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Dunkelgrun. "Bisoprolol and fluvastatin for the reduction of perioperative cardiac mortality and myocardial infarction in intermediate-risk patients undergoing noncardiovascular surgery: a randomized controlled trial (DECREASE-IV)". Annals of Surgery. 2009. 249(6):921-926.

Clinical Question

In patients undergoing intermediate risk non-cardiac surgery, does the use of perioperative bisoprolol and statins reduce the risk of cardiovascular events?

Bottom Line

Bisoprolol was associated with a 30 day decreased rate of cardiac death and myocardial infarctions. However, in 2014 Dr. Poldermans research in the DECREASE trials have been retracted from the scientific community for falsified data.

Major Points

Bisoprolol initiated at a median 34 days before surgery, titrated to a perioperative heart rate of 50-70 beats per minute resulted in a reduction in perioperative cardiac death and nonfatal MIs. However, the DECREASE trials have been questioned and discredited due to falsified information and misconduct.

The study did not demonstrate a significant reduction in cardiovascular events with statin therapy, but lacked statistical power due to early termination of enrollment. Majority of screened patients were on beta blocker and statin therapy during screening for enrollment.

Similar to POISE, beta blockers initiated before surgery was associated with decreased cardiovascular events. However, POISE was associated with increased mortality and stroke. The difference may be in the fact that in DECREASE betablockers were initiated weeks before surgery and had time for titration. Dosage was adjusted for a heart rate near 60 beats per minute. Stroke rates were 0.4% in the DECREASE studies vs 0.5% in POISE.


The 2009 ESC Guidelines support the use of betablockers in non cardiac surgery (Class 1). Due to recent controversy with the DECREASE trials, this will likely change in the near future.


  • Prospective, open-label, multi-center, randomized, placebo-controlled trial
  • 2 by 2 factorial study design
  • N=1,066
    • Bisoprolol (n=264)
    • Fluvastatin (n=265)
    • Combination (n=269)
    • Double Placebo (n=268)
  • Setting: 190 centers in 23 countries
  • Enrollment: 2004-2008, terminated early due to slow recruitment
  • Analysis: Intention-to-treat


Inclusion Criteria

  • Age ≥40 years
  • Elective Non-cardiac surgery,

Exclusion Criteria

  • The use of betablockers
  • The use of statins prior to randomisation
  • Contraindication to use of betablocker and statin
  • Unstable coronary heart disease, evidence of three-vessel disease or left main
  • Elevated cholesterol
  • Emergency surgery
  • Inability to provide consent
  • Previous participation in the trial


Baseline characteristics

  • Demographics: Age 65.4 years, male 60%
  • PMH: D< 10.8%, Angina 5.6%, MI 5.1%, HF 0.8%, stroke 4.3%, Renal failure 1%
  • Preoperative cardiac medications:
    • Aspirin: 9.6%
    • Calcium channel blocker: 3.2%
    • ACE inhibitor 9%, ARB: 5.4%
    • Anticoagulants: 4.5%
    • Antiarrythmics: 0.8%
    • Nitrates: 1.0%
    • Digoxin: 1.4%
    • Diuretic: 9.6%
    • Oral hypoglycemic agent 7.3 %, insulin: 4.5%
    • Glucocorticoids: 8.3%
    • Anesthesia: General 93.9%, Spinal 2.7%, Local 3.4%
    • Type of Surgery: General Surgery 38.9%, Urology 19.3%, Orthopedics 16.3%, ENT 12.4%, Gynceology 5%, Plastics 5.1%, Dental 0.9%, Ophtho 0.9%, Other 0.9%
    • ASA Score: 1 - 36.8%, 2 - 53.8%, 3 - 9.5%


  • Randomized to bisoprolol, fluvastatin, bisoprolol + fluvastatin or placebo
  • Starting dose was bisoprolol 2.5mg orally per day, titrated to 10mg
    • Bisoprolol was withheld if HR<50, SBP<100mmg Hg, heart failure, bronchospasm, PR interval >0.3 seconds, 2nd or 3rd degree heart block
  • Fluvastatin XL fixed daily dose of 80mg slow release
  • Median time between starting medication and surgery was 34 (21-53) days


Comparisons are Bisoprolol therapy vs. bisoprolol control therapy.

Primary Outcomes

Cardiac events death or MI
2.1% vs. 6.0% (HR 0.34; 95% CI 0.17-0.67; P=0.002)

Secondary Outcomes

0.8% vs. 0.6% (HR 1.30; 95% CI 0.92-1.83; P=0.68)

Comparisons are Fluvastatin therapy vs. Fluvastatincontrol therapy.

Primary Outcomes

Cardiac events death or MI
3.2% vs. 4.9% (HR 0.65; 95% CI 0.35-0.20; P=0.17)

Secondary Outcomes

0.6% vs. 0.7% (P=0.71)

Adverse Events

Clinically significant liver dysfunction in the fluvastatin group
1.5% vs. 2.1% (P=0.48)
Clinically significant beta blocker related safety (heart failure, bradycardia, hypotension)
0.6% vs 0.4% (P=0.65)


Supported by unrestricted research grant from Netherlands Heart Foundation, Lijf & Leven foundation, Netherlands Organization of ZonMW. Funding from Erasmus Medical Centre (Netherlands)

Further Reading