Author + information
- Melvin D. Lobo, MBChB, PhD∗ ()
- Barts BP Centre of Excellence, Barts Heart Centre, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, United Kingdom; and the William Harvey Research Institute, Barts National Institute for Health Research Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, United Kingdom
- ↵∗Reprint requests and correspondence:
Dr. Melvin D. Lobo, William Harvey Heart Centre, Centre for Clinical Pharmacology, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom.
The close of 2015 has seen the publication of 2 landmark trials of pharmacotherapy for hypertension (SPRINT [Systolic Blood Pressure Intervention Trial] and PATHWAY-2 [Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension]) that have justly received a great deal of attention in the medical and lay press and are likely to affect future clinical guidelines. However, what do these studies mean for the practicing clinician, and how should we use these data to help our patients in the present?
The SPRINT Trial
Debate over appropriate targets for blood pressure (BP) control in clinical trials has been raging for a long time now. Although it is accepted that with increasing age, systolic blood pressure (SBP) becomes the more important arbiter of risk, few trials have actually managed to achieve their target office SBP levels, and there has been historical concern over a (biologically plausible) “J curve” effect whereby BP reduction to lower levels would lead to greater harm than benefit (1). The SPRINT (Systolic Blood Pressure Intervention Trial) investigators are therefore to be lauded for their immense efforts in undertaking a large, rigorously designed, randomized controlled study of intensive versus standard BP control (2) and actually achieving early reduction to a mean SBP of 121.4 mm Hg in the former group and 136.2 mm Hg in the latter group, which was sustained at similar levels throughout the 3.26 years of follow-up. The trial was terminated prematurely due to a significantly lower rate of the primary composite outcome (myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes) in the intensive-treatment group versus the standard-treatment group (1.65%/year vs. 2.19%/year; p < 0.001), representing a 25% reduction in relative risk of the primary outcome. Although this may not translate into a large reduction in absolute risk (3), the numbers needed to treat are compelling given the modest cost of antihypertensive therapy globally: 61, 90, and 172 to prevent a primary outcome event, death from any cause, and death from cardiovascular causes, respectively, during the trial follow-up.
There was, however, a significant price to pay for the beneficial reduction in primary and secondary outcomes in the trial. Although there was no difference between the groups in the composite renal outcome (first occurrence of halving of estimated glomerular filtration rate, dialysis, or renal transplantation) in participants with prior chronic kidney disease, in those patients without chronic kidney disease at baseline, there was a more than 3-fold increase in renal impairment (≥30% reduction in estimated glomerular filtration rate to <60 ml/min/1.73 m2) in the intensive-treatment group, confirmed by repeat laboratory testing at 3 months. This is of great concern, and the investigators rightly noted that “the possibility of long term adverse renal outcomes cannot be excluded” (2). More importantly, if the findings from SPRINT are to be extended to the wider hypertensive population, what level of scrutiny will be required and is actually deliverable in the clinical setting to ensure the renal safety of patients with an intensive drug regimen aimed at attaining an SBP target of 120 mm Hg? Additional safety concerns include an overall occurrence of serious adverse events in both groups in excess of 37% and a substantial and highly significant increase in serious adverse events possibly or definitely related to the intervention (intensive-treatment group vs. standard-treatment group: relative risk increase of 88%; p < 0.001). Although the investigators note that the magnitude and pattern of differences in adverse events were similar according to treatment assignment in patients over the age of 75 years compared with the overall cohort, this masks some worrying data (Table S6 of SPRINT's Online Appendix ). In participants age >75 years, there was a high incidence of injurious falls resulting in emergency department attendance or hospitalization in both the intensive-treatment group (12.0%) and the standard-treatment group (14.6%) that may have been explained by a 21% incidence of orthostatic hypotension in both groups. Such findings would mandate great caution in extending the SPRINT study results to an older hypertensive population.
The SPRINT trialists correctly comment on the limited generalizability of their findings as patients with diabetes, those with prior stroke, and those age <50 years were not included. Indeed, a recent assessment of the National Health and Nutrition Examination Survey database has determined that only 1 in 6 U.S. adults with treated hypertension meets the eligibility criteria for SPRINT (4). Moreover, clinicians already struggle to manage resistant hypertension with multidrug regimens in patients with resistant hypertension (where the stakes are much higher), and recent evidence indicates that >40% of newly diagnosed hypertensive patients discontinue first-line antihypertensives within 1 year of initial prescription (5) (Figure 1). What hope is there for us to convince patients with mild hypertension (<140/80 mm Hg at baseline in SPRINT) to take 3 antihypertensive drugs for the duration of their lifetime to achieve lower SBP targets?
The PATHWAY-2 Study
For some time now, it has been suggested, but not mandated in international guidelines, that spironolactone be used as a fourth-line therapy for resistant hypertension because of a lack of randomized controlled trial data comparing spironolactone to other antihypertensives. The PATHWAY-2 (Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension) investigators are therefore to be congratulated for finally proving, in a double-blind, placebo-controlled crossover trial, that spironolactone is quite clearly the most effective fourth-line antihypertensive drug compared with doxazosin and bisoprolol in patients with resistant hypertension and carefully confirmed adherence to their 3 antihypertensive drug regimen (6). The basis of the study, that resistant hypertension is largely due to sodium retention, alerts us to an important aspect of hypertension epidemiology. Sodium consumption in the established market economies (and increasingly the emerging economies) is far in excess of physiological requirements and is a major cause of hypertension and consequently resistant hypertension. Furthermore, sodium restriction in patients with resistant hypertension has been clearly demonstrated to lead to substantial and sustained BP reduction (7). In PATHWAY-2, patients were demonstrated to have a 24-h urine sodium excretion of 137.1 mmol, equivalent to a daily sodium intake in excess of 3,000 mg, although current guidance from the World Health Organization is for the general population to reduce sodium intake to <2,000 mg daily and from the American Heart Association is to reduce to <1,500 mg daily, which would be a reasonable target for patients with resistant hypertension. Suboptimal management of life-style was typical of patients recruited into this study, with a mean weight of 93.5 kg and insufficient consumption of fruit and vegetables, as indicated by the lower than desirable 24-h urinary potassium output.
The PATHWAY-2 investigators claim that underuse of diuretic therapy for hypertension may be in part responsible for the high prevalence of resistant hypertension, and their rather overstated conclusion that “truly resistant hypertension can now be considered rare” somewhat disregards patient preferences and merits further consideration. An important reason for underuse of diuretic agents is their side effect profile (including inconvenient diuresis, gastrointestinal upset, and erectile dysfunction), which for many patients is quite understandably unacceptable. In addition, it has been clearly demonstrated in real-world studies that diuretic agents are the most likely class of drug to be discontinued in patients with hypertension as compared with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium-channel blockers (8). Furthermore, of all diuretic agents, spironolactone is the most poorly tolerated, and persistence with spironolactone, even at low doses, is lower than with all other drug classes in studies of both heart failure and hypertensive patients, leading to discontinuation rates of around 70% (9,10). It is remarkable, therefore, to observe that noncompletion of therapy with spironolactone in PATHWAY-2 occurred at a similar rate to placebo. This may reflect a short duration of therapy (12 weeks), Hawthorne effect, or both. However, it is widely acknowledged that side effects of spironolactone are common and are a major cause of nonadherence other than adverse effects such as renal impairment and hyperkalemia leading to cessation (11). An alternative option for the PATHWAY-2 investigators would have been to consider the more recently developed mineralocorticoid receptor antagonist eplerenone, which lacks the estrogen receptor partial agonist and androgen receptor antagonist effects of spironolactone, although this is a more costly option.
There is no escaping the fact that SPRINT and PATHWAY-2 provide us with substantial and key data to inform hypertension management of the future. However, randomized clinical trials of this nature represent an idealized form of drug and patient evaluation: the inevitable selection bias ensures recruitment of a subset of patients whose subsequent altered behaviors in an environment of peerless medical surveillance cannot realistically be sustained (and not at appreciable scale) in the clinical realm. To better serve our patients, much greater emphasis in hypertension management needs to be placed on the fundamentals and, in particular, meticulous input into all aspects of lifestyle modification. Furthermore, hypertension specialists need to devote far more attention to determining the reasons why patients do not adhere to their medications and focus on preventing failure of persistence with drug regimens. The increasing trend for use of serum/urine assays of drugs or their metabolites to prove nonadherence is not the answer here—there is no point closing the stable door after the horse has bolted.
Dr. Lobo has received honoraria from Medtronic, St. Jude Medical, ROX Medical, and Cardiosonic; and his research is supported by the Barts Charity.
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