While the proximate cause of virtually all acute cardiovascular disease (CVD) syndromes is thrombosis, the principal underlying cause is atherosclerosis.
With respect to aspirin, in basic research this drug irrepressibly acetylates the active site of cyclo-oxygenase in platelets which inhibits thromboxane A2, a powerful promoter of aggregation. In randomized trials of secondary prevention and their meta-analyses, aspirin reduces risks of myocardial infraction (MI) by about one-third, stroke by about a quarter, and CVD death by about one-sixth. In randomized trials of primary prevention and their meta-analyses, aspirin significantly reduces risk of first MI by about one-third and all important vascular events by about one-sixth. The US Preventive Services Task Force and the American Heart Association (AHA) have recommended aspirin for all apparently healthy individuals whose risk of a first coronary heart disease (CHD) event is 6% or 10% respectively.
With regard to statins, in basic research these drugs decrease total and low-density lipoprotein (LDL) cholesterol as well as trigylcerides and also increase high-density lipoprotein (HDL) cholesterol. In the early trials of secondary and primary prevention, the benefits of a reduction in coronary events of about one-third, as well as stroke and total mortality by about one-fourth, appear to emerge after one to three years, which are compatible with a primary atherogenic effect of the statins. More recent trials have raised the possibility of early clinical benefits due to pleiotropic effects that may include acute antiplatelet mechanisms.
The fact that aspirin and statins have such different biological mechanisms of action suggests that their beneficial effects on CVD would be at least additive. For several reasons, the anti-inflammatory effects of both aspirin and statins may contribute to the beneficial effects on CVD. First, C-reactive protein (CRP), a sensitive marker of inflammation, predicts future risks of CVD. Second, the benefits of both aspirin and statins on CVD seem to be modified by underlying inflammation. Third, both these agents reduce CRP levels.
With respect to aspirin and CRP, the totality of evidence includes observational epidemiological data within two randomized trials and a randomized cross-over trial in chronic stable angina. All three trials antedated the availability of statins. In the Physician's Health Study, 22,071 apparently healthy men aged 40-84 years without prior MI or stroke, were randomized to 325mg aspirin or placebo every other day. Follow-up was virtually 100% complete for non-fatal MI, non-fatal stroke, and CVD death.
In a prospective, nested case-control study using baseline bloods, CRP levels were significantly higher among the cases. In subgroup analysis, men in the quartile with the highest CRP values had statistically significant approximate three-fold risks of MI and two-fold risks of ischemic stroke. Further, aspirin reduced risk of a first MI by 55.7% among those in the highest quintile of CRP, compared with 13.9% in the lowest. In the Women's Health Study, 39,992 apparently healthy female health professionals aged 50 and over without prior MI or stroke were randomized to 100mg aspirin or placebo every other day. Follow-up was virtually 100% complete for non-fatal MI, non-fatal stroke, and CVD death. In a prospective nested case-control study using baseline bloods, CRP levels were significantly higher among these cases. In subgroup analysis there was a significant approximately four-fold increased risk of CVD events in women in the highest compared with the lowest quartile of CRP levels. In a small trial, 40 patients with chronic stable angina and demonstrated ischemia were randomized to 300mg aspirin daily or placebo followed by a cross-over for an additional three weeks. Aspirin significantly reduced CRP levels by 29%. Placebo values did not differ from the baseline levels.
With regard to statins and CRP, the totality of evidence includes subgroup analyses of baseline bloods in the Cholesterol and Recurrent Events (CARE) trial. In CARE, 4,159 patients with prior MI, with a total cholesterol less than 240mg/dl and LDL cholesterol between 115 and 175mg/dl, were randomized to 40mg pravastatin or placebo. In a prospective nested case-control study, patients who subsequently developed non-fatal MI or fatal CHD had significantly higher baseline levels of CRP. Further, the benefits of pravastatin on risk of MI appeared to be modified by underlying inflammation. The proportion of recurrent coronary events prevented by pravastatin was 54% in patients with evidence of inflammation as compared with 25% among those without evidence of inflammation, even though baseline levels of total, LDL and HDL cholesterol as well as trigylcerides were similar among those with and without evidence of inflammation. In subsequent analyses with longer follow-up CRP decreased over five years among the patients assigned to pravastatin but tended to increase among those assigned to placebo, a significant difference of 17.8%. In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), statins reduced risks of CVD to a far greater extent among those with baseline elevations of CRP.
In the Pravastatin Inflammation/CRP Evaluation (PRINCE) trial pravastatin significantly reduced CRP by 16.9%. Most recently, in the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, 502 patients with established CVD were assigned at random to intensive lipid-lowering with 80mg atorvastatin/day or moderate lipid-lowering with 40mg pravastatin/day. At 18 months, CRP was reduced by 36.4% in the atorvastatin-treated patients compared with 5.2% in the pravastatin-treated patients, a statistically significant difference.
The additive clinical benefits of aspirin and statins have been tested in a meta-analysis of five randomized trials of secondary prevention comprising 73,900 patient years of observation. Patients were randomized to pravastatin 40mg per day, but aspirin use was prescribed in varying frequencies, and data were available on a large number of confounding variables. The two large individual trials, Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) and the CARE Trial, demonstrated additive benefits of pravastatin and aspirin on cardiovascular disease. In meta-analyses, the relative risk reductions for fatal or nonfatal MI were 31% for pravastatin plus aspirin versus aspirin alone. For ischemic stroke, the corresponding relative risk reductions were 29% and 31%. For the composite end point of CHD death, non-fatal MI, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or ischemic stroke, the relative risk reductions were 24% to 13%. All relative risk reductions were statistically significant.
In the meta-analysis, the benefits of combined aspirin and statin tended to be greater than the simple arithmetic sum of the benefits of each agent. Indeed, for the end-point of fatal or non-fatal MI, the probability of synergy was 0.92. The finding of a high probability that the benefits of aspirin and statins are synergistic is intriguing. It is tempting to speculate that the documented anti-inflammatory aspects of aspirin and statins may contribute to a finding greater than the additive benefits.
The finding of additive benefits on CVD of aspirin and statins over aspirin or statins alone is not surprising based on the well-described different primary mechanisms of actions of these drugs. In randomized trials in secondary prevention, aspirin has a predominantly immediate antiplatelet effect as evidenced by the clinical benefit becoming apparent within months after the initiation of therapy, when the statistically significant and clinically important benefits on CVD become manifest.
In randomized trials of secondary prevention in stable patients, statins have a predominantly delayed antiatherogenic effect, as evidenced by clinical benefit becoming apparent more than one year after the initiation of therapy when the statistically significant and clinically important reductions in CVD events become manifest. Recent observations suggest that atorvastatin may have pleiotropic effects leading to early clinical benefits seen in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL), and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT). Curiously, antiplatelet properties are among the postulated pleiotropic effects of the statins leading to early clinical benefits.
The population that would benefit from the combined use of aspirin and statins is large. In the US, in secondary prevention, there are about 12.4 million patients who are candidates for aspirin and statins, of which about 16% have a contraindication to aspirin and 3% to statins. With regard to current use patterns, in a nationwide survey of 165,000 patients with CHD and no contraindications or intolerance to aspirin or statins, 77% were prescribed aspirin and 37% were prescribed statins at discharge. Thus, simply increasing the use of the combination to the current level of aspirin use in secondary prevention would avoid tens of thousands of premature deaths in the US each year.
In primary prevention, aspirin is recommended for all apparently healthy individuals whose 10-year risks of a CHD event are greater than 6% to 10%. Recent revisions of the National Cholesterol Education Program (NCEP) III guidelines suggest that such patients should have an LDL goal of less than 100. This could include about 50% of the adult US population. Thus, wider utilization of aspirin and statins in primary prevention would avoid many first MIs and premature deaths.