#Grand Rounds

Results from the LEGEND-HTN study: Is There a Preferred First-Line Medication to Treat Hypertension?

BACKGROUND AND PURPOSE:

ACC/AHA and other professional bodies recommend a list of medications that can be considered ‘first-line’ in the treatment of hypertension (see ‘Related ObG Topics’ below)
Five classes of first-line BP medications include
- Thiazide or thiazide-like diuretics | Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or calcium channel blockers
Suchard et al. (Lancet, 2019) compared these medications to assess comparative effectiveness, safety and related outcomes

Systematic, large-scale cohort study
- Observational data from millions of patients
- Ability to adjust for confounding, publication bias and manipulation of statistical significance parameters (‘P-hacking’)
Study design and data analysis
- Comprehensive framework for real-world evidence
- Compared all first-line classes across a global network of six administrative claims and three electronic health record databases
Primary outcomes
- Acute myocardial infarction
- Hospitalization for heart failure
- Stroke
Secondary outcomes
- Effectiveness outcomes
- Safety outcomes

Data from 4.9 million patients initiating monotherapy for elevated BP were included
- 22,000 calibrated, propensity score adjusted hazard ratios (HRs) were generated
The majority of these comparisons did not show any effectiveness differences between the different drug classes
However, thiazide or thiazide-like diuretics showed better primary effectiveness than ACE inhibitors for the following
- Acute myocardial infarction: HR 0.84 (95% CI, 0.75 to 0.95)
- Hospitalization for heart failure: HR 0.83 (95% CI, 0.74 to 0.95)
- Stroke: 0.83 (95% CI, 0.74 to 0.95)
Safety profiles
- Thiazide or thiazide-like diuretics demonstrated better safety profiles for significant adverse events compared to ACE inhibitors including
  - Mortality | GI side-effects | Renal disease
- Thiazide or thiazide-like diuretics were more commonly associated with risk of hypokalaemia and hyponatremia
The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes

The authors developed a new framework for doing observational health-care science at a large scale
This study is in keeping with current recommendations regarding overall similarity in effectiveness and safety between these various first-line medications
However
- Thiazide or thiazide-like diuretics was associated with reduced risk with some adverse outcomes and had a superior risk profile compared to ACE inhibitors
- Non-dihydropyridine calcium channel blockers were significantly inferior
Authors suggest that monotherapy initiation with a thiazide drug vs ACE inhibitor may be more effective with less complications

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