User:Ewingdo/sandbox/PROVE-IT TIMI 22

Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 trial (PROVE-IT TIMI 22)
Study type	randomized controlled trial
Dates	November 2000 to December 2001
Locations	North America, Europe, and Australia
Published	2004
Article	Cannon, Christopher P.; Braunwald, Eugene; McCabe, Carolyn H.; et al. (8 April 2004). "Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes". New England Journal of Medicine. 350 (15): 1495–1504. doi:10.1056/NEJMoa040583.

The Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis In Myocardial Infarction 22 (also known as PROVE-IT TIMI 22) trial was a significant clinical study designed to compare the effects of intensive versus standard lipid-lowering therapy with statins on cardiovascular outcomes in patients who had recently experienced an acute coronary syndrome (ACS). The trial aimed to determine whether high-dose atorvastatin could provide greater cardiovascular protection compared to standard-dose pravastatin.

Background

Patients who have experienced an ACS, including myocardial infarction or unstable angina, are at high risk for recurrent cardiovascular events. Statins, which lower low-density lipoprotein (LDL) cholesterol, are a cornerstone of therapy for these patients. The optimal intensity of statin therapy to maximize cardiovascular protection had not been definitively established before the PROVE-IT TIMI 22 trial. This study sought to fill this gap by comparing high-intensity statin therapy with standard therapy.

Study design

The PROVE-IT TIMI 22 trial was a multicenter, randomized, double-blind study that enrolled 4,162 patients from 349 sites in eight countries. Patients were eligible for enrollment if they had recently been hospitalized for an ACS within the previous 10 days. Participants were randomized to receive either high-dose atorvastatin (80 mg daily) or standard-dose pravastatin (40 mg daily) and a 10-day course of the antibiotic gatifloxacin or placebo.

The primary endpoint was a composite of death from any cause, myocardial infarction, unstable angina requiring hospitalization, revascularization (performed at least 30 days after randomization), and stroke. Secondary endpoints included changes in lipid levels, individual components of the primary endpoint, and safety outcomes.

Key findings

The PROVE-IT TIMI 22 trial results, published in 2004, demonstrated several significant outcomes. Patients receiving high-dose atorvastatin had a 16% reduction in the risk of the primary composite endpoint compared to those receiving standard-dose pravastatin. The atorvastatin group achieved a significantly lower mean LDL cholesterol level (62 mg/dL) than the pravastatin group (95 mg/dL). High-dose atorvastatin also led to significant reductions in the rates of death from coronary heart disease, nonfatal myocardial infarction, and revascularization. Both treatment regimens were well-tolerated, with similar rates of serious adverse events, although there was a slightly higher incidence of elevated liver enzymes in the atorvastatin group. The results of the antibiotic portion of the trial were not initially reported.

Clinical implications

The findings of the PROVE-IT TIMI 22 trial had significant implications for the management of patients following acute coronary syndrome. The trial provided strong evidence supporting the use of intensive statin therapy to achieve lower LDL cholesterol levels and improve cardiovascular outcomes in high-risk patients. The results influenced clinical guidelines, which began recommending high-intensity statin therapy for patients with ACS to maximize cardiovascular protection.

Conclusion

The PROVE-IT TIMI 22 trial was instrumental in shaping contemporary lipid management strategies for patients with recent ACS. Its findings reinforced the principle that "lower is better" regarding LDL cholesterol levels and highlighted the benefits of intensive lipid-lowering therapy in reducing the risk of recurrent cardiovascular events.

Criticisms

• Unclear if statins provide benefits because of an effect other than lipid lowering
• Dosages of the two statins were not equivalent, so this trial should not be used to determine the relative efficacy of individual statins
• Insufficient reporting of reasons for drug withdrawal in each group
• No long-term outcomes

Further reading

• Myat, Aung; Gershlick, A. H.; Gershlick, Tony (2012). Landmark Papers in Cardiovascular Medicine. Oxford University Press. pp. 33–35. ISBN 978-0-19-959476-4.
• Topol, Eric J. (8 April 2004). "Intensive Statin Therapy — A Sea Change in Cardiovascular Prevention". New England Journal of Medicine. 350 (15): 1562–1564. doi:10.1056/NEJMe048061.
• Morrissey, Ryan P.; Diamond, George A.; Kaul, Sanjay (October 2009). "Statins in Acute Coronary Syndromes". Journal of the American College of Cardiology. 54 (15): 1425–1433. doi:10.1016/j.jacc.2009.04.093.
• Amsterdam, Ezra A.; Wenger, Nanette K.; Brindis, Ralph G.; et al. (December 2014). "2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes". Journal of the American College of Cardiology. 64 (24): e139–e228. doi:10.1016/j.jacc.2014.09.017.
• O’Gara, Patrick T.; Kushner, Frederick G.; Ascheim, Deborah D.; et al. (29 January 2013). "2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Circulation. 127 (4). doi:10.1161/CIR.0b013e3182742cf6.
• "Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes". New England Journal of Medicine. 351 (7): 714–717. 12 August 2004. doi:10.1056/NEJM200408123510719.