Avodart Cardiovascular Impact Long-Term: What the Evidence Actually Shows

Where the cardiac question comes from

Dutasteride 0.5 mg once daily is approved for symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate, alone or together with tamsulosin [1]. The cardiovascular information in its label comes from two four-year trials built around other questions: CombAT's primary endpoint was time to acute urinary retention or BPH-related surgery [2], and REDUCE tested whether dutasteride reduces biopsy-detected prostate cancer [3]. Neither trial was a cardiovascular outcomes study.

What the Avodart label says about cardiac failure

The Avodart label reports cardiac failure as a composite term and gives counts from both trials [1].

• REDUCE: 0.6% (26 of 4,105) on dutasteride versus 0.4% (15 of 4,126) on placebo [1].
• CombAT: 0.7% (12 of 1,610) on dutasteride plus tamsulosin, 0.1% (2 of 1,623) on dutasteride alone, and 0.6% (9 of 1,611) on tamsulosin alone [1].

The label then states its own reading of these numbers: the clinical significance is unknown, and no causal relationship has been established [1].

REDUCE: the trial behind the numbers

REDUCE was a four-year, multicenter, randomized, double-blind, placebo-controlled trial in men aged 50 to 75 with a PSA of 2.5 to 10 ng/mL and one negative prostate biopsy within the previous six months [3]. It randomized 8,231 men: 4,105 to dutasteride 0.5 mg daily and 4,126 to placebo, mean age 63, and 91% white [1].

Among 6,729 men who had a biopsy or prostate surgery, cancer was detected in 659 of 3,305 on dutasteride and 858 of 3,424 on placebo, a relative risk reduction of 22.8% (95% CI 15.2 to 29.8) [3]. Gleason 7 to 10 tumors were 220 versus 233 overall (P=0.81), but in years 3 and 4 there were 12 Gleason 8 to 10 tumors on dutasteride versus 1 on placebo (P=0.003) [3]. The label reports Gleason 8 to 10 cancer at 1.0% versus 0.5% and warns that 5-alpha reductase inhibitors may increase the risk of high-grade prostate cancer; dutasteride is not approved to prevent prostate cancer [1].

CombAT: combination therapy and the heart

CombAT randomized 4,844 men aged 50 or older with BPH symptoms to dutasteride 0.5 mg, tamsulosin 0.4 mg, or both, daily for four years, with no placebo arm [2]. Combination therapy was significantly better than tamsulosin alone but not better than dutasteride alone at reducing the risk of acute urinary retention or BPH-related surgery; it was better than either monotherapy for symptoms and clinical progression [2].

The 0.7% cardiac-failure figure belongs to the combination arm, the 0.1% figure to dutasteride alone, and the 0.6% figure to tamsulosin alone [1]. With arms of roughly 1,600 men each, these are counts of 12, 2 and 9 events. The label lists them without a causal conclusion [1].

Dizziness with the combination

The combination product adds tamsulosin, an alpha-adrenergic antagonist [1]. In the first six months of CombAT, dizziness was reported in 1.1% of men receiving combination therapy, 0.5% receiving dutasteride alone, and 0.9% receiving tamsulosin alone [1]. Trial withdrawal for adverse reactions occurred in 6% of men on combination therapy versus 4% on either monotherapy, with erectile dysfunction the most common reason at 1% to 1.5% [1].

Heart drugs that change dutasteride exposure

Dutasteride is metabolized extensively by CYP3A4 and CYP3A5 [1]. Heart drugs and CYP3A4 inhibitors can affect dutasteride exposure:

• Verapamil and diltiazem (heart and blood-pressure drugs) decrease dutasteride clearance and increase exposure. The label does not consider the change clinically significant and recommends no dose adjustment [1].

Ritonavir, an HIV drug and a potent, chronic CYP3A4 inhibitor, has not been studied with dutasteride, so its effect on dutasteride levels is unknown; the label advises caution when potent, chronic CYP3A4 inhibitors are prescribed together with dutasteride [1].

On the anticoagulant and heart-failure side, dutasteride 0.5 mg daily for three weeks did not alter the steady-state pharmacokinetics of digoxin, or of the S- or R-warfarin isomers, and did not change warfarin's effect on prothrombin time [1]. Dutasteride also has no effect on the steady-state pharmacokinetics of tamsulosin or terazosin [1].

Length of follow-up

In the BPH program, including open-label extensions, 812 men were exposed to dutasteride for four years [1]. The REDUCE and CombAT trials each ran four years [2][3].

Off-label hair-loss use

Dutasteride is not FDA-approved for androgenetic alopecia; only symptomatic BPH is approved [1]. A 24-week hair-loss trial randomized 917 men aged 20 to 50 to dutasteride 0.02, 0.1 or 0.5 mg, finasteride 1 mg or placebo [4], and reported that the number and severity of adverse events were similar across groups [4]. Twenty-four weeks is the entire follow-up [4].

How long dutasteride stays in the body

The terminal half-life at steady state is about 5 weeks, and serum levels remain above 0.1 ng/mL for up to 4 to 6 months after the last dose [1]. Median serum DHT falls 85% after one week, 90% after two weeks, and 93% to 95% at one through four years on 0.5 mg daily [1].