ALPHA BLOCKERS















Prazosin vs Others for Hypertension in Male Veterans, NEJM (1993) [PubMed abstract]
  • The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
Main inclusion criteria
  • Male veteran
  • DBP 95 - 109 mmHg off medications
Baseline characteristics
  • Average age 59 years
  • Average BP 152/99 mmHg
  • Black race - 48%
  • Current smoker - 32%
Randomized treatment groups
  • Group 1 (188 patients) - Hydrochlorothiazide 12.5 - 50 mg once daily
  • Group 2 (176 patients) - Atenolol 25 - 100 mg once daily
  • Group 3 (188 patients) - Captopril 25 - 100 mg/day given in 2 divided doses
  • Group 4 (177 patients) - Clonidine 0.2 - 0.6 mg/day given in 2 divided doses
  • Group 5 (182 patients) - Diltiazem SR 120 - 360 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Prazosin 4 - 20 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Placebo
  • There was a washout period of 4 - 8 weeks before randomization
  • Patients were titrated over a period of 4 - 8 weeks to a DBP < 90 mmHg or until they reached the maximum drug dose
Primary outcome: Attainment of blood pressure goal during titration (DBP < 90 mmHg) and DBP of < 95 mmHg at one year
Results

Average BP reduction at the end of the titration phase (SBP/DBP mmHg)
HCTZ Atenolol Captopril Clonidine Diltiazem Prazosin Placebo
14 / 10 11 / 12 9 / 10 16 / 12 13 / 14 12 / 11 3 / 5
  • Primary outcome: Diltiazem - 59%, Atenolol - 51%, Clonidine - 50%, HCTZ - 46%, Captopril - 42%, Prazosin - 42%, Placebo - 25%
  • All medications were significantly better than placebo for blood pressure reduction
  • Side effects (prazosin vs placebo): fatigue 13% vs 8%; sleepiness 12% vs 6%; dizziness 12% vs 5% (all statistically significant)

Findings: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of drug.





ALLHAT Study - Doxazosin vs Chlorthalidone for CVD, JAMA (2000) [PubMed abstract]
  • The doxazosin and chlorthalidone arms of the ALLHAT study enrolled 24,335 patients with hypertension and at least one risk factor for heart disease
Main inclusion criteria
  • Age > 55 years
  • SBP ≥ 140 and/or DBP ≥ 90 or treated hypertension
  • One of the following: previous MI or stroke, left ventricular hypertrophy, type 2 diabetes, smoker, low HDL (< 35 mg/dl)
Main exclusion criteria
  • History of hospitalized or treated symptomatic heart failure and/or EF < 35%
Baseline characteristics
  • Average age 67 years
  • Race: White - 47% | Black - 32% | Hispanic - 16%
  • Women - 47%
  • Average BP - 145/83
  • Receiving treatment for hypertension - 90%
  • Qualifying risk factor: CVD - 45% | Diabetes - 35% | Smoker - 22% | LVH - 20% | Low HDL - 12%
Randomized treatment groups
  • Group 1 (15,268 patients) - Chlorthalidone 12.5 - 25 mg a day
  • Group 2 (9067 patients) - Doxazosin 2 - 8 mg a day
  • Treatment was titrated to a BP goal of < 140/90
  • If BP goal was not met taking the maximum tolerated dosage of the initial medication, open-label Step 2 agent (atenolol, 25 -100 mg/d, reserpine, 0.05-0.2 mg/d, or clonidine, 0.1-0.3 mg twice per day), or an open-label Step 3 agent (hydralazine, 25-100 mg twice per day) could be added
  • There were 2 other treatment arms in the full study (amlodipine and lisinopril) that are not presented here
Primary outcome: Composite of fatal coronary heart disease or nonfatal myocardial infarction
Results

Duration: After a median follow-up of 3.3 years, the doxazosin arm was stopped early because of an increased risk of major CVD events
Outcome Chlorthalidone Doxazosin Comparisons
Primary outcome (4-year rate) 6.3% 6.26% RR 1.03, 95%CI [0.90 - 1.17], p=0.71
Overall mortality (4-year rate) 9.08% 9.62% RR 1.03, 95%CI [0.90 - 1.15], p=0.56
Stroke (4-year rate) 3.61% 4.23% RR 1.19, 95%CI [1.01 - 1.40], p=0.04
Congestive heart failure (4-year rate) 4.45% 8.13% RR 2.04, 95%CI [1.79 - 2.32], p<0.001
Taking additional BP meds at 3 years 37% 44% N/A

Findings: Our data indicate that compared with doxazosin, chlorthalidone yields essentially equal risk of CHD death/nonfatal MI but significantly reduces the risk of combined CVD events, particularly CHF, in high-risk hypertensive patients






MTOPS Trial - Doxazosin vs Finasteride vs Combination Therapy, NEJM (2003) [PubMed abstract]
  • The MTOPS trial enrolled 3047 men with BPH symptoms
Main inclusion criteria
  • Age ≥ 50 years
  • AUA BPH symptom score of 8 - 30 (scale is 0 [no symptoms] - 35 [severe symptoms])
  • Maximum urinary flow rate between 4 - 15 ml/second with a voided volume of at least 125 ml
Main exclusion criteria
  • Prior medical or surgical intervention for BPH
  • BP < 90/70
  • PSA > 10 ng/ml
Baseline characteristics
  • Average age 63 years
  • Average AUA score - 16.9
  • Average prostate volume - 36.3 ml
  • Maximum urine flow rate - 10.5 ml/sec
  • Average post-void residual - 68 ml
  • Average PSA - 2.4
Randomized treatment groups
  • Group 1 (737 patients) - Placebo
  • Group 2 (756 patients) - Doxazosin 4 - 8 mg per day
  • Group 3 (768 patients) - Finasteride 5 mg once daily
  • Group 4 (786 patients) - Finasteride 5 mg once daily + Doxazosin 4 - 8 mg per day (combination therapy)
Primary outcome: Composite of an increase from baseline of ≥ 4 points in the AUA symptom score, acute urinary retention, renal insufficiency, recurrent urinary tract infection, or urinary incontinence
Results

Duration: Average of 4.5 years
Outcome Placebo Doxazosin Finasteride Combo Comparisons
Primary outcome (events/100 person-year) 4.5 2.7 2.9 1.5 2 vs 1 p<0.001 | 3 vs 1 p=0.002 | 4 vs 1 p<0.001 | 4 vs 2 p<0.001 | 4 vs 3 p<0.001
Acute urinary retention (events/100 person-year) 0.6 0.4 0.2 0.1 2 vs 1 p=0.23 | 3 vs 1 p=0.009 | 4 vs 1 p<0.001
Invasive therapy due to BPH (events/100 person-year) 1.3 1.3 0.5 0.4 3 vs 1 p<0.001 | 4 vs 1 p<0.001
Serum PSA (median % change from baseline at 1 year) +15% +13% -50% -50% N/A
Dizziness (events/100 person-year) 2.29 4.41 2.33 5.35 2 vs 1 p<0.05 | 4 vs 1 p<0.05
Asthenia (events/100 person-year) 2.06 4.08 1.56 4.20 2 vs 1 p<0.05 | 4 vs 1 p<0.05
Erectile dysfunction (events/100 person-year) 3.32 3.56 4.53 5.11 3 vs 1 p<0.05 | 4 vs 1 p<0.05
Decreased libido (events/100 person-year) 1.40 1.56 2.36 2.51 3 vs 1 p<0.05 | 4 vs 1 p<0.05
Abnormal ejaculation (events/100 person-year) 0.83 1.10 1.78 3.05 3 vs 1 p<0.05 | 4 vs 1 p<0.05
  • AUA symptom scores at one year had improved significantly when compared to placebo in the doxazosin and combination groups, but not in the finasteride group
  • The combination group had significantly greater improvement in the AUA symptom score than all other groups over the course of the study

Findings: Long-term combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression of benign prostatic hyperplasia significantly more than did treatment with either drug alone. Combination therapy and finasteride alone reduced the long-term risk of acute urinary retention and the need for invasive therapy.
COMBAT Study - Tamsulosin vs Dutasteride vs Combination Therapy, European Urology (2010) [PubMed abstract]
  • The COMBAT study enrolled 4844 men with BPH
Main inclusion criteria
  • Age ≥ 50 years
  • BPH diagnosis
  • IPSS ≥ 12
  • Prostate volume ≥ 30 ml by transrectal US
  • PSA ≥ 1.5 mg/ml
  • Qmax > 5 ml/sec and ≤ 15 ml/sec w ith minimum voided volume ≥ 125 ml
Main exclusion criteria
  • PSA > 10 ng/ml
  • History of prostate cancer
  • Previous prostatic surgery
  • History of urinary retention within 3 months
  • 5ARI use within 6 months or d utasteride use within 12 months
Baseline characteristics
  • Average age 66 years
  • Average IPSS score 16
  • Average prostate volume - 54 ml
  • Average PSA - 4
  • Average Qmax - 10.7 ml/sec
  • A verage postvoid residual - 68 ml
  • Previous alpha blocker use - 50%
  • Previous 5ARI use - 11%
Randomized treatment groups
  • Group 1 (1611 patients) - Tamsulosin 0.4 mg once daily
  • Group 2 (1623 patients) - Dutasteride 0.5 mg once daily
  • Group 3 (1610 patients) - Tamsulosin 0.4 mg once daily + Dutasteride 0.5 mg once daily (combination therapy)
Primary outcome: Composite of acute urinary retention or BPH-related prostatic surgery at 4 years
Results

Duration: 4 years
Outcome Tamsulosin Dutasteride Combo Comparisons
Primary outcome 11.9% 5.2% 4.2% 3 vs 1 p<0.001 | 3 vs 2, p=0.18
BPH-related acute urinary retention 5.1% 2.3% 1.6% 3 vs 1, p<0.001 | 3 vs 2, p=0.17
BPH-related surgery 7.8% 3.5% 2.4% 3 vs 1, p<0.001 | 3 vs 2, p=0.074
Symptom worsening (IPSS increase ≥ 4 points) 14.2% 13.1% 8.6% 3 vs 1, p<0.001 | 3 vs 2, p<0.001
PSA (median % change from baseline) +18.4% -56% -57.1% N/A
Drug discontinuation 39% 33% 31% N/A
Erectile dysfunction 5% 7% 9% N/A
Retrograde ejaculation 1% < 1% 4% N/A
Decreased libido 2% 3% 4% N/A
  • Starting at 8 months, the tamsulosin group had a higher incidence of the primary outcome compared to the other groups

Findings: The 4-year COMBAT data provide support for the long-term use of dutasteride and tamsulosin combination therapy in men with moderate-to-severe UTS due to BPH and prostatic enlargement

  • Reference [37]
AUA 2021 BPH recommendations
Initial evaluation
  • Administer IPSS (online IPSS calculator)
  • Check urinalysis
  • Perform prostate exam
  • If available, consider post-void residual and uroflowmetry
    • If post-void residual is > 300 ml, refer to urologist for non-neurogenic chronic urinary retention
Initial treatment
  • All patients
    • Lifestyle modification therapy - see lifestyle modification therapy below
    • Alpha blocker therapy
      • Use one of the following: alfuzosin, doxazosin, silodosin, tamsulosin, or terazosin
      • Terazosin and doxazosin are nonspecific and may lower blood pressure. If hypotension is a concern, use tamsulosin, alfuzosin, or silodosin.
      • Alfuzosin does not reduce ejaculate volume, where silodosin and tamsulosin can. Alfuzosin may be preferred in sexually active men.
    • Men who also have erectile dysfunction
      • Consider starting with tadalafil instead of an alpha blocker

  • Reevaluate patient after 4 - 12 weeks
Follow-up
  • Unsatisfactory response to alpha blockers
    • Consider switching to tadalafil (tadalafil and alpha blocker combination therapy is not recommended)
    • If prostate is > 30 ml in size on imaging, PSA is > 1.5 ng/dl, or prostate is enlarged on digital rectal exam, consider adding 5-alpha-reductase inhibitor (e.g. finasteride, dutasteride)
    • Men with storage-predominant LUTS (marked by altered bladder sensation, increased daytime frequency, nocturia, urgency, and urgency incontinence) may benefit from the addition of an anticholinergic (e.g. oxybutynin, tolterodine) or beta-3-agonist (e.g. mirabegron)
    • Consider referring to a urologist to discuss surgical options

  • Important points about 5-alpha-reductase inhibitor (5ARI) therapy
    • 5ARIs reduce the size of the prostate by 15 - 25% at 6 months
    • 5ARIs reduce PSA production by 50%. For prostate cancer screening purposes, PSA levels drawn after one year of 5ARI therapy should be doubled.
    • 5ARIs prevent the progression of BPH symptoms and lower the risk of future urinary retention and prostate-related surgery




Tamsulosin vs Placebo for Ureteral Stone Passage, JAMA Internal Medicine (2018) [PubMed abstract]
  • The study enrolled 512 patients presenting to the ER with newly-diagnosed, symptomatic ureteral stones < 9 mm in diameter
Main inclusion criteria
  • Symptomatic ureteral stone < 9 mm in diameter confirmed on CT scan
Main exclusion criteria
  • Concurrent UTI
  • Prior ureter/kidney surgery
Baseline characteristics
  • Average age 40 years
  • Average stone size - 3.8 mm
  • Stone size ≤ 4 mm - 74% of patients
  • Stone location: Ureterovesical junction - 44% | Distal ureter - 24% | Proximal ureter 17%
Randomized treatment groups
  • Group 1 (267 patients) - Tamsulosin 0.4 mg once daily for 30 days
  • Group 2 (245 patients) - Placebo once daily for 30 days
Primary outcome: The primary outcome was passage of a ureteral stone within 28 days after randomization, as determined by the participant’s visualization or physical capture of the stone
Results

Duration: 28 days
Outcome Tamsulosin Placebo Comparisons
Primary outcome 49.6% 47.3% p=0.60
Stone passed on follow-up CT (N=238) 83.6% 77.6% p=0.24
Surgery for stone 6.5% 6.9% p=0.89
  • 7.4% of patients in the placebo group crossed over to tamsulosin
  • In subgroup analysis, there was no significant difference in passage rates for stones > 5 mm in diameter (p=0.45)
  • In subgroup analysis, there was no significant difference in passage rates for stone location, although upper ureter stones showed a trend towards significance (Tamsulosin - 41.8%, Placebo - 29.4%, p=0.17)

Findings: Tamsulosin did not significantly increase the stone passage rate compared with placebo. Our findings do not support the use of tamsulosin for symptomatic urinary stones smaller than 9 mm. Guidelines for medical expulsive therapy for urinary stones may need to be revised.
Tamsulosin vs Placebo for Distal Ureteral Stones, Annals of EM (2016) [PubMed abstract]
  • A study in the Annals of Emergency Medicine enrolled 403 patients with distal ureteral stones who presented to the ER with ureteral colic
Main inclusion criteria
  • Distal ureteral stone ≤ 10 mm on CT scan (distal ureter defined as distal to the sacroiliac joint)
Main exclusion criteria
  • GFR < 60 ml/min
  • Temp > 100.4°F
Baseline characteristics
  • Median stone size - 3.8 mm
  • Stones 5-10 mm in size - 26%
  • Vesicoureteric junction stone - 64%
Randomized treatment groups
  • Group 1 (198 patients) - Tamsulosin 0.4 mg once daily for 28 days
  • Group 2 (195 patients) - Placebo once daily for 28 days
  • A prespecified subgroup analysis comparing stone < 5 mm to stones 5-10 mm was performed. Randomization was stratified by stone size (< 5 mm and 5-10 mm)
Primary outcome: The coprimary outcomes were stone expulsion and time to stone expulsion. Stone expulsion was defined as absence of stone on repeated, noncontrast, limited pelvic CT at 28 days. Time to stone expulsion in days was defined as self-reported definitive passage of the calculus or first day of a pain-free 48-hour period, with calculus absent on repeated CT.
Results

Duration: 28 days
Outcome Tamsulosin Placebo Comparisons
Stone expulsion (overall) 87% 82% diff 5%, 95%CI [-3 to 13]
Stone expulsion for stones < 5 mm (N=239) 88% 89.5% diff -1.5%, 95%CI [-9.5 to 6.5]
Stone expulsion for stones 5 - 10 mm (N=77) 83% 61% diff 22%, 95%CI [3.1 to 41.6]
Median time to stone passage (overall) 7 days 11 days p=0.10
  • About 19% of patients in each group had no follow-up CT or had urologic intervention

Findings: We found no benefit overall of 0.4 mg of tamsulosin daily for patients with distal ureteric calculi less than or equal to 10 mm in terms of spontaneous passage, time to stone passage, pain, or analgesia requirements. In the subgroup with large stones (5 to 10 mm), tamsulosin did increase passage and should be considered.
Tamsulosin vs Nifedipine vs Placebo for Kidney Stones, Lancet (2015) [PubMed abstract]
  • A study in the Lancet enrolled 1167 patients with newly diagnosed kidney stones presenting to hospitals with ureteral colic
Main inclusion criteria
  • 18 - 65 years of age
  • One kidney stone ≤ 10 mm in diameter in either ureter identified on CT scan
Main exclusion criteria
  • Sepsis
  • GFR < 30 ml/min
  • Need for immediate intervention
Baseline characteristics
  • Average age 42 years
  • Average stone size 4.5 mm
  • Stone size: ≤ 5 mm - 75% | > 5 mm - 25%
  • Location: Upper ureter 24% | Middle ureter 11% | Lower ureter 65%
Randomized treatment groups
  • Group 1 (391 patients) - Tamsulosin 0.4 mg once daily for 28 days
  • Group 2 (387 patients) - Nifedipine 30 mg once daily for 28 days
  • Group 3 (389 patients) - Placebo once daily for 28 days
Primary outcome: Spontaneous stone passage in 4 weeks (defined as the absence of need for additional interventions to assist stone passage at 4 weeks after randomisation)
Results

Duration: 4 weeks
Outcome Tamsulosin Nifedipine Placebo Comparisons
Primary outcome 81% 80% 80% p>0.05
Average number of days to stone passage 16.5 16.2 15.9 p>0.05
  • Subgroup analyses that considered stone size and stone location found no significant effect of either intervention when compared to placebo. These analyses were underpowered.

Findings: Tamsulosin 400 μg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic




















  • NOTE: Information on metabolic pathways presented here is from the manufacurer's PI, FDA website, and a handful of published reviews. Other metabolic pathways may exist; therefore, the information is not meant to be all-inclusive.
Metabolism and clearance
Drug CYP2C19 CYP2D6 CYP3A4 P-glycoprotein
Alfuzosin - - Substrate -
Doxazosin Substrate Substrate Substrate Inhibitor
Prazosin - - - Substrate and inducer
Silodosin - - Substrate Substrate
Tamsulosin - Substrate Substrate -
Terazosin Not well-defined