Sustained CV benefits of statin treatment after discontinuation
Lowering cholesterol, blood pressure, or both to prevent cardiovascular events: results of 8.7 years of follow-up of Heart Outcomes Evaluation Prevention (HOPE)-3 study participants
Introduction and methods
The Heart Outcomes Evaluation Prevention (HOPE)-3 study investigated whether LDL-c reduction or BP reduction, either alone or in combination, reduced CV events in participants without a history of CVD [1-3]. The study enrolled men aged ≥55 years and women aged ≥65 years with one CV risk factor (elevated waist-to-hip ratio, current smoking, impaired fasting glucose, impaired glucose tolerance, diabetes requiring only diet control, eGFR 45-60 mL/min/1.73m², or a family history with premature CVD in first-degree relatives). Women aged between 60-65 years were enrolled when they had 2 risk factors. A total of 12 705 participants were randomized to receive rosuvastatin 10 mg daily or placebo and candesartan 16 mg daily plus hydrochlorothiazide 12.5 mg daily or placebo.
After an active treatment period of 5.6 years, it was found that rosuvastatin reduced MACE by 24%, compared to placebo. Treatment with candesartan plus hydrochlorothiazide led to a reduction in SBP of 6 mmHg. However, this treatment did not reduce MACE in the overall trial population. Only in those in the upper third of baseline BP, a significant reduction in MACE was observed with candesartan plus hydrochlorothiazide, compared to placebo. To study possible longer-term effects of treatments, participants were asked after the active intervention phase of the study of 5.6 years to enroll in the passive extended follow-up of 3.1 further years in which they no longer received study drug. 9326 participants consented to participate in the passive follow-up. The aims of this passive extended follow-up were to determine whether 1) the benefits observed during the active phase with rosuvastatin were sustained, enhanced, or attenuated during the passive phase and 2) delayed benefits would emerge in those receiving candesartan plus hydrochlorothiazide during the active phase compared with placebo.
The two co-primary outcomes in both the active and extended passive phase were MACE-1 (MI, stroke or CV death) and MACE-2 (MACE-1 plus resuscitated cardiac arrest, HF, or coronary revascularization). A secondary endpoint was MACE-2 plus angina, and coronary ischemic events were analyzed in a post hoc analysis. Median length of total follow-up (active treatment period plus post-trial passive observation period) was 8.7 years (IQR 8.1-9.3 years).
- Patients originally randomized to rosuvastatin had a 20% reduction in MACE-1 during the passive follow-up period of 3.1 years, compared to placebo (HR 0.80, 95%CI 0.64-0.99, P=0.042). A similar trend, although not significant, was seen for MACE-2 (HR 0.83, 95%CI 0.68-1.01, P=0.065). Patients originally randomized to rosuvastatin compared to those originally randomized to placebo also had a reduction in MACE-2 plus angina (HR 0.81, 95%CI 0.67-0.99, P=0.043) and in coronary ischemic events (HR 0.54, 95%CI 0.34-0.86, P=0.01) during the passive follow-up period of 3.1 years.
- There was no significant difference in any of the outcomes during the passive follow-up period of 3.1 years between patients originally randomized to BP lowering compared to placebo.
- There was a significant reduction in coronary ischemic events in those originally randomized to the combination of rosuvastatin and BP lowering compared to those originally randomized to double placebo during the passive follow-up period of 3.1 years (HR 0.46, 95%CI 0.24-0.89, P=0.02). There were no significant differences in MACE-1, MACE-2 and MACE-2 plus angina during the passive follow-up period of 3.1 years between participants originally randomized to combination of rosuvastatin and BP lowering compared to those originally randomized to double placebo.
- During the total follow-up period of 8.7 years (5.6 years of active intervention plus 3.1 years of passive follow-up), patients originally randomized to rosuvastatin compared to placebo had a reduction in MACE-1 (HR 0.79, 95%CI 0.69-0.90, P=0.0005), MACE-2 (HR 0.79, 95%CI 0.69-0.89, P=0.0002), MACE-2 plus angina (HR 0.79, 95%CI 0.70-0.89, P=0.0002) and coronary ischemic events (HR 0.72, 95%CI 0.58-0.90, P=0.003).
- During the total follow-up period of 8.7 years, patients originally randomized to BP lowering compared to placebo did not have a significant reduction in any of the primary and secondary outcomes.
- Patients originally randomized to the combination of rosuvastatin and BP lowering compared to those originally randomized to double placebo during total follow-up period of 8.7 years had a reduction in MACE-1 (HR 0.76, 95%CI 0.63-0.92, P=0.006), MACE-2 (HR 0.77, 95%CI 0.65-0.92, P=0.005), MACE-2 plus angina (HR 0.77, 95%CI 0.65-0.92, P=0.003), and coronary ischemic events (HR 0.63, 95%CI 0.46-0.86, P=0.004).
- After total follow-up of 8.7 years, the benefits of treatment with rosuvastatin were consistent across pre-specified subgroups regardless of sex, age, baseline LDL-c level, CV risk, and ethnicity. Blood pressure lowering only led to reduction in MACE-1 in participants in the highest tertile of baseline systolic BP (>143 mmHg) during 8.7 years of follow-up (HR 0.76, 95%CI 0.62-0.94), compared to placebo. For the combination therapy compared with double placebo, those in the highest tertile of baseline BP had a 24% risk reduction during 8.7 years of follow-up (HR 0.76, 95%CI 0.62-0.96).
The results of this study suggest that the CV benefits of treatment with rosuvastatin for a median of 5.6 years, compared with placebo, are sustained or enhanced for at least 3 years after stopping therapy in individuals without CVD but at intermediate risk for CV events. Similar results were observed for BP-lowering treatment in individuals with elevated systolic BP (>143 mmHg), but not for those with lower systolic BP.
The authors noted: ‘our data should not be interpreted that statins should be discontinued after 5 or 6 years of treatment, but instead indicate that sustained and enhanced benefits occur even after stopping statin therapy.’