Beneficial effects of pravastatin (±colestyramine/niacin) initiated immediately after a coronary event (the randomized lipid-coronary artery disease [L-CAD] study)

doi:10.1016/S0002-9149(00)01230-3

The American Journal of Cardiology

Volume 86, Issue 12, 15 December 2000, Pages 1293-1298

https://doi.org/10.1016/S0002-9149(00)01230-3 Get rights and content

Abstract

Secondary prevention of coronary heart disease by antilipidemic therapy beginning at ≥3 months after an acute coronary syndrome is well documented. The impact, however, of immediate initiation of antilipidemic therapy on coronary stenoses and clinical outcome in patients with acute coronary syndrome is unknown. In our study, patients were randomized, on average, 6 days after an acute myocardial infarction and/or percutaneous transluminal coronary angioplasty secondary to unstable angina, to pravastatin (combined, when necessary, with cholestyramine and/or nicotinic acid) to achieve low-density lipoprotein cholesterol levels of ≤130 mg/dl (group A, n = 70). In controls (group B, n = 56), antilipidemic therapy was determined by family physicians. Quantitative coronary angiography was performed at inclusion, and at 6- and 24-month follow-up. The combined clinical end points were total mortality, cardiovascular death, nonfatal myocardial infarction, need for coronary intervention, stroke, and new onset of peripheral vascular disease. Minimal lumen diameter in group A increased by 0.05 ± 0.20 mm after 6 months and 0.13 ± 0.29 mm after 24 months, whereas it decreased by 0.08 ± 0.20 mm and 0.18 ± 0.27 mm, respectively, in group B (p = 0.004 at 6 months and p <0.001 at 24 months). After 2 years, 29 patients of 56 patients in group B, but only 16 of 70 patients in group A, experienced a clinical end point (p = 0.005; odds ratio 0.28, confidence intervals 0.13 to 0.6). We conclude that pravastatin-based therapy initiated immediately after an acute coronary syndrome is well tolerated and safe, lessens coronary atherosclerosis, and has a pronounced clinical benefit.

Section snippets

Patients and therapy

Patients with total cholesterol of >200 to <400 mg/dl and low-density lipoprotein (LDL) cholesterol of >130 to <300 mg/dl (after exclusion of secondary forms of hyperlipidemia) with an acute myocardial infarction (defined by new Q waves and increase of enzymes of >3-fold the normal value) and/or who underwent emergency percutaneous transluminal coronary balloon angioplasty due to severe or unstable angina pectoris (defined by clinical symptoms and electrocardiographic [ECG] alterations during

Results

Of the 870 patients examined, 135 were eligible and randomized to either intensive treatment (group A) or controls (group B) (Figure 1). Nine patients in group B withdrew their consent after learning to which group they were included. Thus, 70 patients (group A) and 56 patients (group B) entered the study. Baseline characteristics in both groups were well matched (Table 1). Fifty-five patients (44%) had an acute infarction, 37 (67%) of those also had undergone angioplasty, and the remaining 71

Discussion

Pravastatin was effective in reducing cardiovascular events and in slowing the progression of atherosclerosis in primary and secondary prevention populations.2, 3, 9, 18, 19 Compared with previous studies,4, 5, 9 this study is the first to show that cholesterol lowering with pravastatin (in combination with cholestyramine and/or nicotinic acid when necessary) in patients treated immediately after an acute coronary syndrome can prevent progression and achieve regression of coronary lesions

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Cited by (158)

Treatment of dyslipidemia in acute coronary syndrome
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Despite numerous improvements in the management of acute coronary syndrome(ACS), it is a major cause of mortality in India. Lipids play a critical role in pathogenesis of ACS and reduction of lipid parameters plays a pivotal role in secondary prevention. High total cholesterol and high low-density lipoprotein(LDL) are the major lipid abnormalities globally as well as in Indians. Among all the lipid parameters, LDL is the primary target of lipid-lowering therapies across the globe. High-dose statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bempedoic acid are recommended therapies for LDL reduction in ACS patients. Statins have pleiotropic effects on the modulation of thrombogenesis, endothelial dysfunction, and myocardial protection. Multiple randomised controlled trials and meta-analyses have shown that the use of high-dose statin has significant benefits in ACS. LDL reduction goal is < 55 mg/dl or at least 50 % reduction from the baseline regardless of age or gender. Non-fasting LDL should be measured soon after the ACS as it varies minimally with food intake. The first line of therapy after ACS is to advise lifestyle modifications, combination therapy including high-dose statin with ezetimibe, and evaluation after 4–6 weeks of the index event. If the goal is not achieved then PCSK 9 inhibitors or Bempedoic acid should be used in combination with statins and ezetimibe to reduce recurrent ischaemic events. Despite the proven effect of these lipid-lowering therapies, undertreatment is still a big hurdle across the globe. Prohibitive costs, adverse effects, medication non-adherence, variation in health practice in different countries, and clinical inertia to prescribe this medication by physicians are the main reasons for the undertreatment.
Effect of More Intensive LDL-C–Lowering Therapy on Long-term Cardiovascular Outcomes in Early-Phase Acute Coronary Syndrome: A Systematic Review and Meta-analysis
2021, Clinical Therapeutics
The effect of more intensive LDL-C–lowering therapy (ILLT) on long-term cardiovascular outcomes during the early phase of acute coronary syndromes (ACSs) remains uncertain. We aimed to explore the influence of more intensive LDL-C–lowering therapyduring the early disease phase on long-term cardiovascular events among patients with ACSs.
Randomized controlled trials that focused on the effect of more ILLT during early-phase ACSs on long-term major adverse cardiac events (MACEs) were searched in electronic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases) from database inception until November 23, 2019. The end points included the incidence of MACEs, myocardial infarction, stroke, revascularization, heart failure, and death events. Study risk of bias was assessed using the Cochrane Collaboration tools. Fixed- or random-effects models and meta-regression were performed to evaluate the association between baseline/proportional reduction of LDL-C levels during early-phase disease and the risk of end points using risk ratios with 95% CIs.
A total of 53,199 participants were involved from 19 studies. The risk of MACEs decreased by 17% (95% CI, 0.76–0.90; P = 0.0012) for more intensive versus control therapy but varied by baseline and proportional reduction of LDL-C levels during early disease phase. The risk reduction of MACEs for more intensive versus control therapy among different subgroups was 26% (95% CI, 0.57–0.95; P = 0.06) with a baseline level >130 mg/dL, 23% (95% CI, 0.63–0.94; P = 0.02) with a baseline level of 100 to 130 mg/dL, and 10% (95% CI, 0.83–0.99; P = 0.07) with a baseline level <100 mg/dL. A significant difference of risk reduction for MACEs existed between patients treated with statin plus ezetimibe versus statin alone in the subgroup with a baseline level >130 mg/dL and proportional reduction >50%. Patients treated with more intensive therapy benefited from reduced risk of myocardial infarction, stroke, revascularization, and heart failure compared with control therapy.
More ILLT during early disease phase could significantly reduce the risk of long-term cardiovascular outcome in patients with ACSs. This benefit was most pronounced in patients with higher baseline and larger reduction of LDL-C levels in MACEs.
Efficacy and safety of long-term treatment with statins for coronary heart disease: A Bayesian network meta-analysis
2016, Atherosclerosis
Our study aims to evaluate the efficacy and safety of long-term treatment of statins for coronary heart disease (CHD).
Efficacy outcomes included changes in blood lipids, risk of CHD mortality and all-cause mortality. Safety outcomes were evaluated by the risk of adverse events (AE). Bayesian network meta-analysis was used to compare the direct and indirect effects between different statins.
The systematic review showed that levels of blood lipids decreased during statin treatment. High dose of atorvastatin was the most obvious treatment for the reduction of blood lipids. Network meta-analysis showed that statins were significantly more effective than the control in reducing the risk of CHD mortality (Odds Ratio (OR) 0.69, 95% CI 0.61–0.77) and all-cause mortality (OR 0.84, 95% CI 0.80–0.87). In terms of reducing the risk of CHD morality, fluvastatin (77.3%), atorvastatin (72.3%) and lovastatin (68.4%) had higher cumulative probability than other statins, which were more effective treatments for the reduction of CHD morality. In terms of reducing all-cause mortality, atorvastatin (78.6%), fluvastatin (77.1%) and pitavastatin (74.1%) had higher cumulative probability than other statins, which were more effective treatment for reducing the all-cause mortality. Compared with placebo, statins increased the incidence risk of muscle disease (OR 1.05, 95% CI 1.00–1.10) and kidney disease (OR 1.11, 95% CI 1.05–1.72).
Statins significantly reduced levels of blood lipids, with a high dose of atorvastatin being the most effective in blood-lipid level modification. Statins reduced the risk of CHD mortality and all-cause mortality, with atorvastatin and fluvastatin being the most effective in reducing the risk of CHD mortality and all-cause mortality. Statins increased the risk of muscle disease and kidney damage.
Updated evidence on early statin therapy for acute coronary syndromes: Meta-analysis of 18 randomized trials involving over 14,000 patients
2012, International Journal of Cardiology
The short-term effects of early statin therapy in acute coronary syndromes (ACS) on clinical outcomes remain unclear. Our objective was to update the evidence on patient relevant outcomes from all randomized trials comparing early statin therapy with placebo or usual care at 1 and 4 months following ACS.
We performed a systematic review and meta-analysis of randomized trials that compared statins to control, initiated within 14 days after onset of ACS and with minimal follow-up of 30 days. Data were extracted in duplicate and analyzed by a random effects model. Investigators from individual trials contributed additional data where needed.
A total of 18 trials involving 14,303 patients with ACS were included in the meta-analysis. We found no evidence for further trials on the topic. Risk ratios for the combined endpoint of death, myocardial infarction, and stroke of early statin therapy compared to control were 0.93 (95% confidence interval [CI], 0.80–1.08; P = 0.34) at 1 month and 0.93 (95% CI, 0.81–1.06; P = 0.27) at 4 months following ACS. There were favorable trends related to statin use for all individual secondary endpoints but there was no statistically significant risk reduction except for unstable angina with a risk ratio of 0.76 (95% CI, 0.59–0.96; P = 0.02) at 4 months following ACS.
Initiation of statin therapy within 14 days following ACS results in directionally favorable but non-significant reduction in death, myocardial infarction, or stroke up to 4 months, and significant reduction in the occurrence of unstable angina at 4 months following ACS.
Statins in Acute Coronary Syndromes. Do the Guideline Recommendations Match the Evidence?
2009, Journal of the American College of Cardiology
On the basis of the evidence obtained from observational studies, randomized controlled trials and their meta-analyses, current guidelines recommend initiating high-dose statin therapy pre-discharge regardless of the baseline low-density lipoprotein (LDL) level in patients with acute coronary syndromes (ACS). Careful review of the evidence indicates that early initiation of high-dose statin therapy reduces recurrent ischemia and may reduce revascularization, but does not confer benefit in terms of hard clinical outcomes such as death or myocardial infarction in any of the randomized controlled trials, and may be associated with increased liver and muscle-related adverse outcomes leading to increased withdrawal and suboptimal long-term adherence. A mortality benefit is apparent in pooled analyses of randomized controlled trials only at long-term (24-month) but not short-term (4-month) follow-up. The critical role of the timing of initiation of therapy (early vs. late) on the benefit-risk profile of statin treatment has not been systematically assessed. It is unclear whether the clinical benefits are attributable to lipid-lowering or lipid-lowering–independent effects. Finally, an optimal LDL threshold for initiating treatment or target LDL level for treatment in ACS remains yet to be defined. On the basis of these observations, and despite a compelling pathophysiologic rationale, the justification for current Class I, Level of Evidence: A recommendation for statin therapy in patients with ACS remains open to question.
Statins and cardioprotection - More than just lipid lowering?
2009, Pharmacology and Therapeutics
Lipid-lowering using HMG-CoA reductase inhibitors or statin therapy forms the cornerstone of medical therapy in the primary and secondary prevention of cardiovascular disease. In addition, to the improvements in lipid profile, the beneficial effects elicited by this class of drugs may be attributed to their diverse variety of non-lipid lowering pleiotropic effects, including improved endothelial function, reduced oxidative stress, less platelet adhesion, and increased atherosclerotic plaque stability. A less appreciated effect of statin therapy that has been reported in experimental studies is its cardioprotective effect with respect to its ability to directly protect the myocardium from the detrimental effects of acute ischaemia–reperfusion injury. In the current article we review the cardioprotective effects of statin therapy beyond serum lipid lowering, the underlying mechanisms involved and the potential implications for patients with coronary heart disease.

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^☆: This study was supported in part by a grant from Bristol-Myers Squibb Company, Munich, Germany. Manuscript received February 14, 2000; revised manuscript received and accepted June 20, 2000.

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Beneficial effects of pravastatin (±colestyramine/niacin) initiated immediately after a coronary event (the randomized lipid-coronary artery disease [L-CAD] study)☆

Abstract

Section snippets

Patients and therapy

Results

Discussion

J Am Coll Cardiol

Lancet

J Am Coll Cardiol

J Am Coll Cardiol

Randomised trial of cholesterol lowering in 4444 patients with coronary heart diseasethe Scandinavian Simvastatin Survival Study (4S)

Lancet

The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels

N Engl J Med

Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels

N Engl J Med

Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B

N Engl J Med

Effect of simvastatin on coronary atheromathe Multicentre Anti-Atheroma-Study (MAAS)

Lancet

The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts

N Engl J Med

Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levelsthe Regression Growth Evaluation Statin Study (REGRESS)

Circulation

Strategies for the prevention of coronary heart disease

Eur Heart J