpatient visits, with the second measurement taken within 1 week prior to randomization.

      • Both BPs needed to be elevated to be included.

    • Live singleton fetus between 14w0d and 33w6d

  • Exclusion criteria

    • SBP of 160 or higher (but could be included later if they were treated and met all other eligibility criteria)

    • Proteinuria > 0.3mg/day on 24h, or a P:C >0.263, or a dipstic of 2+ or more

    • Used an ACE-I at or after 14 weeks

    • Had a contraindication to either trial group because of preexisting disease

      • Examples provided included pregestational diabetes or renal disease 

    • Multiple gestations, anomalies, or plans for TOP

    • Previous participation in the trial 

• How was the study done?

  • Randomized in blocks of 2 or 4 patients using a telephone line and pager system

  • 1:1 ratio of less-tight control (defined as target DBP 100 or lower) versus tight control (target DBP 85 or lower)

    • Control of BP was expected to the target level until delivery, with a goal of between-group difference of DBP of 5mmHg (goal based on a pilot trial of the protocol).

  • Recommendation for labetalol as drug of first choice.

    • ACE-I, ARBs, renin inhibitors, and atenolol were not permitted prior to delivery.

    • No drugs were provided by the study – this was left to physician discretion. 

  • BP at subsequent prenatal visits were obtained 3x per visit. The average of the 2nd and 3rd DBPs obtained were considered to be the DBP for the visit and used for med targeting.

    • Participants also kept a diary to record this info as well as medications and co-interventions (i.e., ultrasound, clinic visit info)

  • Adherence to protocol based on a “clinically reasonable standard” was assessed within 4 weeks of randomization.

    • This isn’t totally elaborated on, but did follow to some degree blood pressure measurements in the patient’s diary and the interventions listed.

    • Thereafter, patients were seen on a schedule dictated by their doctor/midwife. 

  • A standardized questionnaire was then given to patients at 6 weeks postpartum to identify post discharge complications.

• What outcomes were they looking for?

  • Primary outcome

    • Composite of pregnancy loss (miscarriage, ectopic, termination, stillbirth, or neonatal death) or high-level neonatal care (“greater than normal” newborn care) for more than48 hours until 28 days of life or discharge home, whichever was later.

  •  Secondary outcome

    • Maternal outcomes and complications up to six weeks postpartum, including:

      • Stroke, death, eclampsia, blindness, uncontrolled HTN, use of inotropic agents, pulmonary edema, respiratory failure, myocardial ischemia/infarction, hepatic dysfunction, hepatic hematoma or rupture, renal failure, and transfusion. 

  • Outcomes were adjudicated by a committee who were not aware of group assignments and not involved in patient’s care.

  • Additional outcomes analyzed included fetal growth and newborn complications, and incidence of severe hypertension (> 160/110) in the mother

• Some statistics interestingness:

  • This trial had some interesting analyses that we don’t frequently see in RCTs:

    • There were multiple levels of comparisons planned, and for this reason, the alpha level for significance (i.e., p value to look for) was 0.046.

    • Similarly, for secondary outcome, p<0.01 was needed, and for the additional subsequent outcomes, p<0.001 was needed.

      • We would love to have you super statistics-minded brains email us about why these adjustments are made – it has to do with the number of comparisons made and the two interim analyses that were performed to assure safety during the trial.

Results

• Who did they recruit? 

  • 1030 eligible women were recruited - 519 for less-tight, and 511 for tight control

    • Ultimately, one site needed to be excluded due to concerns about data integrity – so 497 patients were assigned to less-tight, and 490 to tight control.

    • Six patients were lost to follow up or withdrew so no data was available

    • 24 patients discontinued BP treatment prior to delivery, but their data was included as part of an intention-to-treat analysis

    • 10 patients (five in each group) had incomplete data after they were lost to follow up for the postpartum survey. 

    • 21 patients were found to have been ineligible after data analysis.

  • “Clinically reasonable adherence” to assigned treatment protocol was slightly worse in the less-tight group (76.6%) versus the tight group (82%).

  • Baseline characteristics were overall very similar:

    • Similar BMI, nulliparity, gestational age at randomization, gestational DM rate, smoking rate.

    • 25% in each group had gestational hypertension, whereas 75% had chronic HTN

      • 16% in the less-tight and 12% in the tight group had a severe-range BP at some point prior to enrollment (only statistical difference at p=0.049)

      • About 57% in each group were on antihypertensive meds at enrollment

  • Blood pressure was higher in the less-tight control group by average of 5.8 mmHg systolic, and 4.6 mmHg diastolic.

    • SBP: 138.8 vs 133.1 mmHg, p<0.001

    • DBP: 89.9 vs 85.3 mmHg, p<0.001

  • Antihypertensive meds were taken by fewer patients in the less-tight control group after randomization (73.4% vs 92.6%) and this continued after delivery (65.5% vs 78.3%). 

  • Labetalol was most commonly used agent (68.9% vs 68.8% between groups)

    • Four protocol violations for use of atenolol prior to delivery.

• Outcomes

  • Primary: neonatal composite – no difference. 

    • No significant differences with respect to other perinatal outcomes for newborns, including SGA <10% or <3%, or rates of respiratory complications.

• Secondary outcomes

• Maternal outcomes – no difference overall but rare serious events.

  • No maternal deaths.

  • In less severe events:

    • Frequency of severe hypertension was higher in the less-tight control group than tight control group (40.6% vs 27.5%, p<0.01)

    • Higher rates of abnormal labs consistent with severe preeclampsia in less-tight group (more frequent rates of thrombocytopenia, liver enzyme elevations) – however, these did not meet prespecified limit for statistical significance (0.001 for these other outcomes)

Conclusions and What We Do Now

• The authors conclude from this study that: 

  • Infant: “tight versus less tight control of maternal hypertension resulted in no significant difference in risk of adverse perinatal outcomes”

  • Maternal: “Less-tight control did not significantly increase risk of overall serious maternal complications.” 

    • While there was a more significant rate of severe hypertension and markers of severe preeclampsia, they didn’t meet the study’s threshold for significance (admittedly very challenging at p<0.001).

• CHIPS is interesting in that it has dictated how we treat hypertension and allowed for “less-tight control” as the dominant paradigm in US practice:

  • In most places, treatment of hypertension prior to more significant values consistent with severe BP is not performed.

  • Gestational hypertension is not typically treated unless severe-range pressures result

    • And nowadays, that’s classified as severe preeclampsia!

• It is interesting to think about this and the challenges with preeclampsia management – maybe we would prevent some severe preeclampsia with more aggressive treatment?

  • Those numbers are so small though, it’s hard to know.

  • But severe BP control in preeclampsia we know is very important to prevent stroke, seizures, and other complications…

• CHIPS did provide some reassuring data in that tighter and less-tight control paradigms didn’t seem to adversely affect birth weight.

• Given some of the limitations of CHIPS and some of these open questions, the CHAP trial was performed to better evaluate the strategy for treatment of specifically mild chronic hypertension in pregnancy. 

  • We’ll review this in a future podcast – but as a preview, it seems to favor more tight control! So perhaps a new strategy is already being employed at your institution or is incoming!