Intensive lipid lowering confers greater benefit in preventing mortality and cardiovascular events than a standard regimen of lipid-lowering therapy in patients who have recently survived an acute coronary syndrome (ACS) event, according to the results of a recent study that compared a high-dose vs a standard-dose statin regimen. As reported at the American College of Cardiology Annual Scientific Session 2004 and published in The New England Journal of Medicine, patients on a high-dose statin regimen in the Pravastatin or Atorvastatin Evaluation and Infection Therapy -- Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial achieved an approximately 50% reduction in low-density lipoprotein cholesterol (LDL-C), reducing LDL-C down to approximately 62 mg/dL (1.60 mmol/L), which is substantially below current target levels (approximately 100 mg/dL or 2.58 mmol/L). This finding suggests that individuals with ACS derive a clinically significant benefit from intensive lipid-lowering therapy.
PROVE IT-TIMI 22 compared treatment with pravastatin 40 mg/day (standard therapy) or atorvastatin 80 mg (intensive therapy) in patients who had been hospitalized for either myocardial infarction (MI), with or without evidence of ST-segment elevation, or high-risk unstable angina within 10 days prior to enrollment. Their total cholesterol was ≤ 240 mg/dL (6.21 mmol/L) or ≤ 200 mg/dL (5.18 mmol/L) if they were already on lipid-lowering therapy at the time of their ACS event. They were in stabilized condition and post-percutaneous coronary intervention (PCI) if one had been planned.
Patients excluded from the trial included those with expected survival < 2 years or with liver disease, patients on simvastatin or atorvastatin 80 mg or those receiving strong inhibitors of cytochrome P-450 3A4, and patients needing treatment with nitrates, niacin, or coronary artery bypass graft (CABG) surgery.
A total of 4162 patients were enrolled in the PROVE IT-TIMI 22 trial at 349 sites in 8 countries in Australia, Europe, and North America between November 2000 and December 2001. All patients received standard medical and interventional care, including aspirin 75-325 mg/day plus clopidogrel or warfarin (Table 1). They were not permitted to take any other cholesterol-lowering drug.
Table 1. PROVE-IT-TIMI 22: Concomitant Therapies
| Therapy | Patients (%) |
|---|---|
| PCI for initial ACS (pre-randomization) | 69 |
| Aspirin | 93 |
| Warfarin | 8 |
| Clopidogrel – initial | 72 |
| Clopidogrel -- at follow-up | 20 |
| Beta-blockers | 85 |
| ACE inhibitors | 69 |
| ARB | 14 |
Patients were randomized in a double-blind, double-dummy fashion to receive either standard (pravastatin 40 mg; n = 2063) or intensive (atorvastatin 80 mg; n = 2099) statin therapy and a concomitant 10-day course of the antibiotic gatifloxacin or placebo, in a 2 by 2 factorial design. The gatifloxacin results have not yet been reported. Follow-up duration was 2.5 years. Baseline clinical characteristics were well balanced between the 2 groups, including mean age, male population, history of hypertension, and the proportion of patients with ST-segment elevation MI, non ST-segment elevation MI, and unstable angina (Table 2).
Table 2. PROVE-IT-TIMI 22: Baseline Clinical Characteristics
| Standard (n = 2063) | Intensive (n = 2099) | |
|---|---|---|
| Mean age (yrs) | 58 | 58 |
| Male (%) | 78 | 78 |
| Hypertension (%) | 49 | 51 |
| Current smoker (%) | 37 | 36 |
| Diabetes (%) | 18 | 19 |
| CHD (%) | 39 | 37 |
| STEMI (%) | 33 | 36 |
| NSTEMI (%) | 37 | 36 |
| Unstable angina (%) | 30 | 29 |
In the intensive lipid-lowering group, LDL-cholesterol was reduced by 49%, achieving a median level of 62 mg/dL (1.6 mmol/L) during follow-up, compared with a 21% reduction in the standard therapy group for a median of 95 mg/dL (2.46 mmol/L). Both these levels are consistent with current guidelines.
Reductions in Cardiovascular Endpoints
Kaplan-Meier event rates of the primary composite endpoint of all-cause mortality, MI, documented unstable angina requiring hospitalization (> 30 days after revascularization), or stroke at 2 years was 26.3% in the standard therapy group vs 22.4% in the intensive therapy group, for a risk reduction of 16% in favor of atorvastatin (P = .005). This benefit was seen as early as 30 days and continued throughout the follow-up period (Table 3).
Table 3. PROVE-IT-TIMI 22: Primary Endpoint Over Time
| Censoring Time | Risk Reduction (%) | Event Rates (%) per Regimen | |
|---|---|---|---|
| Intensive | Standard | ||
| 30 days | 17 | 1.9 | 2.2 |
| 90 days | 18 | 6.3 | 7.7 |
| 180 days | 14 | 12.2 | 14.1 |
| End of follow-up | 16 | 22.4 | 26.3 |
For the combined incidence rates of all-cause mortality, nonfatal MI, or urgent revascularization, the intensive therapy group showed a significant reduction compared with the standard therapy group (16.7% vs 12.9%, respectively), representing a risk reduction of 25% (P = .0004).
Significant reductions were also seen with intensive therapy in the endpoint components of need for revascularization (P = .04) and unstable angina (P = .02), with nonsignificant reductions in death from cardiovascular heart disease, MI, and death or MI, but stroke rates did not differ between the 2 treatment groups (Table 4).
Table 4. PROVE-IT-TIMI 22: Reductions in Major Cardiovascular Endpoints
| Endpoint | Risk Reduction (%) | 2-Year Event Rates (%) per Regimen | |
|---|---|---|---|
| Intensive | Standard | ||
| All-cause mortality | 28 | 2.2 | 3.2 |
| Death from CHD | 30 | 1.1 | 1.4 |
| MI | 13 | 6.6 | 7.4 |
| Death or MI | 18 | 8.3 | 10.0 |
| Revascularization ≥ 30 days after randomization | 14 | 16.3 | 18.8 |
| Unstable angina requiring hospitalization | 29 | 3.8 | 5.1 |
| Stroke | -9 | 1.0 | 1.0 |
The benefits of intensive lipid lowering were seen among all prespecified subgroups, including men and women, those with/without diabetes, age > 65 or < 65 years, prior statin/no statin treatment, and high-density lipoprotein (HDL) cholesterol > 40 or < 40 mg/dL (> 1.03 or < 1.03 mmol/L). The only subgroup that showed greater benefit was the one comprising patients with LDL-C ≥ 125 mg/dL (≥ 3.23 mmol/L) at baseline, who showed a 34% risk reduction for all-cause mortality or major cardiovascular events compared with the standard therapy group.
Adverse Events
A significantly higher number of patients on intensive therapy had alanine aminotransferase levels 3X the upper limit of normal (3.3% vs 1.1%, P < .001). More patients discontinued intensive therapy than standard therapy due to myalgia or elevated creatine kinase levels (3.3% vs 2.7%, P = .23). None of the myalgia cases were severe.
Implications
These findings indicate that patients recently hospitalized for an ACS event benefit from early and continued use of intensive therapy to lower LDL-C to levels substantially below current target levels, the PROVE IT-TIMI 22 investigators believe. According to Dr Cannon, "Starting today, every patient going home with a heart attack should be given a high-dose statin regimen."
Surprising Results
In an editorial accompanying publication of PROVE IT-TIMI 22, Eric J Topol, MD (Cleveland Clinic Foundation, Cleveland, Ohio), notes that that the trial has confirmed the idea that aggressive lipid lowering is more beneficial, as first suggested by the results of the Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, which -- although it was not designed to detect differences in clinical outcomes -- used the same statin regimens. However, Dr Topol describes the results of PROVE IT-TIMI 22 as "a major surprise," for the following 3 reasons:
The trial was supposed to be a noninferiority trial of pravastatin vs atorvastatin.
The beneficial effect of intensive lipid-lowering therapy appeared "extremely rapidly."
It had been assumed that due to the short duration of follow-up and relatively small number of patients in the trial, it would not be possible to discern any differences between the effects of the 2 treatment regimens.
Taken together, the results of REVERSAL and PROVE IT-TIMI 22 herald the beginning of a "new era of intensive statin therapy," Dr Topol believes. Nevertheless, he points to the global underuse of statins, mainly due to their high costs, which can only "skyrocket" if treatment based on these new data becomes widespread,
American Heart Association (AHA) Reaction
The AHA has issued a statement about the results of PROVE IT-TIMI 22. Robert H Eckel, MD (University of Colorado, Denver), speaking on behalf of the AHA, said,
This is the first head-to head trial comparing clinical events with two statins of proven effectiveness in cardiovascular disease prevention. The group with the greater reduction in LDL (bad) cholesterol had the greater benefit. There is no information to let us know whether the LDL would have been lower and the benefit greater in the pravastatin group if the dose had been higher, but this study represents another step in a continuing line of research that has demonstrated that lowering LDL cholesterol below the currently recommended goal of < 100 mg/dL will be an important way to further reduce these patients' risk of cardiac death.
References
Cannon CP. Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22). Program and abstracts from the American College of Cardiology 53rd Annual Scientific Sessions; March 7-10, 2004; New Orleans, Louisiana. Late Breaking Clinical Trials I.
Cannon CJ, Braunwald E, McCabe CH, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 Investigators. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004. Published online before print (April 8 issue).Abstract available at:
http://content.nejm.org/cgi/content/abstract/NEJMoa040583v1.
Cannon CP, McCabe CH, Belder R, et al. Design of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 trial. Am J Cardiol. 2002;89:860-861.
Topol EJ. Intensive statin therapy – A sea change in cardiovascular prevention. N Engl J Med. 2004. Published online before print (April 8 issue). Abstract available at:
http://content.nejm.org/cgi/content/abstract/NEJMe048061v2.
Nissen SE, Tuzeu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080.
American Heart Association comment on TheNew England Journal of Medicine report titled, "Comparison of Intensive and Moderate Lipid Lowering with Statins after Acute Coronary Syndromes." Available at:
http://www.americanheart.org