HIV infection: pitavastatin dec cardiac events

the recent REPRIEVE trial found that the use of the new statin pitavastatin was very effective in decreasing cardiovascular events in those with controlled HIV infection and otherwise very low cardiovasc risk, as well as documenting its safety (see hiv pitavastatin dec cardiovasc dz NEJM2023 in dropbox, orDOI: 10.1056/NEJMoa2304146)

 

Details:

-- 7769 patients aged 40 to 75 and with HIV infection on a stable antiretroviral therapy and a low-to-moderate risk of cardiovascular disease based on the 2013 AHA/ACC risk calculator were randomized to pitavastatin 4mg versus placebo

-- median age 50, 65% nonwhite, 31% women; international study with 53% from high-income countries, 18% from Latin America/Caribbean, 15% sub-Saharan Africa, rest from Southeast/East/South Asia

-- median CD4 count was 621 and the HIV viral load was below quantification (<20 copies/mL) in 88% of the participants and <400 in  98% (no comment on the HIV meds used)

-- median screening LDL was 108 mg/dL (interquartile range 87 to 128); median 10-year atherosclerotic cardiovascular disease risk was 4.5% (low risk defined as <5%)  [ie these were really low risk individuals from a cardiovascular event]

 

-- primary outcome: the occurrence of major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, TIA, peripheral arterial disease, revascularization, or death from undetermined cause

-- key secondary outcomes included individual components of the primary outcome, as well as death from any cause, LDL and non-HDL cholesterol levels; also assessing targeted safety events (including incident diabetes mellitus, liver injury, myalgia/muscle weakness, or treatment-limiting disability)

 

-- This trial was designed for 8 years but was stopped early at 5.1 years because of clear efficacy of the pitavastatin (rather unusually, there was no comment in this paper about the anticipated length of the study; I could only find it on an internet search)

 

Results:

-- LDL decreased from a median of 107 to 74 mg/dL in the pitavastatin group, and 106 to 105 mg/dL in the placebo group, and non-HDL decreased from 133 to 97 mg/dL without change in the placebo group

    -- the effects of pitavastatin on LDL and non-HDL were durable throughout the follow-up.

-- major adverse cardiovascular events:

    -- 4.81 per 1000 person-years in those on pitavastatin, versus 7.32 per 1000 person-years in the placebo group

        -- 35% decrease with medication, HR 0.65 (0.48-0.90), p=0.002

-- this all translates into a number needed to treat (NNT) of 106 patients (64-303) for five years with pitavastatin [this NNT is in the same range as for treating hypertension]

    -- and, the NNT for patients at higher cardiovascular risk at baseline would be significantly less than 106

-- individual components of MACE (the most common ones being cardiac ischemia and stroke or TIA):

    -- first cardiac ischemia or myocardial infarction (80% were type 1): 1.40 per 1000 person-years in pitavastatin and 2.51 in placebo, HR 0.56 (0.34-0.90), a 44% decrease

    -- none of the other individual components were statistically significant, though all showed a trend to superiority with pitavastatin (though many of these other outcomes were uncommon, making statistical significance more difficult to achieve)

-- no real difference in results in per-protocol analysis

-- no real difference in outcomes for women versus men

-- efficacy of pitavastatin was independent of the global location of the study, and in both low-income and high-income countries

 

-- Here’s the graph over time to the first major adverse cardiovascular event, finding that the curves diverged at about the 12-month mark and continued to splay apart:

 

-- Adverse effects:

 -- no difference in total number of nonfatal serious adverse events, 695 on pitavastatin and 694 on placebo

     -- muscle-related symptoms: 91 participants (2.3%) taking pitavastatin and 53 (1.4%) on placebo, incidence rate ratio IRR 1.74 (1.24-2.45)

        -- muscle-related symptoms led to withdrawal in 44 participants on pitavastatin (1.1%) versus 21 (0.5%) on placebo

    -- diabetes occurred in 206 participants (5.3%) taking pitavastatin versus 155 (4.0%) on placebo, IRR 1.35 (1.09-1.66)

    -- no significant difference in clinically important rhabdomyolysis, or increased ALT levels

    -- trial discontinuation rates were below the predetermined thresholds

  

Commentary:

-- it is well documented that the risk of cardiovascular disease is increased in patients with HIV infection, even if well-controlled: the risk in prior studies suggests that HIV confers twice the risk, likely because of residual inflammation and immune activation/dysfunction, and this seems to be true after controlling for traditional cardiovasc risk factors

    -- however, effective antiretroviral therapy does decrease the cardiovascular risk, but incompletely

-- this was a drug company sponsored study. the paper comments that pitavastatin was chosen as the statin because of its lack of interaction with HIV medications. However, there really are several other statins that also did not interact, eg  neither atorvastatin nor rosuvastatin interact with Biktarvy or Dovato (though best to do a drug interaction check on https://www.hiv-druginteractions.org/ ). So, I suspect the reason for choosing pitavastatin was a tad self-serving by the drug company…

 

-- this trial found that there was a major reduction of clinical cardiovascular events in a group of people with a quite low 10-year calculated atherosclerotic risk, in younger patients, and those with a low baseline LDL level.

    -- The level of cardiovascular protection found in this study was more than what was predicted by the change in LDL levels alone, as anticipated from other statin studies with higher initial LDL levels

        -- as is well known, statins do have an array of pleiotropic effects besides lowering LDL, including decreasing inflammation, oxidative stress, decreased platelet aggregation, decreased cardiac hypertrophy and fibrosis, improving endothelial dysfunction, decreasing thrombosis

        -- and the benefit of pitavastatin, as with other statins, is evident within 12 months

    -- the level of protection in this study was similar to that in the JUPITER study (https://www.nejm.org/doi/full/10.1056/NEJMoa0807646 ), which similarly enrolled people with baseline lower LDL levels (median 108) but in that study with  inflammation as measured by CRP levels (high-sensitivity CRP 4.1); they found that rosuvastatin 20mg was associated with 50% decreases in cardiovascular events after only 1.9 years likely reflecting the importance of statin-associated decreases in these pleiotropic effects on clinical outcomes ( anti-inflammatory effects, etc).  By the way, a Mediterranean diet also decreases inflammation, as found in several dietary studies: eg see https://www.mdpi.com/2227-9059/8/7/201 )

 

-- as per prior blogs, there are a few issues around LDL levels:

    -- LDL seems to be a surrogate marker for cardiovascular disease, with major differences between different LDL moieties that electrophoretically migrate in the LDL range: small, dense LDL particles are three times more atherogenic than the larger particles, yet both may have the same LDL level: http://gmodestmedblogs.blogspot.com/2023/05/cad-presumed-mechanism-and-apob-was.html

    -- for high-risk people, very low LDLs down to 20 mg/dL seem to confer increased benefit without harm: http://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html

  

Per a detailed review: the Cochrane collective compared pitavastatin to other statins for its effect to reduce LDL cholesterol, and pitavastatin is about 6-fold more potent than atorvastatin, 1.7-fold more potent than rosuvastatin  (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387421/pdf/CD012735.pdf ).  The benefit of pitavastatin was a bit greater in women than men (LDL decreased by 45.08 vs 39.50  mg/dL for the 4 mg pitavastatin dose).  and there were very few adverse effects leading to dropping out of studies: 3 of 262 people, vs 0 of 109 in the placebo groups (there were not enough data to assess the risk of withdrawals)

-- pitavastatin is also lipophilic (as is atorvastatin and simvastatin, but not rosuvastatin) and could have the benefit of decreasing neuroinflammation and perhaps subsequent development of dementia. But clinical studies to date have not been impressive for this anticipated result. For example, a recent systematic review found that there was a 20-30% decreased risk of dementia and of Alzheimer’s in those on statins, more so if higher statin doses, and this was independent of patient sex or the lipophilicity of the statin  (eg see statin dementia decrease EuropSocCardiol2022 in dropbox, or doi:10.1093/eurjpc/zwab208)

 

-- the association of pitavastatin and diabetes as well as myalgias has been found in many statin studies. There are, however, some questions about the real issues here: see https://gmodestmedblogs.blogspot.com/2017/11/statin-use-and-diabetes-is-that-real.html .  and the benefit of statins seems to outweigh the risks of developing diabetes anyway; the association with myalgias has been largely debunked in several studies: http://gmodestmedblogs.blogspot.com/2022/09/uspstf-recommendations-statins-in.html

 

Limitations:

-- as pointed out in many of the cardiovascular studies, the combination of multiple cardiovascular outcomes into a single composite entity is beneficial in determining statistical significance (i.e., lots of patients with this composite), though this amalgamation is not really so clinically useful: there is a large difference in the actual personal value between having a cardiovascular death or a stroke versus a revascularization or hospitalization for unstable angina (I, for one, would really prefer one of the latter outcomes...)

-- a trial that is stopped earlier than its expected endpoint does raise the issue to me of an unequal balance between benefits and risks: the benefits were clearly shown at a shorter time than the study was designed for, though longer-term risks may not be identified in that eclipsed timeframe

-- this study included people aged 40 to 75, so likely but unclear if the benefit of pitavastatin would extend to other age groups

-- it would be important to know exactly  what overall medications these participants took (some meds could increase cardiovascular disease, eg diabetics on insulin or sulfonylureas), or the HIV meds themselves (eg abacavir, which is a component of Triumeq, one the new powerful HIV meds; and protease inhibitors)

-- it is difficult to disentangle all of the potential contributors to cardiovascular risk in persons with HIV. There may well be other issues that might affect cardiovascular risk, such as stress, depression, living situations, socioeconomic status, etc, which might be higher in people with HIV

 

So,

-- this study showed an impressive reduction of cardiovascular events in patients on the new statin pitavastatin. And this occurred in younger persons and those who had quite low traditional risk for cardiovascular disease, and began after only 12 months on the med

-- recommendations for HIV patients who are at high cardiovascular risk does include using a statin; this study extends this benefit to younger patients at much lower cardiovascular risk

-- it is a reasonable assumption that other statins achieving a similar degree of LDL reduction would yield similar results; and the pleiotropic effects of pitavastatin apply to other statins

-- and, of course, primary prevention therapy for those with HIV should be similar for all patients, emphasizing nonpharmacologic management, especially diet and exercise

 

-- I personally have never prescribed pitavastatin so far because of its being a new medication (and, we have very effective older statins with known risk profiles) as well as the exorbitant cost of a new medication still on patent

    -- hopefully the prohibitive cost of pitavastatin (90 days of a 1 mg dose being over $1000) is likely to decrease at some point in the not so distant future, as its patent expires on February 2, 2024 . and it will be a useful addition to our statins, since it lowers LDL more powerfully

    -- this study, as well as the Cochrane report noted above, do allay my concerns about adverse effects of the med

 

 

geoff

-----------------------------------

If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@bidmc.harvard.edu

  

to get access to all of the blogs:

 

 go to http://gmodestmedblogs.blogspot.com/ to see the blogs in reverse chronological order

  -- click on 3 parallel lines top left, if you want to see blogs by category, then click on "labels" and choose a category​

  -- or you can just click on the magnifying glass on top right, then type in a name in the search box and get all the blogs with that name in them

 

if you would like to see the articles in this blog, please email me. 

 

please feel free to circulate this to others. also, if you send me their emails (gmodest@bidmc.harvard.edu), i can add them to the list