Long‐Term Follow‐Up of Moderately Hypercholesterolemic Hypertensive Patients Following Randomization to Pravastatin vs Usual Care: The Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT‐LLT)

Abstract

A randomized, controlled, multicenter trial assigned well-controlled hypertensive participants ≥55 years, with moderate hypercholesterolemia to receive pravastatin (n=5170) or usual care (n=5185) for 4-8 years, when trial therapy was discontinued. Passive surveillance using national databases to ascertain deaths and hospitalizations continued for total follow-up of 8-13 years to assess whether mortality and morbidity differences persisted or new differences developed. During the post-trial period, fatal and nonfatal outcomes were available for 98% and 64% of participants, respectively. Primary outcome was all-cause mortality; secondary outcomes included cardiovascular mortality, coronary heart disease (CHD), stroke, heart failure, cardiovascular disease, and end-stage renal disease. No significant differences appeared in mortality for pravastatin versus usual care (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89-1.03), or other secondary outcomes. Similar to the previously reported in-trial result, there was a significant treatment effect for CHD in Blacks (HR, 0.79; 95% CI, 0.64-0.98). However, the in-trial result showing a significant treatment by race effect did not remain significant over the entire follow-up (P=.08). These findings are consistent with evidence from other large trials that show statins prevent CHD and add evidence that they are effective for CHD prevention in Blacks.

Interpretation of the evidence for the efficacy and safety of statin therapy

“…the higher rate of myopathy with simvastatin 80 mg daily than with 20-40 mg daily 78 ). Combination of precise information about the treatment that is received during a specific period in a randomized trial and prolonged follow-up of outcomes after the trial has ended (perhaps through linkage to electronic health records 96 ) may also allow the reliable assessment of the later effects of the treatment (as has been done for statin therapy [97][98][99][100][101][102][103][104] ) while still avoiding the potential biases that are inherent in observational studies.…”

“…For example, 5 years of treatment with a statin regimen that lowers LDL cholesterol by 2 mmol/L would be expected to prevent major vascular events in about 1000 (10%) higher-risk patients per 10,000 treated and in about 500 (5%) lower-risk patients per 10,000 treated ( Figure 5; which also provides estimates of the absolute benefits with 1.5 and 1.0 mmol/L LDL-reductions ). 32 The continued follow-up of patients beyond the end of the trials has found that the benefits of statin therapy persist [97][98][99][100][101][102] (and may even become larger 96,103,104 ) for many years after the differences in statin use between the randomized groups have ceased. However, of more relevance for a treatment that is intended to be continued life-long once it has been started, the meta-analyses show that statin therapy reduces the risk of major vascular events during each year that it is continued (Figure 4).…”

“…Some of these trials have extended follow-up for up to 15 years beyond the scheduled study treatment period (after which the use of statin treatment in the randomized groups was similar), with no evidence that any effects on non-vascular mortality or on incident cancer were emerging subsequently. [96][97][98][99][100][101][102][103] All-cause mortality was reduced by statin therapy in both secondary and primary prevention settings 32 in the CTT meta-analyses of the randomized trials. However, separate assessments of the effects of statin therapy on vascular mortality and on non-vascular mortality (supplemented by analyses of more specific causes of death and of the even more definite effects on related non-fatal outcomes 3 ) are likely to be more sensitive to the beneficial effects, and the absence of adverse effects, of statin therapy on mortality than are analyses of the composite outcome of death from all causes combined (i.e.…”

Comparison of the efficacy and safety of intensive-dose and standard-dose statin treatment for stroke prevention

“…Almost no trials were described the allocation method. Most trials reported that the outcome assessment was blinded; only 2 studies [8,20] were considered high risk in this category. Almost all the endpoints were reported in most of the selected trials; thus, we considered the studies with incomplete outcome data to have an unclear or low risk of incidence bias; for other reasons, the risk of bias was characterized as high.…”

“…3B). The analysis of standard-dose statin treatment [12,20,22–29] compared with placebo showed moderate heterogeneity in the effect estimates ( P = 0.01; I 2 = 58%). Because there were 3 trials on renal transplant recipients or patients undergoing regular hemodialysis, a subgroup analysis of patients in these trials [22,24,29] was conducted using the random-effects model.…”