Achieving optimal blood pressure goals -
The Multiple Risk Factor Intervention Trial 10 identified significant associations between BP and the rate of renal dysfunction, thereby creating a presumption for a causal role for hypertension.
In that study, a strong, graded relationship was demonstrated between both systolic and diastolic BP and ESRD, independent of associations between the disease and age, race, income, use of hypoglycemic medication, history of myocardial infarction, serum cholesterol concentration, and cigarette smoking.
In short, the higher the BP, the higher the risk for renal disease. The JNC VI also states that use of angiotensin-converting enzyme ACE inhibitors, calcium channel blockers CCBs , and low-dose diuretics is preferred because of fewer adverse effects on glucose metabolism, lipid profiles, and renal function.
Increased urinary protein or albumin excretion microalbuminuria is a fundamental sign of and an independent predictor for the outcome of renal and cardiovascular disease. The Modification of Diet in Renal Disease Study 15 found that strict BP control slowed the decline in glomerular filtration rate GFR in a subgroup of patients with proteinuria, an independent risk factor for the progression of renal disease.
Based on the Modification of Diet in Renal Disease Study, patients with urinary protein levels of 0. Some antihypertensive agents confer more renoprotection than do others.
The JNC VI 11 states that low-dose diuretics have a favorable impact on type 2 diabetes mellitus. Diuretics are often preferred in patients with concomitant diabetes mellitus because of fewer adverse effects on glucose homeostasis and renal function than β-adrenergic blocking agents, another class that is recommended as first-line therapy in hypertension.
Combining a loop diuretic with a long-acting thiazide diuretic, such as metolazone or hydrochlorothiazide high dose , is effective in patients resistant to a loop diuretic alone. Treatment with ACE inhibitors can also benefit the hypertensive patient with concomitant diabetes mellitus.
A meta-analysis 16 of 41 studies showed that although all the available antihypertensive drug classes lowered BP to a greater extent than did placebo, ACE inhibitors lowered urinary protein excretion more than the other classes. A meta-analysis 17 of studies of patients with type 1 and type 2 diabetes mellitus concluded that appropriate lowering of BP by any means slowed the rate of loss of renal function.
However, only ACE inhibitors seemed to preserve GFR and decrease proteinuria independent of the BP effects. The salutary effects of ACE inhibitors may be related to their ability to dilate efferent arterioles, thereby reducing intraglomerular pressure.
The beneficial effects may also result from restoration of glomerular permselectivity in proteinuric nephropathies. Clinically, studies have shown that ACE inhibitors slow the deterioration in GFR and delay progression to ESRD.
Adrenergic receptor binders have been shown in short-term clinical studies to lower urinary protein levels in patients with renal disease. A 6-month study 24 of valsartan therapy showed a sustained reduction in BP and urinary protein levels, even in patients with advanced renal failure.
A week study 25 using losartan potassium showed that for comparable BP reductions, a greater reduction in urinary albumin levels was seen with losartan vs felodipine a CCB use in hypertensive patients with or without type 2 diabetes mellitus.
Long-term studies are needed to confirm whether these antiproteinuric effects of losartan can be deemed renoprotective. Although use of an ACE inhibitor is key in antihypertensive therapy of a diabetic patient, other drugs may also have renal benefits.
In fact, some combinations are more beneficial together than they would be if used alone. Because not all patients attain BP control with monotherapy, use of an additional antihypertensive agent may be necessary.
One reason BP is so difficult to control is because only half of all hypertensive patients respond to monotherapy. Therefore, use of 2 or more complementary agents may improve response rates because more than 1 physiologic pathway is interrupted.
Studies have underscored the need for combination therapy. The cardioprotective effect of low-dose combination therapy exceeded that of higher-dose monotherapy. Clinical trials 6 , 27 - 30 that have randomized patients to lower levels of BP require an average range of 2.
Which drugs work best in a combination that can benefit the kidneys and the rest of the cardiovascular system? A 3-year comparison 31 between captopril and nifedipine-based therapy on the progression of renal insufficiency showed no difference between the agents on BP reduction or progression of renal insufficiency in the first 2 years.
In the last year, however, 5 times more people went on to receive dialysis in the nifedipine group. In general, this study 31 demonstrated that better BP control lowered the rate of decline in renal function in both treatment groups as opposed to any independent renoprotective pathway.
Thus, administering an ACE inhibitor with a CCB can be potentially useful. In another study 32 of proteinuria, when an ACE inhibitor was combined with a long-acting dihydropyridine CCB, amlodipine, the results were more favorable than when the CCB was used as monotherapy.
Benazepril monotherapy produced, as expected, significantly reduced urinary albumin excretion UAE. This study supports the results of an earlier study 33 that suggest that the combination of an ACE inhibitor, lisinopril, and a CCB, verapamil, provides greater reduction in UAE than does use of either agent alone.
That combination resulted in the slowest decline in renal function over time, an effect that correlated with reductions in albumin excretion. Moreover, this benefit on proteinuria occurred without additional BP reduction.
An additional study 34 demonstrates that the combination of an ACE inhibitor and a nondihydropyridine CCB reduces proteinuria better than either agent used alone; this effect occurred independent of its BP-lowering activity. A recent trial 35 compared the effects of felodipine added to ramipril therapy in hypertensive patients with type 2 diabetes mellitus and impaired renal function.
This ACE inhibitor—CCB combination improved UAE and led to further improvement in BP control and renal function than did ACE inhibitor monotherapy. Additional drugs can also be added to ACE inhibitor therapy to achieve target BP.
For example, very low doses of a diuretic eg, hydrochlorothiazide, 6. Diuretic and ACE inhibitor combinations seem to be ideal as initial therapy based on both drug classes' records of reducing cardiovascular events and renal disease progression Figure 4.
If goal BP is achieved, then the patient should be converted to a fixed-dose combination product ie, an ACE inhibitor and a CCB or an ACE inhibitor and a diuretic. For example, the combination of a nondihydropyridine and a dihydropyridine CCB has additive, even synergistic, BP-reducing capabilities.
The application of these principles is described in the following patient management case. The patient is a year-old black woman who recently moved to the city and has a 5-year history of diabetes mellitus and a year history of hypertension.
She stated that she was feeling well and had no somatic complaints. She was seen at the office because she needed to establish a relationship with a physician who would continue managing her diabetes mellitus and hypertension.
Her review of systems was unremarkable. The patient's family history was positive for cardiovascular disease; her parents both died of myocardial infarction. Her mother also had diabetes mellitus and hypertension. She was uncertain whether her father was hypertensive.
Regarding her social history, she works as a receptionist in a business office and denies smoking cigarettes or drinking alcohol. She is married and has 3 children. Physical examination showed that she is moderately obese, cm in height, and The patient's current medications included hydrochlorothiazide, 25 mg once daily; metformin, mg twice daily; and glyburide, 2.
When queried why she was not taking an ACE inhibitor, she stated that her former physician considered ACE inhibitors to be ineffective in black persons. A head, eyes, ears, nose, and throat examination revealed grade 2 hypertensive retinopathy but was otherwise unremarkable.
Laboratory analysis findings were unremarkable except for a hemoglobin A 1c level of 8. Her serum creatinine level was 1. This patient has several risk factors—age, dyslipidemia, diabetes mellitus, and family history of cardiovascular disease—that highlight her need to achieve goal BP and lipid management.
First, glucose control should be improved, with stronger emphasis on dietary restraint and weight loss, particularly because her body mass index is Also, an increase in the dose of her oral hypoglycemic agent may be beneficial.
Second, lipid management should be obtained with dietary modifications and lipid-lowering therapy. Concomitantly, the patient's BP management must be changed. Using the previously recommended scheme for treating elevated BP Figure 4 , the following approach is suggested for this patient.
This patient needs to take an ACE inhibitor to protect her kidneys because ACE inhibitors have renal benefits in patients with diabetes mellitus, including impeding the increase in UAE, slowing the transition from microalbuminuria to overt albuminuria, and delaying the progression of albuminuria to overt nephropathy in diabetic patients.
The physician prescribed the following medications: benazepril, 10 mg once daily; hydrochlorothiazide, 25 mg once daily; metformin, mg 3 times daily; glyburide, 2.
After 4 weeks, the patient returned to the physician's office. Her fasting blood glucose level had decreased slightly. The physician increased her benazepril dose to 20 mg once daily.
At this point, the physician opted to include a long-acting CCB in her antihypertensive regimen because, as discussed, such a combination may control BP and renal complications better than ACE inhibitor monotherapy.
The physician gave her amlodipine, 5 mg once daily. Six weeks later, this patient returned to her physician. With her goal in sight, the physician decided to use a fixed combination of an ACE inhibitor and a CCB ie, amlodipine and benazepril, Fixed-dose combination agents serve the purpose of providing 2 different antihypertensive agents in a single dosage form, and, thus, compliance is enhanced.
What if this patient still had not approximated her BP goal? This case study has several lessons. Second, physicians should take their time in achieving BP control. A patient may need to be seen monthly for 4 to 6 months before actually achieving the desired BP goal.
Immediate- or short-acting CCBs or other types of agents ie, hydralazine will not produce long-standing benefits in these patients. Such agents have never been shown to reduce cardiovascular mortality rates, and, although they reduce the BP numbers, they markedly increase sympathetic nerve activity.
Finally, hypertension is a multifactorial disease. Using more than 1 agent can attack BP from different vantage points. Administering a single agent, and maximizing the dosage, can expose the patient to adverse events that may result in total noncompliance. Good BP control is important in protecting the human kidney from damage.
The latest position paper from the American Diabetes Association suggests that urinalysis be performed annually in adults: if the findings are positive for protein, a quantitative measure can be helpful in the development of a treatment plan to decrease proteinuria; if the results are negative for protein, then a test for the presence of microalbumin is necessary.
Such screening should begin at the time of diagnosis for type 2 diabetes mellitus; for patients with type 1 diabetes mellitus, screening should begin at puberty and then at 5 years' disease duration. Encourage smoking cessation: cigarette smoking is associated with the development and progression of microalbuminuria Control for hyperlipidemia: limited data confirm that correction of lipid abnormalities is important in slowing the progression of renal insufficiency Elevated systolic and diastolic BP markedly accelerate the progression of diabetic nephropathy.
Aggressive antihypertensive management can greatly reverse a decline in GFR. Moreover, 2 recent trials support the concept that angiotensin receptor blockers may be the drugs of first choice to prevent nephropathy in patients with type 2 diabetes mellitus 47 , 48 ; thus, they should be considered first-line agents in this clinical setting.
Adding another drug to ACE inhibitor or angiotensin receptor blocker therapy may result in more renoprotection than the ACE inhibitor or angiotensin receptor blocker therapy used alone.
More studies are emerging that show such a trend when ACE inhibitors are administered in conjunction with CCBs. Future trials should concentrate on whether the effects of such combinations offer novel pathways that curb renal damage independent of their BP-lowering effects.
In that way, we can determine the proper therapies and dosages that can provide renoprotection before renal damage is extensive.
All patients with diabetes mellitus or renal insufficiency should be taking an ACE inhibitor as part of their antihypertensive regimen, unless specifically contraindicated. An alternative to ACE inhibitor therapy may be angiotensin receptor blockade; however, data from clinical trials are not yet available to offer such a recommendation.
The addition of either a diuretic or a CCB should be second-line therapy in these patients to help achieve the BP goal. Also, clinicians should understand that, in most cases, 2 or even 3 different antihypertensive medications will be needed to help achieve these goals and that failure to do so will minimize the benefit of antihypertensive treatment on renal or cardiovascular event reduction.
Corresponding author and reprints: George L. Bakris, MD, Departments of Preventive Medicine and Internal Medicine, Rush Presbyterian-St Luke's-Medical Center, Rush University Hypertension Center, W Van Buren, Suite , Chicago, IL e-mail: gbakris rush.
full text icon Full Text. Download PDF Top of Article Abstract Importance of bp control vs glucose control Controlling proteinuria can curb renal damage Renal benefits of various antihypertensive agents Bp control may require multiple drugs A PLAN TO ACHIEVE TARGET BPs Patient management case Comment Conclusions Article Information References.
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Tuomilehto JRastenyte DBirkenhager WH et al. When prescribing, take into account cost of the drug, any potential side-effects and any contraindications. Without specific indications, consider monotherapy or single pill combination with one of the following first-line drugs 32 :.
Among these, thiazide diuretics are the least costly agents. Evidence suggests a non-significant difference in CV events and all-cause mortality between chlorthalidone and hydrochlorothiazide. Note that alpha-blockers and beta-blockers are no longer considered to be a first-line option.
If desirable BP is not achieved with standard-dose monotherapy, use combination therapy by adding one or more of the first-line drugs. Combination of ACE-I and ARB is not recommended, and caution with combining a non-dihydropyridine CCB i.
For a list of commonly prescribed antihypertensive medications in each class, refer to Appendix D: Commonly Used Antihypertensive Drugs. Refer to Table 4 for recommended first-line and second-line treatments. Table 4.
Pharmacologic treatment recommendations of hypertension complicated by co-morbidity 7. Two weeks after initiating antihypertensive medications, follow-up with an eGFR to monitor kidney function and monitor for adherence to medications. Then, follow-up with the patient at monthly intervals until BP is in a desired range for two consecutive visits.
Review every 3 - 6 months as long as the patient remains stable. Periodically, consider discontinuing or reducing antihypertensive medications to assess the appropriate level of pharmacologic management. Monitor kidney function whenever medications are changed e. Implement self-management strategies to assist the patient in managing their BP including measurement of their BP at home, committing to healthy behaviours and appropriate use of medications.
A paradoxical relationship between lower BP and increased mortality in older adults has been suggested to be explained by frailty. Finally, frailty is associated with limited life expectancy. Therefore, the time-until-benefit of a given treatment might exceed the life expectancy in frail individuals and may modify the risk—benefit ratio of preventive treatments for chronic diseases, including hypertension.
At this time, substantial uncertainty exists around the evidence on the link between Hydrochlorothiazide HCTZ and skin cancer. Although photosensitivity is a known rare adverse reaction of HCTZ, and patients are advised of possible skin reactions such as sunburn, premature aging, and rash, malignancy is not one of them.
Patients should be advised of the potential risk. Advise patients to regularly check for skin lesions, limit sun exposure and use adequate sun protection.
Engage in shared-decision making with patients to find alternative medications especially in those with high risk for non-melanoma skin cancer. HCTZ is a commonly prescribed medication for hypertension.
In January of , Health Canada issued a safety alert that concluded that prolonged use of HCTZ may be associated with a risk of non-melanoma skin cancer that is at least four times the risk of not using HCTZ. The studies suggested that high use of HCTZ i. The guideline was developed by the Guidelines and Protocols Advisory Committee and adopted by the Medical Services Commission.
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