ALLHAT Study: Worsening of Kidney Function-A Major Contributor of HF Risk in Hypertensives

26 Feb, 21

Introduction

The diagnosis, pathophysiology, prognosis, and treatment of the cardiorenal syndrome is based on the established chronic kidney disease (CKD) and HF, yet; the role of impaired kidney function as a mechanism that predisposes to the development of incident HF in hypertensive patients is not completely understood. In fact, the role of severity of impaired kidney function as a marker of HF severity or a reflection of a mechanism contributing to HF progression in patients with hypertension has not been explored completely till date.

Aim

To quantify the extent to which the impact of antihypertensive drugs on incident HF is mediated by their impact on kidney function.

Patient Profile

Adults aged ≥55 years with hypertension and at least 1 additional cardiovascular disease (CVD) risk factor (coronary heart disease [CHD], type 2 diabetes mellitus [T2DM], left ventricular hypertrophy [LVH] on electrocardiogram [ECG] or echocardiogram, smoking, high-density lipoprotein [HDL] <35 mg/dl, and ST-T ECG changes indicative of ischemia (n=27,918; mean age 66 years; 32.4% Black, 56.3% men)
Data on estimated glomerular filtration rate (eGFR) changes during in-trial follow-up (24-48 months) was available for all the patients included in this study

Methods

Study Design

A secondary analysis of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) study
ALLHAT was a multicenter, randomized, double-blind trial

Treatment Strategy

Patients were randomised to antihypertensive medications as follows:
- Chlorthalidone: n=10,487
- Doxazosin: n=5,388
- Amlodipine: n=6,166
- Lisinopril: n=5,877
The amlodipine and doxazosin groups were merged and considered as control group during analysis

Outcomes

Primary Outcome

Incident symptomatic congestive HF

Secondary Outcome

Hospitalized/fatal HF

Median follow-up

3.2 years in doxazosin group
5 years in lisinopril, chlorthalidone and amlodipine groups

Results

During the study, 1,769 incident HF events, including 1,359 hospitalized/fatal HF events occurred.
The relative eGFR changes in the study participants were very small (on an average, eGFR reduced by <1%). The risk of both HF outcomes increased in a linear manner with relative eGFR decline, on the contrary; increase in eGFR had no significant impact on HF outcomes.
As compared with control, chlorthalidone was associated with 28% and 15% relative risk reduction (RRR) in symptomatic HF and hospitalized/fatal HF, respectively; and lisinopril was associated with 23% and 14% RRR in symptomatic HF and hospitalized/fatal HF, respectively.
As per a fully adjusted causal mediation analysis, the relative change in eGFR mediated 18% of the effect of chlorthalidone, and 33% of lisinopril on incident symptomatic HF, and 25% of the effect of chlorthalidone, and 41% of lisinopril on hospitalized/fatal HF.
A significant treatment-mediator interaction was evident between eGFR decline and the outcomes in both the study groups. Thus, an eGFR reduction of 50%, was associated with 42% and 40% RRR for symptomatic HF and hospitalized/fatal HF, respectively in the chlorthalidone vs. control group; via the direct effect. Similarly, an eGFR reduction of 50% was associated with 33% and 29% RRR for symptomatic HF and hospitalized/fatal HF in lisinopril vs. control group, via the direct effect.
Change in eGFR thus exhibited 2 opposing effects: mediating an increase in HF risk and mediating the increased strength of the direct HF-protective effect of lisinopril and chlorthalidone.
With regards to diabetes status, amongst patients with diabetes, the relative change in eGFR mediated 47% of the effect of lisinopril on incident symptomatic HF, as compared to only 17% in patients without diabetes.
Amongst patients with diabetes treated with chlorthalidone; an eGFR decline of 50% was associated with 58% RRR for hospitalized/fatal HF and 42% RRR for symptomatic HF, compared to 8% and 24% RRR, respectively, in patients without diabetes.

Conclusions

Amongst patients with hypertension and normal baseline kidney function, the cardiorenal syndrome is the main mechanism of incident HF.
On the risk difference scale, change in eGFR accounted for more than 50% of the mechanism by which antihypertensive medications affect HF.
Clinicians should target renal function and choose antihypertensive medications that prevent eGFR decline, to substantially cut down the HF risk.

J Am Coll Cardiol HF 2021; 9:100–11.