Primary Care Corner with Geoffrey Modest MD: Statin Primary Prevention in Intermediate Risk Patients

Posted on by

By Dr. Geoffrey Modest

2 articles were in the NEJM this week from the HOPE-3 study presented at the Am Heart Assn meetings, looking at lipid and blood pressure lowering in people at “intermediate-risk” (see DOI: 10.1056/NEJMoa1600176 ). This blog will review the cholesterol one (the hypertension one will be reviewed Tuesday). Study funded by Canadian Institute of Health Research and a drug company. Details for the lipid arm of the study (this was a 2×2 factorial design with the hypertension arm):

  • 12,705 people in 21 countries/6 continents (eligibility criteria: men ≥​ 55 yo/women ≥​ 65, with at least one of: elevated waist-to-hip ratio, history of low HDL, current or recent smoking, dysglycemia, family history of premature CVD, mild renal dysfunction; also women ≥​​60 yo with 2 or more of these criteria), all without baseline cardiovascular disease (CVD) and at intermediate CVD risk (defined at annual risk of approx 1% per the INTERHEART risk score, a score from 0-49, where the low-risk group had a score ≤ 9), then randomized to rosuvastatin 10 vs placebo.
  • Median age 66, 87% with elevated waist-to-hip ratio, mean BMI 27, 27% current/recent smokers, 6% diabetes,mean HDL 44.7 mg/dl, LDL 127.8, triglycerides 128.8, hs-CRP 2.0, INTERHEART risk score of 14.5, 29% Chinese/27% Hispanic/20% White/15% South Asian/2% Black
  • Initial 4 week run-in period where people got both rosuvastatin and the BP med (candasartan/HCTZ) to make sure they were tolerated. the most common adverse effect was hypotension in 2%
  • First coprimary outcome: composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke; second coprimary outcome: the first one plus revascularization, heart failure, and resuscitated cardiac arrest
  • Followup 5.6 years
  • Results:
    • Rosuvastatin lowered LDL by 26.5% (35 mg/dl), triglyceride by 21.2 mg/dl, and hs-CRP by 0.19 mg/L. overall med adherence was 77.3% by the end of the study (74.8% in the placebo group)
    • Rosuvastatin (vs placebo) resulted in:
      • First coprimary outcome: in 235 people (3.7%) vs 304 (4.8%), a 24% reduction [HR 0.76 (0.64-0.91, p=0.002)], NNT (number-needed-to-treat) to prevent a first coprimary outcome was 91
      • Second coprimary outcome: in 277 people (4.4%) vs 363 (5.7%), a 25% reduction [HR 0.75 (0.64-0.88, p<0.001)]​, NNT was 73 for the second coprimary outcome​
      • In terms of the actual outcomes: statistically significant decrease in MI (35%), stroke (30%), revascularization (32%), hospitalizations for cardiovasc reasons (25%)
    • The above results were consistent in subgroups of baseline cardiovascular risk, lipid level, C-reactive protein level, blood pressure, race/ethnicity (though, interestingly, the subgroups doing better included those the lowest cardiac risk score, the lowest initial LDL of <112.3/mean of 89.1, the lowest SBP of ≤​131.5/mean of 122.2; and men and those of European descent)
    • The curves began to separate after 1 year and continued to splay apart for both outcomes. Also, there was pretty much no difference in the group on just rosuvastatin and those on double therapy with candesartan/HCTZ)
    • No excess diabetes or cancer with rosuvastatin, but increased cataract surgery (3.8% vs 3.1%, p=0.02) and myalgias with CK rise >10 ULN (5.8% vs 4.7%, p=0.005) — though no difference in number of people who discontinued the rosuvastatin from myalgias. And fewer people on rosuvastatin had a DVT or PE (14 vs 31, p=0.01) [FYI, this has been found in many of the statin trials]. Overall the rate of med discontinuation for adverse events was somewhat higher in the placebo group….

So, this trial addresses primary prevention in a less high-risk group than previous studies, which had been largely done in North American and Europe in white people. A few points:

  • Internationally, CVD is associated with 18 million deaths/yr and an equal number of nonfatal cardiovasc events. 80% of the global burden is in low- and middle-income countries
  • High LDL levels provide a population-attributable risk of about 50%, and this risk is graded with no documented threshold
  • There was no attempt to achieve a target lipid level, though of note, most people had “normal” LDLs
  • The degree of CVD reduction was consistent with the degree of LDL reduction found in previous statin trials (approx 25% decrease in CVD per 1 mmol/L, or about 40 mg/dl, decrease in LDL)
  • The low level of adverse events supports the approach of just giving the med and not doing lots of blood tests afterward (which makes this approach even more useful in resource-poor countries). And cheaper generic statins are readily available in most areas
  • This trial does extend the results for statin treatment in primary CVD prevention to include even those at intermediate CVD risk as well as to those from an array of different ethnic backgrounds. [The placebo group had a 5.0% incidence of CVD events over 5.6 years, confirming this was a truly intermediate group]

So, how should this affect our practice?? There are several points that would support a more aggressive approach to lipid control, despite the fact that over 5.6 years, the absolute benefit was not so dramatic (73 people treated to prevent only one event):

  • These were relatively low risk patients, with the placebo group having only having CVD events at a rate of about 1%/yr, so not so surprising that one would need a longer trial to see more potential clinical efficacy
  • ​On subgroup analysis, those who seemed to benefit the most were those at even lower risk: those with the lowest LDL, the lowest blood pressure, the lowest INTERHEART risk score; so, one might project the most benefit in those with an even lower than 1%/yr CVD risk, requiring an even longer study
  • And, overall the curves, to me, look like they are showing increasing benefit of statins over time, especially in the last 1-2 years of the study (and this is despite decreasing medication adherence and increasing LDL levels)
  • From my perspective, I think this really reinforces the importance of the primary role of lifestyle changes:
    • Overall these participants were overweight
    • Mean LDL was 128 (which maybe really isn’t “normal”, since in non-Western populations without significant heart disease, they have much lower LDLs, with total cholesterol levels of about 130)
    • Mean blood pressures was 138/82 (more on this in the next blog) and this is not “normal” (in fact, the majority of blood-pressure-attributable-mortality occurs in this range, mostly because this is actually elevated and is much more common/disproportionately represented in the population overall)
    • 27% were current or recent smokers
  • Therefore, I strongly feel that our primary role in health care is prevention; these risk factors should be addressed aggressively by us in primary care and there should be broad-based public health initiatives to promote a healthy lifestyle. And that we not be complacent about mild elevations in the LDL or blood pressure, even though our guidelines suggest “no treatment”. This is reinforced by our sense of the “new normal” when we see so many patients with really high blood pressures and cholesterol levels. And, I certainly include myself in this category. It is hard for me to get excited about someone with a blood pressure of 135/85 or an LDL of 125 when I see so many patients with 190/120 and 220, respectively. But this study reinforces how important it is to focus on this very large group with somewhat high risk.
  • But, that being said, I think this study also reinforces that we should really be somewhat more aggressive medically in treating people at intermediate risk
(Visited 3 times, 1 visits today)