🎙️ Episode 44: Thiazide Throwdown: HCTZ vs Chlorthalidone in Real Life

🧠 Clinical Context

Hydrochlorothiazide (HCTZ) vs. Chlorthalidone—a classic cardio debate! ALHAT once hinted at chlorthalidone’s superiority, but did a modern head-to-head trial confirm that? Let's break it down.

🧪 Study Snapshot: The HEADS-UP Trial

• Design: Randomized, head-to-head trial
• Population: ~14,000 patients, age ≥65, already on HCTZ 25–50 mg + 1–2 antihypertensives
• Prior CV disease: 15% had MI, stroke, or HF
• Groups:
  • Continue HCTZ
  • Switch to Chlorthalidone 12.5–25 mg daily
• Follow-up: Median 2.4 years

📈 Outcomes

• Primary endpoint: Composite of MI, stroke, HF, urgent revascularization, or non-cancer death
  → Occurred in 10% of both groups
• BP Control: No significant difference
• Hypokalemia:
  • Chlorthalidone: 4.4%
  • HCTZ: 6.0%

💡 What About CKD?

• 23% had GFR <60 at baseline, but…
• No strong data on severely reduced renal function for HCTZ
• In a 12-week placebo-controlled study, chlorthalidone lowered BP in GFR 15–30, but HCTZ didn’t have similar data
• Still, in randomized trials: no difference in mortality or cardiovascular outcomes

⚠️ Surprises & Caveats

• Despite historical bias toward chlorthalidone, outcomes and BP control were equivalent
• Hypokalemia was actually slightly lower with chlorthalidone
• More robust data is still needed for advanced CKD patients

🧩 Clinical Takeaway

Despite all the hype, chlorthalidone isn’t clearly superior. In practice, both meds perform similarly for hypertension control and cardiovascular outcomes in older adults. But if your patient has significantly impaired renal function, chlorthalidone may edge ahead—at least for now.

💬 Bottom line? Choose the thiazide based on patient profile, tolerance, and renal function—not legacy dogma.

Chapters

• 0:26 Introducing the Thiazide Comparison
• 1:00 Primary Outcomes & Trial Results
• 1:50 Efficacy in Reduced Renal Function

Transcript

Speaker 1: 0:17

Let's have a discussion on hydrochlorothiazide versus chlorothalidone for hypertension treatment. Ever since the ALHATCH trial, it was suspected that chlorothalidone was superior. So this is a large head-to-head trial. This patient's greater than 65 years old and the patient's already taken hydrochlorothiazide 20, 50 milligrams at baseline. In most patients, hydrochlorothiazide plus one 50 milligrams at baseline. In most patients, hydrochlorothiazide plus one or two additional antihypertensive drugs. 50% of the patients had prior MI, stroke or heart failure. They randomized switch to continue hydrochlorothiazide or switch to chorthodone, which is 12 to 25 milligrams daily, and they followed up for almost two and a half years and the primary outcome was MI stroke, heart failure, hospitalization, urgent coronary revascularization or non-cancer-related death, which was 10% in each group, and the individual components of endpoints were virtually identical. The only thing that was interesting is that in chlorothalidone versus hydrochlorothiazide had chlorothalidone, the hyperkalemia, which is always suspected to be worse, was 4.4% versus 6.0%. In the hydrochlorothiazide, the blood pressure management were about the same, which is always thought that chlorothalidone would be superior.

Speaker 1: 1:41

In our continued discussion on hydrochlorothiazide versus chlorothalidone, both are very similar, but the trials only included people who are 65 or older and 23 of the patients had a GFR less than 60%. What about the patients with severely impaired renal function. It's thought that thorazite is going to lose effectiveness when GFR is markedly reduced. And in another recent 12-week placebo-controlled study, chorthondin lowered BP in patients with GFR between 15% and 30%, but not similar data for hydrochlorothiazide. So in the market worse GFRs. Chlorothiolodone is suspected to be superior to hydrochlorothiazide, but in the randomized controlled study. So no differences in cardiovascular outcomes or mortality. So this is a surprise. There's been data in the past and recently it's always been thought that chlorothiolodone had been superior to hydrochlorothiazide.