The Role of Early Initiation of Statin Therapy in Acute Coronary Syndromes:

 A Systematic Review of the Literature

 

Maria A. Gelyon

 

University of Medicine and Dentistry of New Jersey

School of Health Related Professionals

 

In partial fulfillment of the requirements for IDST 6400:

Critical Literature Review and Scientific Writing

Fall 2004

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Death from coronary artery disease (CAD) remains a leading cause of mortality worldwide. According to the most recent statistics from the American Heart Association, CAD is the single largest cause of death in males and females in the United States.  Every 29 s an American will suffer a coronary event, and about every minute someone will die from one (Dam, Wissen, & Kastelein, 2002). 

Strong evidence supports the use of statin lipid-lowering agents in patients with documented CAD and in patients at risk of clinical CAD who have hyperlipidemia unresponsive to diet and exercise (Wright, Murphy, Bybee, Kopecky, & LaBlanche, 2002). In a series of pivotal clinical trials, statins have been shown to reduce both atherogenic lipoproteins and cardiovascular morbidity and mortality (Nissen et al., 2004).  The evidence that statins have potent effects in reducing death and re-infarction in a patient who has suffered a coronary event is now overwhelming. These effects have been shown in patients with elevated plasma cholesterol in the Scandinavian Simvastatin Survival Study (4S), in patients with cholesterol in the average range in the Cholesterol and Recurrent Events (CARE), and in Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies (McKeown & Thompson, 2002).  These 3 large-scale secondary prevention studies have an important limitation: they have not examined treatment in the period immediately following the coronary event.  Treatment did not start until at least 3 months in CARE and LIPID and 6 months in 4S after the index event.  However, it is important to note that patients are at the greatest risk of recurrent ischemic events in the early months following an acute coronary syndrome (ACS).  Based on this fact, strategies to stabilize vulnerable coronary plaques are valuable during this high-risk period.  

 Until recently, lipid-lowering therapy was viewed exclusively as a long-term strategy to reduce cardiovascular risk.  This viewpoint was based on evidence that lipid-lowering therapy promotes gradual removal of lipid from the core of atherosclerotic plaques accompanied by gradual and modest regression of arterial stenoses. It was also based on evidence from the landmark trials that event rates in statin and placebo arms do not diverge during the initial 1-2 years of treatment (Olsson & Schwartz, 2002). 

Challenging this conventional viewpoint, a growing body of experimental evidence suggests that statins act rapidly to reverse some of the abnormalities of the arterial wall that may predispose to recurrent ischemic events after ACS, including endothelial dysfunction, a local inflammatory response, and an exaggerated thrombogenic tendency (Olsson & Schwartz, 2002).  Each of these mechanisms might be expected to have a favorable impact in the early period following an ACS.  The purpose of this review is to examine the evidence from randomized, multi-center trials and to see if it can support the author’s hypothesis that early use of lipid-lowering agents after ACS will reduce the risk of subsequent ischemic cardiovascular events.

Methods

An electronic literature search was conducted using an OVID search engine for Medline database from 1996 to September 2004 to identify original research and for Cochrane to identify all evidence-based medicine reviews. In order to focus on the most current findings in the literature, it was necessary to limit my Medline search to the 1996 to September 2004 time frame.  Another consideration was that other reviews were published in 2002, and I wanted to focus on the most recent clinical findings. The search terms statins, atorvastatin, simvastatin, pravastatin, lovastatin, and rosuvastatin were used and mapped to MeSH headings individually and then combined.  Boolean operators were used to combine the terms early initiation, intensive treatment, and aggressive treatment and their MeSH headings.  Additionally, the results of the combined statin search were matched with combined treatment time frames.  A search was initiated for reduction and mapped to MeSH headings. Next, Boolean operators were used to combine myocardial infarction, stroke, angina, cardiovascular events, and cardiovascular death and their MESH headings. Then, those results were combined with the reduction search. From there, the results of the initial match of combined statins and combined time factors were matched with the combined risk factors and reduction results.  The results of this search were first limited to humans and to the English language then further limited to controlled clinical trials, practice guidelines, or randomized controlled trial or review (Appendix B). 

The search provided 32 possible references.  Each reference was reviewed to determine inclusion criteria, exclusion criteria, and study design. Criteria for inclusion were acute coronary syndrome and high-risk patients.  Criteria for exclusion were falling outside of the limitations of English language, human study, and inclusion criteria.  Systematic reviews of randomized controlled trials (RCTs), individual RCTs, observational studies, cohort studies, and practice guidelines were reviewed for consideration.  Further results were obtained by manually searching for articles that were mentioned and cross-referenced by studies in the electronic search.  All research articles reviewed and included were available through full-text, on-line, medical library journals.  Of the 32 articles retrieved, I identified 21articles that were relevant to my question by excluding articles that either did not meet my study type criteria or that did not specifically address my question.  Of the 21 relevant articles, 13 articles were included in this review and the others were used as background information.       

 

 

Review of the Literature

The articles that are included in this review are classified into two categories: moderate therapy and intensive therapy. The approach is a little unconventional because the review not only includes placebo-controlled trials but also head-to-head comparisons, which compare one statin against another statin. There is significant, new data in this field of study, and it happens to be in head-to-head comparisons.  Each category will include several studies, which will be discussed chronologically.   

Moderate Therapy

            The Scandinavian Simvastatin Survival Study (4S) was a double blind, randomized, clinical trial of long-term treatment with simvastatin, which was dosed 20 mg per day with titration to 40 mg at 12 or 24 weeks or matching placebo in patients with myocardial infarction (MI) or angina pectoris (Wilhelmsen et al., 2001). The study consisted of 3525 patients, who had a previous MI. The study included both men and women 35 to 70 years old (mean 58.7 years) with all patients being accounted for at the end of the study. Primary end-point was death from any cause.  Secondary end-points were coronary events, coronary death, nonfatal infarction, definite silent myocardial infarction, and resuscitate cardiac arrest.  The relative risk in the simvastatin treatment in low, medium, and high predicted risk was 38%, 39%, and 42%, with a 95% confidence interval.  The corresponding absolute benefit per 100 patients treated for 6 years increased from 7.9 to 16.2. 4S included more men than women, which make it difficult to apply these results to women.  The relative benefit from simvastatin treatment was independent of predicted risk, but the absolute benefit increased from low to high risk. This study supports initiation of statin therapy in patients with a history of MI or angina.  Even patients at low-risk for MI can benefit from statin therapy; however, those at greatest risk have the most to benefit. 

            Cardiovascular complications are the most important cause of perioperative morbidity and mortality among patients undergoing vascular surgery. Statin therapy may reduce perioperative cardiac events through stabilization of coronary plaques.  The effect of atorvastatin was compared to placebo on the occurrence of a 6-month composite of cardiovascular events after vascular surgery in a prospective, randomized, placebo-controlled, double-blind clinical trial. One hundred patients aged 36 to 86 years were randomly assigned to receive atorvastatin 20 mg or placebo once a day for 45 days, regardless of their serum cholesterol concentrations (Durazzo et al., 2004).   Surgery was performed within 31 days of randomization.  Primary endpoints were cardiovascular death, nonfatal myocardial infarction (MI), unstable angina, and stroke.  The study had a statistical power of 0.80.  An intent-to-treat analysis was adopted. The risk for an event was 3 times higher in placebo group (26%) vs. atorvastatin group (8%; P=0.031).  Atorvastatin group had a significant decrease in the rate of cardiovascular events within 6 months of surgery (P=0.018).  This study supports the early initiation of statin therapy and suggests that the non-lipid properties, such as improved endothelial function, inflammatory responses, and plaque stability, can be observed earlier than lipid effects in patients using statin agents.  In the authors’ opinion, these results need to be confirmed with a large, multicenter, randomized clinical trial.

            Additionally, statins are believed to reduce recurrent ischemic events when they are administered early in patients with ACS.  In a cohort study, 19537 patients with a mean age of 67 and with an ACS were enrolled from 94 hospitals in 14 countries (Spencer et al., 2004).  Statin use before and after presentation with an ACS and associated rates of MI, hospital complications, and hospital mortality were measured. End points include death, in-hospital MI, and stroke.  Patients already on statins were less likely to have ST-segment elevation (OR, 0.79 [95% CI, 0.71 to 0.88]) or MI (OR, 0.78 [95% CI, 0.70 to 0.86]).  Patients who continued to take statins in the hospital were less likely to experience complications or die than patients who never received statins (OR, 0.66 [95%CI, 0.56 to 0.77]).  Patients not previously taking statins in the hospital were less likely to die than patients who never received statin therapy (OR, 0.38 [95%CI, 0.30 to 0.48]).  The limitations of this study include the following:  the inability to exclude confounding by clinical and hospital factors, the need to be validated with a randomized trial, the inability to compare differences between statins, dosages, or previous duration of therapy on observed outcomes, and the inability to document the reason for discontinuation of statin therapy during hospitalization. On the other hand, this study’s strengths are its large sample size, the extent of the data collected, and the ability to contrast the use and effect of statin therapy in a broad spectrum of patients.  This study confirms the findings of the Scandinavian Simvastatin Survival Study (4S) study, which demonstrated that statins have numerous pleiotropic actions. Overall, the results suggest that patients who present with an ACS having taken their statin have less severe presentation, fewer in-hospital complications, and lower hospital death rates.

Intensive Therapy

            The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is one of the largest, most important studies conducted in this area.  It determined whether early, rapid, profound cholesterol-lowering therapy with atorvastatin 80 mg per day could reduce recurrent cardiovascular events.  MIRACL is a randomized, double-blind trial, which included 3086 patients with a mean age of 65 and with unstable angina or non-Q-wave MI from four continents (Schwartz et al., 2001).  Treatment was initiated 24 to 96 h after hospitalization. The patients had a mean LDL-C level of only 121 mg/dL and received either atorvastatin 80 mg per day or placebo for 16 weeks.  Patient compliance was high with rates of 88% in the atorvastatin group and 86% in the placebo group. There was a small limitation that 23 atorvastatin patients and 26 placebo patients had to be treated with an open-label lipid-lowering medication.  A primary end point occurred in 14.8% of patients in the atorvastatin group and 17.4% of patients in the placebo group (RR, 0.84; 95% CI; P=0.048), which were defined as time to first occurrence of nonfatal MI, cardiac arrest with resuscitation, worsening angina, or death. Overall, there was a 2.6% absolute risk and a 16% relative reduction in the primary combined end point. There were no significant differences in the incidence of secondary end-points of coronary revascularization procedures, worsening heart failure, or angina.  However, there were fewer strokes in the atorvastatin group compared to placebo (12 vs. 24 strokes, P=0.045). MIRACL is the first study where lipid-lowering was initiated during hospitalization to show an early reduction in incidence of recurrent ischemic events.  It demonstrated that intensive lipid-lowering with atorvastatin reduces recurrent ischemic events in the first 16 weeks after an acute coronary syndrome.

            MIRACL corroborates data from another study, which evaluated the role of statin therapy initiated early after an acute coronary event.  Arntz (2002) conducted a single-center, open-label study in which patients were blindly assigned to intensive antilipidaemic therapy with pravastatin or usual care. This study found that early initiation of statin treatment in patients with acute myocardial infarction is associated with reduced 1-year mortality (Dam, Wissen, & Kastelein, 2002). 

The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial was an international, multi-center, randomized, double-blind trial to compare the standard degree of LDL cholesterol lowering to approximately 100 mg/dL with more intensive lipid lowering to approximately 70 mg/dL as a mean for preventing death and major cardiovascular events in patients with acute coronary syndrome (Cannon et al, 2004). The trial included 4,162 patients with a total cholesterol level of 240 mg/dL or less and with a mean age of 58 years.  Patients had to be hospitalized for acute MI or high-risk unstable angina within the preceding 10 days and had to be in stable condition.  Subjects were randomly assigned to receive pravastatin 40 mg or titrated to 80 mg (n=2063) or atorvastatin 80 mg (n=2099), in addition to aspirin plus standard medical therapy (Cannon et al., 2004).  The two groups were well matched with regard to baseline characteristics, with the exception of a history of peripheral arterial disease, which was more common in the pravastatin group than the atorvastatin group (P=0.03).  Patients were followed for 18 to 36 months, with an average follow-up of 24 months.  All efficacy analyses were based on the intention-to-treat principle, and only eight patients (0.2 percent) were lost to follow-up.  The validity of this trial was increased by the randomization and blinding. The primary efficacy outcome measure was the time from randomization until the first occurrence of a component of the primary end-point: death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization occurring within 30 days after randomization, and stroke.  There was a consistent pattern of benefit favoring atorvastatin.  The results reported that the Kaplan-Meier event rates at two years were 26.3 percent in the standard-dose pravastatin group and 22.4 percent in the high-dose atorvastatin group, representing a 16 percent reduction in the hazard ratio favoring atorvastatin (P=0.005; 95% CI, 5%-26%). The secondary end point of death was reduced by 14 percent in the atorvastatin group (P=0.029), with a two-year event rate of 19.7 percent, as compared with 22.3 percent in the pravastatin group.  The risk of death was reduced by 25 percent in the atorvastatin group (P<0.001). Although the trial was unable to meet the pre-specified criterion for equivalence, it did demonstrate the superiority of the more intensive regimen, which provides greater protection against death or major cardiovascular events than a standard regimen, as stated by the investigators.  In as early as 30 days, atorvastatin provided significant differences in risk reduction, and these reductions were consistent over time. Similar results were seen with atorvastatin in the MIRACL trial and in prior observational studies.  In addition, a physician would only need to treat to 26 patients to prevent an event.

            Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) is a double-blind, randomized active control multicenter trial performed at 34 community and tertiary care centers in the United States comparing the effects of 2 different statins administered for 18 months (Nissen et al., 2004). Similar to the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT), REVERSAL randomized patients to receive a moderate lipid-lowering regimen consisting of pravastatin 40 mg per day or an intensive lipid-lowering regimen consisting of atorvastatin 80 mg per day; however, REVERSAL differed in primary efficacy parameters.  Intravascular ultrasound (IVUS) was used to measure progression of atherosclerosis, which was calculated as a percentage change in atheroma volume. The study included 654 patients, aged 30 to 75 years, who required coronary angiography for a clinical indication and demonstrated at least one obstruction with angiographic luminal diameter narrowing of 20% or more. Both groups were similar before randomization. There were 155 patients lost to follow up with 78 patients in the pravastatin group and 74 patients in the atorvastatin group.  In light of this, 2 sensitivity analyses were performed and found that the primary efficacy analysis and both major secondary efficacy analyses retained statistically significant. Baseline LDL was reduced to 110mg/dL in the pravastatin group with 65% of patients reaching their LDL-C goal and to 79 mg/dL in atorvastatin group (P<0.001) with 97% of patients reaching their LDL-C goal.  The primary end point showed a significantly lower progression rate in the atorvastatin group (p=0.02).  Progression of coronary atherosclerosis occurred in the pravastatin group (2.7%; 95% CI, 0.2% to 4.7%; P=0.001) compared with baseline.  Progression did not occur in the atorvastatin group (-0.4%; 95% CI, -2.4% to 1.5%; P=. 98) compared with baseline.  Reversal confirms the results of  MIRACL and PROVE IT by demonstrating that intensive lipid-lowering treatment with atorvastatin reduced progression of coronary atherosclerosis compared with pravastatin in patients with coronary heart disease.

            Phase Z of the A to Z trial is to date the largest trial testing the effects of aggressive statin therapy in ACS.  The investigators randomized 4497 patients, with a mean age of 61 years, following an ACS event to receive either high-dose simvastatin at 40 mg per day for 1 month and then 80 mg per day thereafter (n=2265) or to a regimen of placebo for 4 months and then a 20 mg per day dose of simvastatin thereafter (De Lemos et al., 2004).  The high-dose regimen failed to show a statistically significant benefit for reducing the primary composite end point of cardiovascular death, myocardial infarction, readmission for ACS, or stroke (ARR, 2.3%; HR, 0.89; 95% CI, 0.76 to 1.04; P=. 14).  In addition the high-dose simvastatin regimen was associated with a usually high rate of myopathy.  Ten patients experienced elevated creatine kinase levels greater than 10 times the upper limit of normal with accompanying muscle symptoms and 3 patients developed rhambdomyolysis. Because 32 clinical events were avoided, approximately 1 adverse myopathic event occurred for every 3 patients. The trial did not meet the prespecified end point; however, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.  In fact these results are contrary what we would expect to see based on the results of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) and the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) (See Discussion). 

Discussion

            A review of the literature identified varying degrees of results regarding moderate statin therapy and intensive statin therapy in patients with acute coronary syndrome.  These differences can be described by the variance in methodology, subject selection criteria, outcomes measures, duration of follow-up, and scientific advances.  The majority of studies were in agreement that early intensive statin therapy will improve patient outcomes with the exception of early results in the A to Z Trial, which will discussed in this section.  In fact, regardless of moderate therapy or intensive therapy, all patients with ACS saw benefits with their statin therapy.  In the moderate therapy group, the patients that needed it the most had the greatest benefit.

            The studies included in Appendix C varied in designs and include randomized clinical trials, a cohort trial, and an observational trial.  The duration of follow-up in these studies varied from a minimum of 14 weeks to a maximum of 3 years.  The age and the sample size varied from 30 to 86 years, and 100 to 19537 patients, respectively.  The trials were also well balanced in comparative groups, with the exception of a lack of women in the trials.

Regarding the discrepancy in the A to Z trial, the lack of efficacy and the unfavorable adverse event profile is somewhat surprising, after seeing the data from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) and the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT).  MIRACL compared 80 mg per day of atorvastatin with placebo for 4 months in 3086 patients and demonstrated a 16% reduction in events.  PROVE IT compared outcomes of 4162 patients taking 80 mg per day of atorvastatin compared to 40 mg of pravastatin per day and also demonstrated a 16% reduction in events.  In MIRACL, the study lasted only 4 months, and in PROVE IT the event curves separated in the first 30 days, reaching statistical significance by 6 months.  In contrast, the A to Z trial showed no effect during the first 4 months, but there appeared to be a benefit later in the aggressive treatment group.

When the results of MIRACL, PROVE IT, and A to Z are combined, it is easy to see that the beneficial effects of statin therapy in ACS cannot be predicted merely from LDL cholesterol reduction.  As mentioned in almost every review, there is a belief that statins have a pleiotropic effect, which includes their anti-inflammatory properties.  The most widely examined inflammatory biomarker, high sensitivity C-reactive protein, is commonly measured in statin trials.  In the 2 successful ACS trials, MIRACL and PROVE IT, the difference in C-reactive protein between treatment subgroups was 34% and 38%, respectively, at trial completion.  In the A to Z trial, the between group reduction was much smaller at 16.7%.  These findings suggest that the early benefits of statin therapy are derived largely from the anti-inflammatory effects of the drug, and the delayed benefits are lipid-modulated (Nissen et al., 2004).  

Implications

Patients with acute coronary syndrome are at very high risk for suffering recurrent coronary events in the near future.  The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial suggested that intensive LDL-lowering therapy would reduce risk for recurrent cardiovascular events in the first 18 months after acute coronary syndromes. The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial greatly strengthens the evidence for benefit of intensive LDL-lowering in the first 2 years after acute coronary syndrome, which is why intensive therapy should be considered for all patients admitted to the hospital for acute coronary syndromes. PROVE IT and Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) make a strong case for achieving the optimal LDL-C goal of < 70 mg/dL in high-risk patients.  Choice of drug and dosage should be guided in part by measurement of LDL-C within 24 hours of admission to the hospital.  Modification of therapy can be made at follow-up if necessary to achieve the desired LDL-C level.  If the baseline in-hospital LDL-C is relatively low, even a LDL-C level of < 70 mg/dL may be achieved by a standard dose of a statin.  If the baseline LDL-C level is higher, a high dose of a statin may be required.

Wright et al. (2002) states that early initiation of stains during hospitalization for ACS patients leads to the highest percentage of patients achieving target LDL goals and the greatest patient compliance by 6 months of follow-up.  He also believes that early initiation of statin therapy during hospitalization has a proven secondary preventive benefit.  In Wright’s opinion, the randomized clinical trials have shown no harm from aggressive, early use of statin therapy, which is why physicians and surgeons should initiate statin therapy within 24 hours of hospital admission.

Despite the evidence at hand, many important questions regarding lipid-lowering in ACS remain unanswered. Additional randomized controlled trials need to be conducted to explore the pleiotropic effects of statins.  If statins are found to have pleiotropic effects, statins may be prescribed to categories of patients that would not ordinarily receive statin therapy.  It is also uncertain if the benefit of early statin treatment is a class effect or an effect only related to statins, which was seen in this review comparing atorvastatin in MIRACL and PROVE IT to simvastatin in A to Z Trial.  To determine the optimal dose of a statin in ACS will require additional research, which should include head-to-head comparisons of statins. Researchers and patients need to be diligent with follow up so that we can have a true picture with intention to treat analyses and with the inclusion of more women.  Last, the current evidence from MIRACL, PROVE IT and REVERSAL should lead physicians to consider treatment with a high dose statin, initiated in the critical care unit and continued for several months following ACS.   

            From the evidence of previous statin trials, the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III panel expanded both the scope and intensity of LDL-lowering therapy for higher-risk individuals (Grundy et al., 2004). These new trials have strongly reinforced ATP III recommendations for the benefit of LDL-lowering therapy for patients with diabetes and in older patients.  They also provide new information on the efficacy of risk reduction in high-risk patients with relatively low LDL-C levels.  Although the full benefit of LDL-C reduction is higher-risk patients with low or very low LDL-C levels is still under investigation, the recent results open the door to the use of cholesterol-lowering drugs in patients with very high absolute risk, who are most likely to benefit from added therapy (Grundy et al., 2004). For high-risk patients, the recommended LDL-C treatment goal remains at < 100 mg/dL; however, a target goal of < 70 mg/dL represents a therapeutic option for persons considered to be at very high risk.

            There will soon be a change in the way that we use stains.  New data suggests that statins may not only help with management of atherosclerosis but also its prevention.  The proportional reduction in major clinical outcomes that results from aggressive statin therapy is similar to a statin when compared to a placebo in controlled trials (Cannon et al., 2004).  Intensive therapy with statins is likely to result in great movement towards actualizing the full benefit of this class of medication.  We have just begun to see a glimpse of their potential.

 

 

References

Cannon, C.P., Braunwald, E., McCabe, C.H., Rader, D.J., Rouleau, J.L., Belder, R., Joyal, S.V., Hill, K.A., Pfeffer, M.A., & Skene, A.M. (2004).   Intensive versus moderate lipid lowering with statins after acute coronary syndromes.  New England Journal of Medicine, 350, 1495-1504.

 

Dam, M. van, Wissen, S. van, & Kastelein, J.J. (2002). Declaring war on undertreatment: rationale for an aggressive approach to lowering cholesterol. Journal of Cardiovascular Risk, 9, 89-95.

 

De Lemos, J.A., Blazing, M.A., Wiviott, S.D., Lewis, E.F., Fox, K.A., White, H.D., Rouleau, J.L., Pedersen, T.R., Gardner, L.H., Mukherjee, R., Ramsey, K.E., Palmisano, J., Bilheimer, D.W., Pfeffer, M.A., Califf, R.M., & Braunwald, E. for the A to Z Investigators (2004). Early intensive vs. a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA, 292, 1307-1316.

 

Durazzo, A.E., Machado, F.S., Ikeoka, D.T., De Bernoche, C., Monachini, M.C., Puech-Leao, P., &  Caramelli, B. (2004). Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial.  Journal of Vascular Surgery, 39, 967-975.

 

Grundy, S.M., Cleeman, J.I., Merz, C.N., Brewer, H.B., Clark, L.T., Hunninghake, D.B., Pasternak, R.C., Smith, S.C., Stone, N.J., & Coordinating Committee of the National Cholesterol Education Program (2004). Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.  Journal of the American College of Cardiology, 44, 720-732.

 

McKeown, B., & Thompson, P.L. (2002).  Early initiation of statin therapy after a coronary event.  Current Opinion in Lipidology, 13, 631-635.

 

Nissen, S.E., Tuzcu, E.M., Schoenhagen, P., Brown, B.G., Ganz, P., Vogel, R.A., Crowe, T., Howard, G., Cooper, C.J., Brodie, B., Grines, C.L., & DeMaria, A.N. for the REVERSAL Investigators (2004). Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.  JAMA, 291, 1071-80.

 

Olsson, A.G., & Schwartz, G.G. (2002). Early initiation of treatment with statins in acute coronary syndromes.  Annals of Medicine, 34, 37-41.

 

Schwartz, G.G., Olsson, A.G., Ezekowitz, M.D., Ganz, P., Oliver, M.F., Waters, D., Zeiher, A., Chaitman, B.R., Leslie, S., & Stern, T. for the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Investigators (2001). Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.  JAMA, 285, 1711-1718.

Spencer, F., Allegrone, J., Goldberg, R., Gore, J.M., Fox, K., Granger, C.B., Mehta, R., & Brieger, D. for the GRACE Investigators (2004).  Association of Statin Therapy with Outcomes of Acute Coronary Syndromes: The GRACE Study. Annals of Internal Medicine, 140, 857-866.

 

Wilhelmsen, L., Pyorala, K., Wedel, H., Cook, T., Pedersen, T., & Kjekshus, J. (2001). Risk factors for a major coronary event after myocardial infarction in the Scandinavian Simvastatin Survival Study (4S). Impact of predicted risk on the benefit of cholesterol-lowering treatment.  European Heart Journal, 22, 1119-1127.

 

Wright, R.S., Murphy, J.G., Bybee, K.A., Kopecky, S.L., & LaBlanche, J.M. (2002).  Statin lipid-lowering therapy for acute myocardial infarction and unstable angina: efficacy and mechanism of benefit.  Mayo Clinic Proceedings, 77, 1085-1092.

 

 

 

 

Appendix A

Bibliography

Arntz, H.R. (2002). The case for early statin therapy in acute coronary syndromes. Cardiology in Review, 10, 91-96.

 

Bybee, K.A., Wright, R.S., & Kopecky, S.L. (2002).  Effect of early statin therapy after acute coronary syndromes:  A concise review of the recent data. Cardiology in Review, 10, 301-305.

 

Colhoun, H.M., Betteridge, D.J., Durrington, P.N., Hitman, G.A., Neil, H.A., Livingstone, S.J., Thomason, M.J., Mackness, M.I., Charlton-Menys, V., & Fuller, J.H. for the CARDS Investigators (2004). Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicenter randomized placebo-controlled trial. Lancet, 364, 685-696.

 

Li, J.J., Chen, M.Z., Chen, X., & Fang, C.H. (2003). Rapid effects of simvastatin on lipid profile and C-reactive protein in patients with hypercholesterolemia. Clinical Cardiology, 26, 472-476.

 

Marz, W., Wollschlager, H., Klein, G., Neiss, A., & Wehling, M. (1999).  Safety of low-density lipoprotein cholesterol reduction with atorvastatin versus simvastatin in a coronary heart disease population (the TARGET TANGIBLE trial).  American Journal of Cardiology, 84, 7-13.

 

Okazaki, S., Yokoyama, T., Miyauchi, K., Shimada, K., Kurata, T., Sato, H., & Daida, H. (2004).  Early Statin Treatment in Patients With Acute Coronary Syndrome: Demonstration of the Beneficial Effect on Atherosclerotic Lesions by Serial Volumetric Intravascular Ultrasound Analysis During Half a Year After Coronary Event: The ESTABLISH Study. Circulation, 110, 1061-1068.

 

Rosenson, R.S., & Brown, A.S. (2002).  Statin use in acute coronary syndromes: cellular mechanisms and clinical evidence.  Current Opinion in Lipidology, 13,  625-30.

 

Simes, J., Furberg, C.D., Braunwald, E., Davis, B.R., Ford, I., Tonkin, A., & Shepherd, J. (2002). Effects of pravastatin on mortality in patients with and without coronary heart disease across a broad range of cholesterol levels. The Prospective Pravastatin Pooling project.  European Heart Journal, 23,  207-215.

 

 

 

 

Appendix B

 

Search History

 

 

Database: Ovid MEDLINE(R) <1996 to September Week 4 2004>

Search Strategy:

--------------------------------------------------------------------------------

1     statins.mp. (3132)

2     atorvastatin.mp. (1215)

3     simvastatin.mp. or SIMVASTATIN/ (1985)

4     pravastatin.mp. or PRAVASTATIN/ (1549)

5     lovastatin.mp. or LOVASTATIN/ (1635)

6     rosuvastatin.mp. (175)

7     1 or 2 or 3 or 4 or 5 or 6 (6736)

8     Time Factors/ or early initiation.mp. (189483)

9     intensive treatment.mp. (871)

10     aggressive treatment.mp. (1684)

11     8 or 9 or 10 (191848)

12     7 and 11 (425)

13     reduction.mp. or RISK REDUCTION BEHAVIOR/ (156611)

14     Myocardial infarction.mp. or Myocardial Infarction/ (37130)

15     stroke.mp. or Cerebrovascular Accident/ (33402)

16     angina.mp. or ANGINA PECTORIS, VARIANT/ or ANGINA PECTORIS/ or ANGINA, UNSTABLE/ (12977)

17     Coronary Disease/ or Myocardial Infarction/ or Cardiovascular Diseases/ or cardiovascular events.mp. or Heart Diseases/ (78679)

18     cardiovascular death.mp. (560)

19     14 or 15 or 16 or 17 or 18 (118407)

20     13 and 19 (8444)

21     12 and 20 (48)

22     limit 21 to (human and english language) (41)

23     limit 22 to (controlled clinical trial or practice guideline or randomized controlled trial or "review") (32)

24     from 23 keep 1-6,10-19,21-22,24-27,29 (23)

 

 

 

 

 

 

 

 

 

Appendix C

 

Literature Matrix for Randomized Controlled Trials

 

Citation	Patients/Subjects	Interventions	Comparisons	Outcomes	Level*	Evaluation (Strengths, Limitations, Relevance)+
Athyros VG, Papageorgiou AA, Symeonidis AN, Didangelos TP, Pehlivanidis AN, Bouloukos VI, Mikhailidis DP, GREACE Study Collaborative Group (2003). Early benefit from structured care with atorvastatin in patients with coronary heart disease and diabetes mellitus.  Angiology. 54(6): 679-90.	Patients with CHD (history of prior MI, or >70% stenosis of at least one artery, patients with recent ACS were included (n=1600).	A specialist clinic and treatment with atorvastatin 10mg to 80 mg. Patients were titrated to reach NCEP ATP III guidelines.	Usual care by general practioners, which included life-style changes, such as hypolipidaemic diet, weight loss, exercise plus all necessary drug treatment (lipid-lowering agents)	Primary endpoints were total and coronary mortality, as well as non-fatal MI, unstable angina, CHF, revascularization, and stroke.   Atorvastatin  was well tolerated and it significantly reduced overall mortality by 43% (p=.0021),  coronary mortality by 47% (p=.0017),  risk of non-fatal MI (p=.0001), and stroke by 47%.  95% of atorvastatin patients met NCEP goals.  95% confidence interval.	1b, RCT	Strengths: ·          RCT ·          Groups were randomized and equally distributed. ·          Unfunded Study ·          Highly significant results with 95% CI. Limitations: ·          Better if a placebo group had been used for comparison. ·          Trial conducted in Greece where usual care is slightly different than in the USA. ·          Fewer women than men. ·          Short duration. Relevance: ·          The GREACE trial emphasizes the urgent need for the wider-use of lipid-lowering drugs in high-risk patients.
De Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau JL, Pedersen TR, Gardner LH, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW, Pfeffer MA, Califf RM, Braunwald E, A to Z Investigators (2004) Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA, 292(11): 1307-16.	Patients with ACS between the ages of 21-80.  They had either non-ST elevation ACS or ST-elevation MI with total cholesterol of 250 mg/dL.  (n=4497)	40 mg/d of simvastatin for 1 month followed by 80 mg/d (n=2265)	Placebo for 4 months followed by 20 mg/d of simvastatin (n=2232)	Primary endpoint was a composite of CV death, nonfatal MI, readmission for ACS, and stroke.  Primary endpoint was 16.7% in placebo group and 14.4% in simvastatin group.  [HR = .89 with 95% CI (p=.14)].  CV death was 5.4% vs. 4.1% [HR = .75 with 95% CI (p=.05)].  Early intensive statin regimen was associated with a reduction in CV mortality of 25% (AR=1.3% and p=.05) and congestive heart failure of 28% (AR=1.3% and p=.04)	1b, RCT	Strengths: ·          RCT ·          International ·          Double-blind ·          Groups were equally distributed ·          Good F/U  (lost 22 patients in both groups) Limitations: ·          Treatment was d/c in 32% of placebo group and 34% in simvastatin group. ·          Did not achieve prespecified end point and the 11% relative reduction in the rate of primary end point in the early intensive statin group was not statistically significantly planned ·          Less statistical power than was what original Relevance: ·          Among patients with ACS, early initiation of an aggressive statin regimen will help to reduce major CV events.
Durazzo AE, Machado FS, Ikeoka DT, De Bernoche C, Monachini MC, Puech-Leao P, Caramelli B (2004). Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial.  Journal of Vascular Surgery, 39(5): 967-75.	Patients who were undergoing cardiovascular surgery (n=100).  Surgery was performed within 31 days after medication was started.	Atorvastatin 20mg, daily for 45 days. (n=50)	Placebo for 45 days. (n=50)	Primary endpoints were CV death, nonfatal MI, unstable angina, and stroke.  The risk for an event was 3x higher in placebo group (26%) vs. atorvastatin group (8%) (p=.031).  Atorvastatin group had a significant decrease in the rate of CV events within 6 months of surgery.	1b, RCT	Strengths: ·          RCT ·          Double-blind ·          Groups were randomized and equally distributed. ·          Sample size was calculated to detect a reduction in combined primary end points from 22% to 1%, with statistical power of .80 and 95% CI. Limitations: ·          Small trial.  It needs to be confirmed with a multi-center, RCT. Relevance: ·          Vascular surgeons should consider initiating atorvastatin after vascular surgery to help reduce major CV events.
Li JJ, Chen MZ, Chen X, Fang CH (2003). Rapid effects of simvastatin on lipid profile and C-reactive protein in patients with hypercholesterolemia. Clinical Cardiology, 26(10): 472-6.	Patients with CHD, who had undergone revascularization. (n=42)	Simvastatin 20 mg, daily	Simvastatin 40 mg, daily	Results showed that both doses (20 and 40) induced significant reduction in TC (25 and 38) and LDL (31 and 46); the 40mg dose resulted in significantly greater reductions in TC and LDL (p=. 04, p=. 02).   Both doses significantly reduced mean CRP in 14 days (22.3 and 23.1)  (p<. 001).	1b, RCT	***Limited because I only have the abstract***   Strengths: ·          RCT Limitations: ·          Small trial Relevance: ·          Statins (especially higher doses) not only reduce LDL and Tags, but also benefit the vascular endothelium by reducing the CRP levels.
Mars W, Wollschlager H, Klein G, Neiss A, Wehling M (1999).  Safety of low-density lipoprotein cholesterol reduction with atorvastatin versus simvastatin in a coronary heart disease population (the TARGET TANGIBLE trial.  American Journal of Cardiology. 84(1): 7-13.	Patients with CHD (58%) or a high risk for CHD (42%) (n=2,856 in drug therapy group)	Atorvastatin 10mg to 40mg, daily (n=1897)	Simvastatin 10mg to 40mg, daily (n=959)	Primary end points were safety and tolerability of in atorvastatin and simvastatin.  AE were equal with atorvastatin @ 36.3% and simvastatin @ 35.7%.  No statistical difference in myalgia rates (1.1% vs. .4%, p=.062). Secondary analysis was to evaluate changes in lipid parameters including LDL, TC, HDL, and TGs.  Atorvastatin 20mg comparable to Simvastatin 40mg.  Statistical significance in favor of atorvastatin in LDL and TC.  There was difference in HDL.	1b, RCT	Strengths: ·          Parallel-group ·          Large trial with 591 investigators ·          Withdrawals similar for both groups (9%) Limitations: ·          Open-label ·          Randomized was 2:1 for atorvastatin ·          Conducted in Germany Relevance: ·          Physicians should consider initiating therapy with atorvastatin over simvastatin.  Atorvastatin allows more patients to reach their cholesterol goals with an equivalent safety profile.
Okazaki S, Yokoyama T, Malachi K, Shimada K, Kurata T, Sato H, Daida H (2004).  Early Statin Treatment in Patients With Acute Coronary Syndrome: Demonstration of the Beneficial Effect on Atherosclerotic Lesions by Serial Volumetric Intravascular Ultrasound Analysis During Half a Year After Coronary Event: The ESTABLISH Study. Circulation. 110(9): 1061-1068.	Patients with ACS who underwent emergency percutaneous coronary intervention (PCI) (n=70)	Atorvastatin 20mg, daily (n=35)	Usual care, which includes lipid-lowering diet and a cholesterol absorption inhibitor if the LDL was > 150 mg/dL (n=35)	LDL was significantly reduced by 41.7% in the atorvastatin group vs. .7% in the control group (p<. 0001).  Plaque volume was significantly reduced by 13.1% +/- 12.8% in the atorvastatin group and increased by 8.7% +/- 14.9% in the control group (p<. 0001).  Percent change in plaque volume showed a significant positive correlation with follow-up LDL (R=.456, p=.0011) and percent LDL reduction (R=.612, p<.0001).	1b, RCT	Strengths: ·          RCT ·          Parallel-group ·          IVUS examination provided high-quality images in the acute phases and F/U. ·          Good F/U – only 2 patients lost. Limitations: ·          Small study ·          Regression of plaque area was not observed.  Only retardation of the progression was found. ·          Tissue characterization was not performed. Relevance: ·          Early aggressive lipid-lowering therapy with atorvastatin will reduce the plaque volume in patients with ACS, even in patients with low baseline LDL.. ·          Cardiologists should initiate statin standing orders for patients undergoing PCI.
Spencer F, Allegrone J, Goldberg R, Gore JM, Fox K, Granger CB, Mehta R, Brieger D, GRACE Investigators (2004).  Association of Statin Therapy with Outcomes of Acute Coronary Syndromes: The GRACE Study. Annals of Internal Medicine. 140(11):857-866.	Patients with an ACS (n=19,537)	Long-term statin therapy and  in-hospital statin use (n=3628), Long-term statin therapy only (n=428), In-hospital statin use only (n=5959)	No statin use (n=9522)	Statin use before and after presentation with an ACS and associated rates of MI, hospital complications, and hospital mortality.  End points include death, in-hospital MI, and stroke.  Patients already on statins were less likely to have ST-segment elevation (OR=.79 with 95% CI) or MI (OR=.78).  Pts who continued to take statins in the hospital were less likely to experience complications or die than pts who never received statins(OR=.66).  Pts not previously taking statins in the hospital were less likely to die than pts who never received statin therapy (OR=.38)	2b, cohort study	Strengths: ·          Large, multinational observational study   Limitations: ·          Observational vs. RCT ·          Cannot exclude confounding by clinical and hospital factors. ·          RCT is needed to confirm results ·          No firm conclusions can be made about a casual relationship between early statin therapy and withdrawal or hospital outcomes. ·          Did not examine differences between statins, dosages, or previous duration of therapy on observed outcomes. ·          Could not document the reasons for d/c of statin therapy during hospitalization. Relevance: ·          Clinicians should initiate statin therapy early in ACS patients.  There are additional benefits past lowering cholesterol parameters, such as pleiotropic actions, including inhibition of inflammation, antithrombotic and antiplatelet effects, and modulation of endothelial functions.
Wilhelmsen L, Pyorala K, Wedel H, Cook T, Pedersen T, Kjekshus J (2001). Risk factors for a major coronary event after myocardial infarction in the Scandinavian Simvastatin Survival Study (4S). Impact of predicted risk on the benefit of cholesterol-lowering treatment.  European Heart Journal. 22(13):1119-27.	Patients with a history of MI or angina (n=3525)	Simvastatin 20mg/d with titration to 40mg at 12 or 24 weeks.	Placebo	Primary end point was death from any cause.  Secondary end-point was major coronary events, coronary death, nonfatal infarction, resuscitated cardiac arrest, and definite silent MI.  The RR in the simvastatin treatment in patients at low, medium, and high-predicted risk was 38%, 39%, and 42%.  The corresponding absolute benefit per 100 patients treated for 6 years increased from 7.p to 16.2	1b, RCT	Strengths: ·          Randomized controlled trial ·          Double-blind, placebo-controlled ·          Multicenter ·          95 percent confidence interval Limitations: ·          Small number of women ·          Groups were not parallel Relevance: ·          Clinicians should consider the initiation of statin therapy in patients with a history of MI or angina. Even patients at low-risk for MI can benefit from statin therapy; however, those at greatest risk have the most to benefit.
Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM (2004).   Intensive versus moderate lipid lowering with statins after acute coronary syndromes.  New England Journal of Medicine, 350(15): 1495-504.	Hospitalized patients who had been admitted within the preceding 10 days for an acute coronary syndrome (n = 4162)	40 mg of Pravastatin daily (standard therapy)	80 mg of Atorvastatin daily (intensive therapy)	Primary end point was death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization, and stroke.  Kaplan-Meier estimates the rates of primary end points at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ration in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent.	1b, RCT	Strengths:             ·          Randomized controlled trial ·          Only 8 patients were lost to follow-up ·          Groups were randomized, equally       distributed, and equivalent care ·          Double-blind, double dummy ·          Large trial (349 sites in eight countries, n = 4162) ·          95 percent confidence interval                                 Limitations:           ·          The study did not meet the prespecified criteria for equivalence but did identify the superiority of the more intensive regimen (atorvastatin 80 mg).  ·          Looked at only patients with acute coronary syndrome Relevance:            ·          Cardiology and physicians that treat acute coronary syndrome patients.  The data demonstrated that an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen.
Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN, REVERSAL Investigators (2004). Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.  JAMA, 291(9):1071-80.	Patients with CHD (n=654)	40 mg of Pravastatin daily (standard therapy) (n=329)	80 mg of Atorvastatin daily (intensive therapy) (n=328)	Percent change in atheroma volume.  Baseline LDL was reduced to 110mg/dL in the pravastatin group and to 79 mg/dL in atorvastatin group (p<.001).  The primary end point showed a significantly lower progression rate in the atorvastatin group (p=.02).  Progression of coronary atherosclerosis occurred in the pravastatin group (2.7% with a 95% CI, p=.001) compared with baseline.  Progression did not occur in the atorvastatin group (-.4% with 95% CI, p=.98) compared with baseline.	1b, RCT	Strengths: ·          Randomized controlled trial ·          Groups were randomized, equally       distributed, and equivalent care ·          Double-blind, randomized active control ·          Multi-center ·          95 percent confidence interval ·          First active-control statin trial of CAD progression Limitations: ·          Lost 78 patients in the pravastatin group and 74 patients in the atorvastatin group. ·          Too few events for meaningful analysis because f/u was only 18 months. ·          80mg of pravastatin has been released since this trial was completed. ·          Study was funded by Pfizer. Relevance: ·          Clinicians should consider initiating intensive lipid-lowering therapy with atorvastatin in their patients with CHD.
Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators (2001). Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.  JAMA, 285(13): 1711-8.	3086 patients with unstable angina or non-Q-wave acute MI.	Atorvastatin 80mg/d, initiated 24 to 96 hours after an ACS for 16 weeks. (N=1538)	Placebo for 16 weeks. (n=1548)	Primary end point was defined as death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic MI with objective evidence and requiring emergency hospitalization.  Primary end point occurred in 14.8% in the atorvastatin group and 17.4% in the placebo group (RR=.84 with 95% CI).  Atorvastatin significantly reduced the risk of primary combined end point (RR=.84 with 95% CI, p=.048).  There was a 2.6% AR and a 16% RR in the primary combined end point of death, nonfatal MI, etc.	1b, RCT	Strengths: ·          Randomized controlled trial ·          Groups were randomized, equally       distributed, and equivalent care ·          Double-blind ·          Multi-center in 4 contents ·          95 percent confidence interval ·          Good patient compliance (88 Atorva and 86 Placebo) ·          NNT was met Limitations: ·          Twenty-three atorvastatin pts and 26 placebo pts had to be treated with an open-label lipid-lowering medication. ·            Relevance: ·          Clinicians should consider initiating aggressive treatment early in patients with ACS. ·          Atorvastatin should be considered based on its efficacy and safety profile.