Pharmacotherapy of severe hypertension in pregnancy
In a parallel group, open label, three arm randomised controlled trial involving pregnant women >28 weeks of gestation and severe hypertension, 894 women were randomised: 298 (33%) to receive nifedipine, 295 (33%) to receive labetalol, and 301 (33%) women to receive methyldopa. The primary outcome was BP control (defined as SBP 120–150 mm Hg, DBP 70–100 mm Hg) within 6 h without adverse effects ( hypotension, fetal distress, caesarean section for fetal distress up to 2 h after the end of the study period, severe headache, severe headache requiring discontinuation of drug, or eclampsia).
Primary outcome was significantly more common in women in the nifedipine group than in those in the methyldopa group (249 [84%] women vs 230 [76%] women; p=0·03). However, the primary outcome did not differ between the nifedipine and labetalol groups (249 [84%] women vs 228 [77%] women; p=0·05) or the labetalol and methyldopa groups (p=0·80). However a higher incidence of NICU admissions was noted in nifedipine group: nifedipine versus labetalol (p=0·009) and methyldopa (p=0·004). Authors conclude about near equivalence of the three commonly used oral drugs to control BP in this setting, these findings are reassuring especially when there is an acute (artificial) shortage of methyldopa across the country. Moreover, labetalol is manifolds costly than other 2 drugs, results should comfort physicians and gynecologists working in resource poor settings.
Trial was completed at 2 public hospitals in India (you just need to look more carefully to locate 3 of the 9 authors there from here!), and participants and healthcare workers must be congratulated for their work. Several important points should not be missed however. First, they could enrol only a third of the screened patients, largely excluding mothers who were at the highest risk of complications, we should be cautious before extrapolating results to such patients. Second, higher rates of NICU admissions in nifedipine group (although they were mainly for low birth weight, given the acute BP drop with this drug and higher incidence of maternal tachycardia, this needs further evaluation). Third, significant differences were noted with regards to severity of illness in the 2 centres. One of the centers being a maternity hospital, whether the lower systolic BP at enrollment, higher gestational age, lesser need of iv MgSO4, lower incidence of abnormal renal, hepatic and coagulation profiles, at this center reflected better antenatal care and monitoring or simply cared for less sick women? Finally, elevated BP is only one of the features of the multisystem involvement in this disease, and ultimately the multidisciplinary protocolised care would have far greater impact on maternal outcomes than achievement of goal BP; this precisely happened here, maternal outcomes were better than expected in trial participants (no maternal deaths, adverse CNS outcomes, maternal admissions for critical care, or need for dialysis and <1% incidence of eclampsia despite use of magnesium sulphate in 12% of women).
What should be the first line antihypertensive drug?
Hypertension has almost reached epidemic proportions and is second only to ‘being alive’ as a CV risk factor. All credit to our changing lifestyle and ACC/AHA guidelines-about 103 million adults are affected in USA alone. When you get to see a new hypertensive adult, what is the best first choice antihypertensive agent? Guidelines recommend multiple first-line drug classes: thiazide, ACEis, ARBs, CCBs and rarely beta blockers.
ACEi/ARBs are the most commonly chosen (63%), followed by thiazides (17%), CCBs (~20%) as seen in a massive retrospective database analysis published in this issue of Lancet. Authors used state of art statistical methods (to study the effect of these choices on CV outcomes in 4.9 million patients who got initiated on monotherapy for HTN across 9 different databases from 4 countries. Effect estimates after propensity score matching favoured diuretics with regards to three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) favoured thiazide users: AMI (HR 0·84, 95% CI 0·75–0·95), hospitalisation for heart failure (0·83,
0·74–0·95), and stroke (0·83, 0·74–0·95) risk while on initial treatment.
What do the results mean? By choosing other drugs, are we depriving majority of the hypertensives on monotherapy of the CV benefits of diuretics ? While the huge size of the databases is a strength of this study, results can’t be considered definitive. Whatever methods we use to address confounding [confounding by indication being an obvious (table 2) and likely to be a big issue here: patients at high CV risk are much more likely to receive ACEi/ARBs], effect of residual confounding can’t be completely eliminated. Patients getting initial monotherapy are likely to be at lower risk of CV events (than those getting combinations), chance of type 1 error with huge sample size remains. Also it is difficult to comprehend how a median on treatment time of few months bring such CV benefit with thiazide use. So, while results are interesting and question the preferential use of ACEi/ARBs, they are hypothesis generating at the best and warrant head to head comparison of the first line antihypertensives. Until then, ‘How well’ is far more important in BP control than ‘with what.’
Baclofen toxicity in CKD
Importance of kidney function is most realised when it is lost. This is best understood when renally excreted drugs create havoc in patients with reduced kidney function. Any new symptom in patient with CKD therefore should alert us to check the medication list (and the box, virtually anything is available OTC here, I always ask fellows to complete examination with ‘box-check’. Some of my memorable “box check surprises” were inadvertent replacement methotrexate for Metformin and Daonil (glibenclamide) for Diamox (acetazolamide)!
Encephalopathy in patients on dialysis can be due to variety of reasons but prescription or OTC medication can be one of the common, serious and potentially life threatening reasons for this situation. In this retrospective population-based cohort study of 15 942 patients with CKD, 9707 [61%] patients started baclofen at ≥20 mg/d and 6235 [39%] at <20 mg/d). 30 day risk of hospitalisation with encephalopathy was significantly higher in high dose group: 108/9707 (1.11%) for greater than or equal to 20 mg per day and 26/6235 (0.42%) who started baclofen at less than 20 mg per day; weighted RR, 3.54 (95% CI, 2.24 to 5.59).
Baclofen is predominantly excreted unchanged by kidney, and it’s no surprise that it can produce problems in those with CKD. A nice review of its pharmacokinetics here in this teaching case. Manufacturers only suggest caution while using this drug in CKD and don’t recommend any specific dose adjustment. Results of this study provide a rationale for reduction in the dose if its used. Also it is wise to ask oneself (or patient’s primary care doctor), whether baclofen is needed in the first place.
Angiotensin Receptor Blocker use and suicide
‘Marriage is strongly associated with happiness’ one group of social scientist concluded, only to realise latter that results were confounded by the fact that happy people are more likely to get married. Interested folks can check this.
I recalled this after reading this nested case control study that associates ARB use with risk of suicide. Compared with ACEI exposure, ARB exposure was associated with higher risk of death by suicide (adjusted odds ratio, 1.63; 95% CI, 1.33-2.00). Although findings were consistent in a sensitivity analysis excluding individuals with a history of self-harm, several characteristics of ARB users like higher comorbidity burden, higher prevalence of psychiatric disorders, higher antidepressant use and higher likelihood of prior self harm suggest that result may be due to residual confounding .