In one of the seminal studies on risk factor modification – the Multiple Risk Factor Intervention Trial (MRFIT) – more than 350,000 patients were screened and nearly 13,000 enrolled to look at the impact that multifactor intervention would have on mortality from coronary heart disease (CHD). (1) Since then, numerous studies have analyzed MRFIT data in an effort to better understand cardiovascular risk factors, CHD treatments, and the multiple and varied interactions between risk factors and therapy.
Ten years after MRFIT was published, members of the research group returned to assess data from more than 300,000 of the men screened in an effort to ascertain the influence of specific risk factors, including blood pressure (BP), on mortality. After an average follow-up of 12 years, there had been 6,327 CHD deaths in the MRFIT screened population. (2) Both systolic (>110 mm Hg) and diastolic (>70 mm Hg) BP as well as total cholesterol (>180 mg/dl) were all strongly related to CHD mortality. The evidence clearly pointed to the need for intensive prevention efforts, particularly among individuals with multiple risk factors.
Cholesterol lowering has been the topic of some 4,000 papers in MedLine. One landmark paper was theTreating to New Targets (TNT) trial, which randomized approximately 10,000 patients with stable CHD to either atorvastatin 10 mg or 80 mg to evaluate the safety and efficacy of lowering low-density lipoprotein (LDL) cholesterol to <100 mg/dl. (3) Intensive cholesterol-lowering therapy produced a mean LDL of 77 mg/dl versus 101 mg/dl for the 10 mg dose group, although the latter was still lower than that seen in many other placebo-controlled, secondary prevention statin trials. Overall, high-dose statin therapy led to a 22% relative risk reduction in major cardiovascular events (p < 0.001).
Professor John B. Kostis, UMDNJ-Robert Wood Johnson Medical School,New Brunswick, New Jersey (USA), and colleagues sought to determine whether the benefits of high-dose statin therapy remained when analyzed together with patient blood pressure levels. They conducted a post hoc analysis on 9,739 TNT patients who had both baseline and 3 month measurements of SBP and LDL. At 3 months, these patients – all of whom had stable CHD – were stratified according to SBP (<140 mm Hg or >140 mm Hg) and tertiles of LDL (<73, 74-94, or >95 mg/dl). (4)
Those with higher SBP were slightly older, which might account for the fact that the hypertensive group was more likely to have a medical history of diabetes, cerebrovascular accidents, and peripheral vascular disease than normotensive participants. Those with elevated SBP were less likely to smoke or have a history of myocardial infarction (MI).
The primary endpoint was first occurrence of a major cardiovascular event, including CHD death; nonfatal, non-procedure-related MIs, or resuscitated cardiac arrest; or fatal or nonfatal stroke. At a median follow-up of 4.9 years, the rate of major cardiovascular events was lowest in those patients with the lowest levels of LDL and SBP http://www.eshonline.org/education/congresses/2008/esh/a. This represented a 42% relative risk reduction compared to those in the highest LDL tertile with an SBP of 140 mm Hg or higher.
Similar relationships were seen in regard to CHD death, nonfatal MI, and stroke, with varying levels of significance. The effect of lower SBP on stroke was most pronounced in the lowest LDL tertile.
In summary, for major cardiovascular events, the benefit of LDL cholesterol lowering was observed in patients with or without hypertension. Overall, in terms of the primary endpoint, the benefit was most pronounced in the lowest LDL tertile among patients with an SBP <140 mm Hg. The investigators did not detect a significant statistical interaction between LDL and SBP. However, Dr. Kostis noted, on multivariate analysis SBP was predictive of additional significant benefit (p = 0.0142) independent of the benefit of lower on-treatment LDL.
The bottom line: “Intensive management of both LDL cholesterol and blood pressure is important in patients with stable CHD to reduce their overall risk of major cardiovascular events,” said Dr. Kostis.
- [No authors listed] Multiple risk factor intervention trial. Risk factor changes and mortality results. Multiple Risk Factor Intervention Trial Research Group. JAMA. 1982;248:1465-77.
- Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med. 1992;152:56-64.
- LaRosa JC, Grundy SM, Waters DD; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-35.
- Kostis JB, Breazna A, Deedwania PC, LaRosa JC; Treating to New Targets Steering Committee and Investigators. The benefits of intensive lipid lowering in patients with stable coronary heart disease with normal or high systolic blood pressure: an analysis of the Treating to New Targets (TNT) study. J Clin Hypertens (Greenwich). 2008;10:367-76.