Statins: Game Changers in CVD

In a recent post we had discussed the use of aspirin in the setting of an acute MI. Our second look at landmark trials examining the treatment of coronary vascular disease (CVD) focuses on primary prevention of CVD. Elevated cholesterol levels have long been implicated in the progression of CVD, and numerous medications have been developed to reduce plasma cholesterol levels as a means to reduce the incidence of myocardial infarctions and other cardiovascular events. In fact, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) revealed that the CVD risk reduction was proportional to the reduction in LDL cholesterol. Through the 1980s, fibrates and bile acid resins (cholestyramine) were in use, and studies from multiple institutions had demonstrated their ability to moderately reduce cholesterol levels. Used alone, neither cholestyramine nor the fibrates could achieve greater than a 10-15% reduction in LDL. The most promising development was the approval of HMG-CoA reductase inhibitors, otherwise known as statins. Several smaller studies suggested an improvement in plasma cholesterol levels and cardiovascular outcomes with statin therapy. The Scandinavian Simvastatin Survival Study (4S) assessed the effect of simvastatin on total mortality and cardiovascular outcomes and confidently addressed the question.

Between 1988 and 1994, 4444 patients between the ages of 35 and 70 were randomly assigned to receive various doses of simvastatin or placebo. Dosing was titrated to a specific serum cholesterol value; patients who were above this value received up to 40mg per day, and those below this value were titrated down. The study group was followed for an average of 5.4 years. The primary endpoint for 4S was total mortality – an important distinction since a few research trials with fibrates, including one from the WHO, had shown an increase in non-cardiovascular deaths. Randomization was successful in evenly dividing patients already on multiple medications for hypertension, angina and diabetes. A similar study conducted at the same time in Scotland, the WOSCOP study, was looking at the effect of pravastatin on primary prevention. While 4S was not as straightforward as WOSCOPS, it was far more generalizable in a number of ways. For one, it included women. Other aspects of the study that stand out are the broader age range, existing CVD or diabetes and a percentage of smokers closer to that of the US.

The data from 4S were impressive. Patients on simvastatin on average saw a 35% decrease in LDL cholesterol. More importantly, this decrease correlated with a relative risk of death of 0.70 when compared to placebo (182 vs 256 deaths). This reduction in deaths was attributable to a 42% decrease in cardiovascular mortality. Likewise, simvastatin also lead to a pronounced decrease in non-fatal cardiovascular events (RR 0.66). Adverse effects were few – 1 episode of rhabdomyolysis in the simvastatin group. Complaints of myalgias and elevations in LFTs were similar between placebo and simvastatin.

Prior to this study, the benefits of lipid-lowering therapy lacked a consensus. The 4S trial conclusively determined that statin therapy was a safe and more effective treatment choice in lowering serum LDL cholesterol than other lipid-lowering agents. Moreover, it provided the largest reduction in cardiovascular mortalities, and the benefit was witnessed in all age groups. Today many newer variations of statins exist but simvastatin continues to be the first line therapy for many of our patients.


The Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994. 344:1383-1389.


ISIS-2: Managing an Acute MI

Got chest pain? Then pop some aspirin and head to the ER. This was, in a nutshell, the conclusion of the Second International Study of Infarct Survival (ISIS-2). 1.5 million Americans suffer from a heart attack every year and many are treated in the ER with morphine, oxygen, nitrates, aspirin and beta-blockers. Some are taken to the cath lab. Part of this methodical management stems from the results of ISIS-2. Prior to ISIS-2, there was exactly one trial that examined the use of aspirin, an anti-platelet agent, acutely during a myocardial infarction (MI). (In that study, one dose of aspirin was given for a suspected MI, and mortality was assessed at one month. The single dose conferred no mortality benefit and the authors concluded that aspirin was not beneficial in the acute setting.) The focus on streptokinase in ISIS-2 was less groundbreaking as there were a number of other concurrent trials studying the use of thrombolytic therapy for MIs. Still, in conjunction with other randomized clinical trials (GISSI, ISAM, etc), they quickly established a time frame of 3 hours for thrombolytic therapy, giving rise to the phrase “time is muscle”. Today, with rapid triage at the ED and improved times to percutaneous coronary intervention (PCI), we know it as 90 minutes for “door to balloon”.

The methodology in the study was consistent throughout the trial. Eligibility was made straight forward to encourage participation in various countries and ultimately 17,187 patients were recruited for the study. Patients were randomized for both aspirin and streptokinase. This created 4 distinct groups: streptokinase infusion, aspirin 160mg, streptokinase + aspirin, or placebo infusion and tablets. Participating physicians were encouraged to continue all other aspects of patient care as they saw fit, though they were required to report the intention to use any anticoagulation in addition to the trial medications. At the time of publication, discharge information on 204 patients (1.1%) was not available. Otherwise follow-up was strong, with 97% follow-up at 5 weeks after discharge and a median follow-up of 15 months.

Both 5-week mortality and 24-month mortality were analyzed. Aspirin afforded a 23% reduction in the odds of death when given within 24 hours of the onset of chest pain and continued for a month. This translates into 25 deaths avoided per 1000 patients treated (NNT of 40) and 15 non-fatal cardiovascular events avoided. This effect was further enhanced if aspirin was given within 4 hours of pain; mortality benefits were less pronounced if given after 4 hours. When examining both fatal and non-fatal events in the years following a myocardial infarction, the number needed to treat is far less than 40. This survival benefit was independent of the survival gains witnessed with streptokinase therapy. The combination of thrombolytic and anti-platelet therapy, administered within 4 hours of onset of chest pain, lead to a reduction of 40-50% in odds of death.

The administration of aspirin in the setting of an acute MI can substantially alter the outcome. Moreover, the gains in survival over the first few weeks persist well into the future with smaller amounts of daily aspirin. These benefits, definitively established by ISIS-2, cannot be understated. Simply put, for the 1.5 million MIs that occur in the US every year, taking a drug that is already found in nearly all households can prevent tens of thousands of deaths.

ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988. Aug 13;2(8607):349-60.

(for those at UTSW, I can e-mail you a photocopy of the article since it isn’t available online through the library)