CURRICULUM IN CARDIOLOGY - JOURNAL CLUB

Year : 2017  |  Volume : 3  |  Issue : 1  |  Page : 34-35

Hypertension: The J curve revisited. The CLARIFY study

Preetam Krishnamurthy
Department of Cardiology, AIIMS, New Delhi, India

Correspondence Address:
Preetam Krishnamurthy
Department of Cardiology, AIIMS, New Delhi
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jpcs.jpcs_15_17

Background

• Lower targets for blood pressure (BP) reduction not clear
• J-curve hypothesis: Cardiac events increase at lower BP targets^[1]
• Post hoc analysis of BP intervention trials supporting J-curve hypothesis
  • ONTARGET^[2]
  • INVEST trial^[3]
  • TNT trial.^[4]

Methods

• Prospective, observational longitudinal registry
• Inclusion criteria
  • Stable coronary artery disease (at least one)
    • Documented myocardial infarction (MI) >3 months before enrollment
    • Angiographic coronary stenosis >50% coronary stenosis
    • Chest pain with evidence of myocardial ischemia (stress electrocardiography or imaging)
    • Coronary artery bypass grafting or percutaneous coronary intervention >3 months before enrollment.
  • Hypertension (≥140/90 mmHg)
    • Treated hypertension and
    • Use of 1 ≥antihypertensive drug (at baseline).
• Exclusion criteria
  • Hospital admission for cardiovascular reasons (including revascularization) in <3 months
  • Planned revascularization
  • Advanced heart failure (HF)
  • Severe valve disease
  • History of valve repair or replacement.
• Standardized e-case report forms at baseline
• Patient visit every year (± 3 months) — 5 years
  • Symptoms/clinical examination
  • Clinical and biological tests
  • Treatment
  • Clinical outcomes.
• Observational: No recommendation about BP.

• Primary endpoint: Composite of cardiovascular death, MI, or stroke
• Secondary outcome
  • Cardiovascular death
  • MI
  • Stroke
  • All-cause death
  • Hospital admissions for HF
  • Association between BP and cardiovascular outcomes.
• Cox proportional hazards model
• Sensitivity analysis: Excluding patients with HF or left ventricular ejection fraction <45%.

Results

• 22,672 adult patients
• Mean age (at baseline): 65·2 years
• Men: 17,019 patients (75%)
• Median follow-up: 5 years (interquartile range 4.5–5.1)
• Mean BP
  • Systolic BP (SBP): 133.7 mmHg
  • Diastolic BP (DBP): 78.2 mmHg
• Change in BP during study: <2 mmHg
• Primary composite outcome: 2101 patients (9.3%)
• Cardiovascular death: 1209 (5.3%)
• All-cause death: 1890 (8.3%)
• MI (fatal or not): 827 (3.6%)
• Stroke (fatal or not): 526 (2.3%)
• Hospital admission for HF: 1306 (5·8%)
• Results were consistent
• Fully adjusted model including baseline drugs
• Sensitivity analysis excluding patients with HF
• Baseline BP
• Last BP before an event
• Interaction analysis for primary outcome: There was no difference across diabetes mellitus/stroke/HF/previous revascularization/chronic kidney disease
• Age: Significant interaction was present
• Greater than 75 years increased risk of the primary outcome for SBP of 150 mmHg or more (heart rate [HR] 1.43) and SBP of <120 mmHg (HR 1·47)
• For DBP, the increased risk of low BP was only significant for DBP of <60 mmHg in patients older than 75 years, whereas it was significant as early as 70 mmHg in the younger patients.

Discussion

• Observational study
• Low SBP (<120 mmHg) and low DBP (<70 mmHg): Increased risk of cardiovascular events
• Steep J-curve for primary and secondary outcomes
• Association persisted with multiple adjustments
• Low SBP/DBP not associated with risk for stroke
• SPIRIT^[5] versus CLARIFY
  • SPIRIT Trial had Comparable baseline groups
  • The Trial excluded patients with diabetes
• Unattended BP measurements were taken
• SBP target only
• Defined drug treatment protocol.
• McEvoy et al. analyzed data from the Atherosclerosis Risk In Communities cohort and found that compared with a DBP of 80–89 mmHg, a DBP <60 mmHg was associated with incident coronary heart disease and mortality.^[6]

Limitations

• Applicable to patients with hypertension and coronary artery disease
• Observational data: Less robust data
• Significant intergroup differences
  • Low BP groups: More MI, revascularization, HF (baseline)
  • Cardiovascular outcomes except stroke.
• Casual BP measurements: Less accurate
• Heterogeneity of treatment.

Conclusion

• At 5 years, increased SBP of 140 mmHg or more and DBP of 80 mmHg or more were associated with increased risk of cardiovascular events. SBP of <120 mmHg was also associated with increased risk for the primary outcome, as well as increased risk for all secondary outcomes except stroke. Similarly, DBP of <70 mmHg was associated with an increase in the primary outcome and in all secondary outcomes except stroke.

References

1.	Cruickshank JM, Thorp JM, Zacharias FJ. Benefits and potential harm of lowering high blood pressure. Lancet 1987;1:581-4.   [PUBMED]
2.	Redon J, Mancia G, Sleight P, Schumacher H, Gao P, Pogue J, et al. Safety and efficacy of low blood pressures among patients with diabetes: Subgroup analyses from the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial). J Am Coll Cardiol 2012;59:74-83.   [PUBMED]
3.	Mancia G, Messerli F, Bakris G, Zhou Q, Champion A, Pepine CJ. Blood pressure control and improved cardiovascular outcomes in the International Verapamil SR-Trandolapril Study. Hypertension 2007;50:299-305.   [PUBMED]
4.	Bangalore S, Messerli FH, Wun CC, Zuckerman AL, DeMicco D, Kostis JB, et al. J-curve revisited: An analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) Trial. Eur Heart J 2010;31:2897-908.   [PUBMED]
5.	SPRINT Research Group, Wright JT Jr., Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. Arandomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.
6.	McEvoy JW, Chen Y, Rawlings A, Hoogeveen RC, Ballantyne CM, Blumenthal RS, et al. Diastolic blood pressure, subclinical myocardial damage, and cardiac events: Implications for blood pressure control. J Am Coll Cardiol 2016;68:1713-22.   [PUBMED]