JIRSS (2013) Vol. 12, No. 1, pp 71-112 Modeling and Inferential Thoughts for Consecutive Gap Times Observed with Death e de Strasbourg, Strasbourg, France. Abstract. In the perspective of biomedical applications, consider a re-current event situation with a relatively low degree of recurrence. In thissetting, the focus is placed on successive inter-event gap times which areobserved in the presence of both a terminal event like death and inde-pendent censoring. The terminal event is potentially related to recurrentevents while the censoring process is an independent nuisance that bearson the total observation time i.e. on the sum of the successive gap times.We review diﬀerent modeling and inferential strategies. We also presenta nonparametric estimation method of joint distribution functions andoutline the need for future developments.
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Hmscl.org.inSUPPLEMENT TO JAPI • FEBRUARY 2013 • VOL. 61 Management of Hypertension
Goals of Therapy
• In low risk patients, it is suggested to institute life style modifications and observe BP for a period of 2-3 months, he primary goal of therapy of hypertension should be before deciding whether to initiate drug therapy.
effective control of BP in order to prevent, reverse or delay the progression of complications and thus reduce the overall risk • In medium risk patients, institute life style modifications of an individual without adversely affecting the quality of life. and initiate drug therapy after 2-4 weeks, in case BP remains Patients should be explained that the lifestyle modifications and above 140/90.
drug treatment is generally lifelong and regular drug compliance • In high and very high-risk groups, initiate immediate drug is important.
treatment for hypertension and other risk factors in addition Initiation of therapy
to instituting life-style modification.
Having assessed the patient and determined the overall risk Targets of therapy
profile, management of hypertension should proceed as follows: • Gradual reduction of BP is a prudent therapeutic approach except in stage 3 hypertension.
Table 8 : Lifestyle interventions for blood pressure reduction
Expected systolic blood pressure reduction (range)
Maintain ideal body mass index Below 23 Kg/m2 5-20 mm Hg per 10 kg weight loss DASH* eating plan Consume diet rich in fruits, vegetables, low-fat dairy products with reduced content of saturated and total fat.
Dietary sodium Restriction Reduce dietary sodium intake to <6 g salt or < 2.4 g sodium. Physical activity Engage in regular aerobic physical activity, for example, brisk walking for at least 30 min most days Alcohol moderation Men<60 ml per day, twice a week Women<30 ml per day, twice a week. Abstinence is preferred.
*DASH= Dietary Approaches to Stop Hypertension Table 9 : Sodium content of foods per 100 gms54,55
Bengal gram whole Table 10 : Food items to be avoided in hypertensives54,55
• In Hypertension Optimal Treatment (HOT) study (target diastolic pressure less than 90, 85 or 80 mm Hg) there was no increase in cardiovascular risk in patients randomized Salt preserved foods
to the lowest target group (DBP<80 mm Hg).31 Mono sodium glutamate Pickles and canned foods • Among diabetic patients participating in the HOT study, Ketchup and sauces there was a significantly lower risk of coronary artery disease in patients with the lowest target DBP.31 Sodium bicarbonate Ready to eat foods • The results of United Kingdom Prospective Diabetes Study Highly salted foods
(UKPDS) demonstrated that a tight control of BP (average Potato chips, cheese, peanut achieved : 144/82 mm Hg) in diabetic patients conferred a butter, salted butter, papads substantial reduction in the risk of Coronary Artery Disease Bakery products : Biscuits, cakes,
compared to a less tight control of BP (average achieved: breads and pastries SUPPLEMENT TO JAPI • FEBRUARY 2013 • VOL. 61 Table 11 : Foods with high potassium54,55
Life style measures should be instituted in all patients including those who require immediate drug treatment. These • Patient education: Patients need to be educated about the various aspects of the disease, adherence to life style changes on long term basis and need for regular monitoring and • Weight reduction: Weight reduction of even as little as 4.5 kg has been found to reduce blood pressure in a large • The PROGRESS trial showed that in patients with a proportion of overweight persons with hypertension.44 history of stroke or TIA, stroke risk was reduced not only • Physical activity: Regular aerobic physical activity can in participants classified as hypertensive, but also among promote weight loss, increase functional status and decrease those classified as non-hypertensive, among whom the mean the risk of cardiovascular disease and all-cause mortality. blood pressure at entry was 136/79 mm Hg.33 A program of 30-45 minutes of brisk walking or swimming • In view of the above studies, it would seem desirable to at least 3-4 times a week could lower SBP by 7-8 mm Hg. achieve optimal or normal BP (<140/90 mHg) in the young Isometric exercises such as weight lifting should be avoided and middle aged. In diabetic patients BP lowering to around as they lead to pressor effects.
140 / 80 mm Hg is recommended. In patients who have • Alcohol intake: Excess alcohol intake causes a rise in blood survived stroke, a BP of around 130/85 mm Hg is suggested. pressure, induces resistance to antihypertensive therapy and In elderly patients a high normal BP around 140-145/90mm also increases the risk of stroke.45,46 Alcohol consumption Hg should be taken as the target BP.34 should be limited to no more than 2 drinks per day (24oz • Initially the J-shaped hypothesis was accepted, and it was felt beer, 10oz wine, 3oz 80-proof whiskey) for most men and that lowering BP below a certain level (140/90 mmHg) would no more than 1 drink per day for women and lighter weight increase the risk of coronary events by lowering diastolic perfusion pressure in coronary circulation. Data from the • Salt intake: Epidemiological evidence suggests an HOT study and UKPDS study showed BP reduction to association between dietary salt intake and elevated blood levels of 130/80 specially in high-risk individuals (diabetics, pressure. The total daily intake of salt should be restricted CKD, and CVA) was more beneficial. Hence, at the time of to 6 gms (amounting to 3-4 gms of sodium), however, in hot second guidelines it was suggested that the lower the better summer this may be relaxed. Patients should be advised to policy holds true for target BP in hypertension. More recent avoid added salt, processed foods, and salt-containing foods data (ADVANCE,ACCORD,INVEST) shows lowering of such as pickles, papads, chips, chutneys and preparations diastolic BP to below 70 mmHg can be deleterious, specially containing baking powder. In the Indian context, salt in patients with coronary artery disease.115-117 restriction is more important as Indian cooking involves a • As compared to the previous guidelines of 2007, we now high usage of salt.
realize that a relatively less aggressive approach towards • Smoking: Smoking or consumption of tobacco in any form achieving lower target BP is a reasonable goal, since as is the single most powerful modifiable lifestyle factor for suggested above, recent data shows no additional benefit prevention of major cardiovascular and non-cardiovascular of lowering diastolic BP below certain levels in specific disease in hypertensives.47-49 Cardiovascular benefits of cessation of smoking can be seen within one year in all age • Yoga and Meditation: Yoga, meditation and biofeedback • Recent evidence suggests that the level of SBP control have been shown to reduce blood pressure.50-53 correlates better with reduction of mortality than the level of DBP control.28,35-42 • Diet:
• Impressive evidence has accumulated to warrant greater Vegetarians have a lower blood pressure compared attention to the importance of SBP as a major risk factor to meat eaters.54 This is due to a higher intake of for CVDs. The rise in SBP continues throughout life, in fruit, vegetables, fibers coupled with a low intake of contrast to DBP, which rises until approximately 50 years saturated fats and not due to an absence of intake of of age. It tends to level off over the next decade, and may remain the same or fall later in life. Diastolic hypertension Intake of saturated fats is to be reduced since predominates before 50 years of age, either alone or in concomitant hyperlipidaemia is often present in combination with SBP elevation. DBP is a more potent cardiovascular risk factor than SBP until age 50; thereafter, Regular fish consumption may enhance blood pressure SBP is more important.2 reduction in obese hypertensives.56 • Trials describe population averages for the purposes of
Adequate potassium intake from fresh fruits and developing guidelines, whereas physicians must focus on vegetables may improve blood pressure control in the individual patient's clinical responses.43 Caffeine intake increases blood pressure acutely but there is rapid development of tolerance to its pressor SUPPLEMENT TO JAPI • FEBRUARY 2013 • VOL. 61 Table 12a : Guidelines for selecting the most appropriate first- line antihypertensive drugs
Class of drugs
Systolic hypertension Post-myocardial infarction Diabetes Physically active Peripheral vascular disease Elderly persons > 50 years Asthma and chronic pulmonary disease (COPD) Metabolic syndrome Congestive heart failurea Metabolic syndrome Moderate renal failure (Creatinine levels >3 mg/dl) Left ventricular Significant proteinuria Angiotensin II Receptor Metabolic syndrome Moderate renal failure Diabetes mellitus (Creatinine levels >3 mg/dl) ACE inhibitor induced aVerapamil or diltiazem Table 12b: Guidelines for other drugs
Class of drugs
Prostatic hypertrophy Glucose Intolerance Orthostatic hypotension Chronic Kidney Disease Congestive Heart Failure Centrally acting agents
Hypertension in Pregnancy Resistant Hypertension Acute or Chronic Liver Resistant Hypertension Pregnancy, Lactation Resistant Hypertension Coronary Artery Disease Hypertension in Pregnancy Direct renin inhibitors
Resistant Hypertension Moderate Renal Failure (Creatinine > 3mg/dl) B/L Renal Artery Stenosis effect. Epidemiological studies have not demonstrated • Five classes of drugs can be recommended as first line a direct link between caffeine intake and high blood treatment for stage 1-2 hypertension1,2 These include :1) ACE inhibitors, 2) angiotensin II receptor blockers, 3) calcium • Thus, the diet in hypertensives should be low calorie, low
channel blockers, 4) diuretics and 5) newer β-blockers. fat, and low sodium, with normal protein intake.59,60 • The Blood Pressure Lowering Treatment Trialists' Collaboration concluded that treatment with any commonly used regimen reduces the risk of total major cardiovascular Principles of drug treatment
events and larger reductions in blood pressure produce larger reductions in risk.62 • Over the past decade, the goals of treatment have gradually shifted from optimal lowering of blood pressure, which is • Choice of an antihypertensive agent is influenced by age, taken for granted, to patient's overall well being, control concomitant risk factors, presence of target organ damage, of associated risk factors and protection from future target other co-existing diseases, socioeconomic considerations, availability of the drug and past experience of the physician.
• Achieve gradual reduction of blood pressure. Use low doses • Combining low doses of two or more drugs having of antihypertensive drugs to initiate therapy.
synergistic effect is likely to produce lesser side effects. In SUPPLEMENT TO JAPI • FEBRUARY 2013 • VOL. 61 Table 13 : Anti-hypertensive drugs and their usual dosage
Nifedipine (Long-acting) Centrally acting drugs Direct renin inhibitors 60-70 % of patients, goal blood pressure will be achieved with two or more agents only.
Angiotensin Converting Enzyme inhibitors (ACE inhibitors) • Use of fixed dose formulations should be considered to ACE inhibitors are effective in lowering blood pressure and improve compliance.
are well tolerated. These are first line agents in post-MI patients, • Drugs with synergistic effects should be combined those with heart failure, diabetes, and in patients with other pertinently to enhance BP lowering effect so as to achieve metabolic risk factors. In individuals with diabetes mellitus, they retard the onset and progression of renal disease (patients • Use of long acting drugs that provide 24-hour efficacy with with microalbuminuria and early CKD). The HOPE trial (a once daily administration ensures smooth and sustained primary prevention trial) showed that in high and average risk control of blood pressure; which in turn is expected individuals, use of ramipril reduced overall mortality and to provide greater protection against the risk of major cardiovascular endpoints, even with small reductions in blood cardiovascular events and target organ damage. Once daily pressure.63 As a class, they are metabolically favorable. The administration also improves patient compliance.
most common side effect is dry cough. ACE inhibitors are • Although antihypertensive therapy is generally lifelong, an contraindicated in pregnancy. Serum creatinine and potassium effort to decrease the dosage and number of antihypertensive should be monitored in patients receiving ACE inhibitors. drugs should be considered after effective control of Ramipril and Perindopril have greater tissue ACE inhibition hypertension (step-down therapy).
effect than other agents. Perindopril in combination with Indapamide has been particularly shown to reduce mortality in • Due to a greater seasonal variation of temperatures in India, patients who have survived stroke (PROGRESS trial).33 marginal alterations in dosages of drugs may be needed from time to time.
SUPPLEMENT TO JAPI • FEBRUARY 2013 • VOL. 61 Table 14:Adverse drug reactions for first-line drugs
Common side effects
Calcium channel blocker
Postural hypotension Cold hands and feet Angiotensin II Receptor Blockers (ARBs) (adding thiazide as required) in terms of reducing the incidence Angiotensin II receptor blockers block the angiotensin II of all types of cardiovascular events and all-cause mortality, and AT-1 receptors, and thus prevent the action of angiotensin II. risk of subsequent new-onset diabetes.37 In the LIFE trial, losartan was better than atenolol in reducing Short acting dihydropyridines (nifedipine) should be the frequency of the primary composite endpoint of stroke, avoided. Amlodipine has no effect on heart rate and cardiac myocardial infarction and cardiovascular death; this was contractility, and has been shown to be safe even in the presence due to a significant reduction in stroke.64 In the Valsartan of congestive heart failure.69 Antihypertensive Long-term Use Evaluation (VALUE) trial, both valsartan and amlodipine reduced blood pressure in hypertensive patients at high cardiovascular risk, but the effects Diuretics are widely used as first line agents. They are effective of the amlodipine-based regimen were more pronounced, and inexpensive. Although high dose diuretic therapy was especially in the early period.65 These drugs have many features in associated with side effects, currently recommended low dose common with ACE inhibitors, but do not cause an accumulation diuretic therapy is generally well tolerated. Low dose diuretics of bradykinin. Consequently, cough and angioedema are much have lesser metabolic side effects like worsening of glycemic less likely to occur than with ACE inhibitors.9 Initially, some control, hyperuricemia and dyslipidemia. Diuretics should be fears were raised regarding increase of coronary events with used in doses equivalent to 12.5 mg daily of chlorthalidone or use of these agents, however, these have been disproved ever hydrochlorothiazide to avoid adverse metabolic consequences. since. Also, one retrospective meta-analysis suggested increase Chlorthalidone is preferred over hydrochlorothiazide as an in neoplasm with ARBs, however no prospective study has antihypertensive.70 Indapamide use has been shown to be suggested this and is generally believed not to be a significant associated with minimal metabolic side effects and is a useful issue at present. In fact, the ONTARGET trial shows telmisartan agent. Combinations of thiazides and potassium-sparing (80mg OD) is as effective as ramipril (10mg OD) in reducing CV diuretics are available and are effective options. Aldosterone events in high-risk individuals in patients with vascular disease antagonists (Spironolactone, Eplerenone) are being increasingly or high-risk diabetes. Also, the incidence of angioedema was less used as add-on agents to reduce BP in patients with resistant than with ramipril.66 A combination of ACE and ARB should not hypertension even without documenting hyperaldosteronemia. be used due to increased risk of hypotension and hyperkalemia. In cases of heart failure and/or renal failure, Furosemide (40- In the recent randomized double blind ROADMAP68 trial 80mg), Torsemide (10-40mg), Metolazone (2.5-5mg) can be used involving 4447 diabetic patients with olmesartan (40mg OD), as add-on therapy. the onset of microalbuminuria has been shown to be delayed in Newer β -blockers patients with type 2 diabetes.
Emerging evidence suggests that β-blockers are losing their Calcium Channel Blockers (CCBs) pre-eminent place as first-line antihypertensive agents. This The two subgroups of CCBs are dihydropyridines (amlodipine, is based on the head to head trials where it was found that felodipine, nifedipine, cilnidipine) and non- dihydropyridines β-blockers are less effective than ACEIs or CCBs at reducing (verapamil and diltiazem). Amlodipine is the most commonly the risk of diabetes and stroke. This was particularly true in used agent in this group. Besides blood pressure lowering effect, patients taking β-blockers and diuretics. In most of the studies, they also have antianginal effects and are devoid of metabolic the β-blocker used was atenolol and in the absence of substantial side effects. CCBs are particularly recommended for elderly data on other agents it would not be wise to apply this conclusion patients with isolated systolic hypertension. Verapamil and to all β-blockers. β - blockers reduce central aortic pressure to diltiazem reduce heart rate and have negative inotropic effects. a lesser extent than other classes and this is additional reason In the Nordic trial,67 diltiazem was shown to be as effective as for lack of mortality reduction with their use. They also have treatment based on diuretics, β-blockers or both, in preventing limitations in patients with dyslipidemia and impaired glucose the combined primary endpoints of stroke, myocardial infarction tolerance. However, they are used in young hypertensives, and cardiovascular deaths. The findings of the ASCOT- those with stable and unstable angina and post-MI patients BPLA (Blood Pressure Lowering Arm) study show that an with hypertension. Agents with intrinsic sympathomimetic antihypertensive drug regimen starting with amlodipine (adding activity and highly selective β-blockers such as bisoprolol and perindopril as required) is better than one starting with atenolol nebivolol have lesser metabolic adverse effects. Labetalol is an SUPPLEMENT TO JAPI • FEBRUARY 2013 • VOL. 61 Add: either α-blocker or spironolactone or other diuretic A : ACE Inhibitor or angiotensin receptro blocker C : Calcium Channel Blocker D : Diuretic (thiazide) *Combination therapy involving B and D may induce more new onset diabetes compared with other combination therapies. Use β blockers only in special situ- ations. B = Newer β blockers. Younger age: <55 years, Older: >55 years Fig. 1 : Algorithm for recommended drug combination
α and β blocker and can be particularly used in hypertension Newer modalities: A novel baroreflex activation therapy has in pregnancy.
been evaluated recently. It stimulates baroreceptors through Other drugs an implanted device and has been shown to reduce significant α-blockers: Prazosin, terazosin and doxazosin - effectively change in BP in patients with resistant hypertension. Renal reduce blood pressure both as monotherapy and in combination. sympathetic denervation therapy has been evaluated in which They have a special place in the management of elderly radiofrequency ablation of sympathetic plexus around renal hypertensives with benign prostatic hyperplasia (BPH) and arteries is performed. In the SYMPLICITY hypertension -2 trial,76 it has been shown to reduce BP significantly over and above 2,71,72 Since postural hypotension can occasionally occur, the dose of α-blockers should be carefully up-titrated. Data the pharmacological therapy. Presently, both these modalities from the Antihypertensive and Lipid Lowering treatment to are under evaluation for management of patients with resistant prevent Heart Attack Trial (ALLHAT) shows that patients in the doxazosin - based arm had 25% increase in the cardiovascular Table 12a and 12b presents guidelines for selecting the most events and twice the risk of congestive heart failure.73 appropriate antihypertensive drugs. Table 13 presents commonly Centrally acting drugs : Α-methyldopa, clonidine and used anti-hypertensive drugs and their usual dosage.
moxonidine - have been in use for several years. In particular, Table 14 lists some common side effects of these drugs.
methyldopa remains an important agent for the treatment of hypertension in pregnancy. Clonidine, though a potent Antihypertensive Drug Combinations
antihypertensive agent, is infrequently used these days due Combination therapy is gaining ground for effective control of to side effects such as postural hypotension and problem of hypertension since a majority of patients will require two or more withdrawal-related rebound hypertension. These agents are drugs for sustained and effective control of blood pressure.2,9 used in CRF patients with resistant hypertension.
One often needs to combine different classes of drugs with Direct vasodilators : Hydralazine and minoxidil - are effective, different mechanisms of action to achieve effective control of but some of their side effects (such as tachycardia, headache, and blood pressure with minimal side effects. Combinations with retention of sodium and water) may make it difficult to use them additive hypotensive effects will produce greater blood pressure in modern day treatment of hypertension.
reductions than those obtained with monotherapy. When a Direct renin inhibitors: Aliskiren - has been evaluated and subject is in stage 2 or above, therapy can be initiated either with found to be effective. In the ALLAY trial, aliskiren was found to two drugs or as a fixed dose combination. The ACCOMPLISH be as effective as losartan in regressing LVH.74 In the more recent trial has shown that combination of ACEIs with CCBs is better ACCELERATE trial,75 combination of aliskiren and amlodipine than a combination of ACEI with diuretic and should be the was found to be more effective than monotherapy. It is a useful preferred combination.77 agent in resistant hypertension and also reduces the proteinuria Younger individuals have high renin hypertension, hence in diabetes with hypertension. ACE inhibitors/ARBs or newer β-blockers are preferred; while Racemic forms: of calcium channel blockers and β-blockers older individuals have low renin hypertension and hence are presently available. However, long-term studies regarding diuretics or CCBs are preferred as first line agents.
their efficacy and safety are not available.
In combination, one out of the two groups A [ACE inhibitor/ SUPPLEMENT TO JAPI • FEBRUARY 2013 • VOL. 61 Table 15: Undesirable combinations
Table 16 : Drug interactions78
• Β-blocker and ACE inhibitor
ACE inhibitors, diuretics and β-Blockers
• Β-blocker and centrally acting drugs
NSAIDs including COX-2 inhibitors decrease efficacy of diuretics, β-blockers and ACE inhibitors • Β-blocker and verapamil/diltiazem
Calcium channel blockers
• ACE inhibitors and ARBs
Verapamil increases the blood levels of several statins, such as • Two drugs from the same class
atorvastatin, simvastatin and lovastatinNifedipine is broken down by hepatic CYP3A4 system. Cimetidine ARB] or B [β-blocker] is combined with C [calcium channel inhibits the CYP3A4 system and thus the breakdown of nifedipine blocker] or D [thiazide diuretic] (step 2). In refractory patients, also potentially increases blood levels and antihypertensive effects. when 3 agents are to be used, A+C+D is a good choice (step 3).9 Conversely, phenobarbital, phenytoin and rifampin induce the CYP3A4 system to metabolise nifedipine, so that blood levels should Since multiple drugs are used in hypertensive patients and Amlodipine should not be used with statins such as simvastatin, atorvastatin or lovastatin since both drugs are metabolised by hepatic often these patients have other co-existing conditions, certain common drug interactions should be kept in mind.
Cyclosporin levels are increased with diltiazem and verapamil
Maintenance and Follow-up of
Steroids can worsen diuretic-induced hypokalemia. Steroids also produce sodium retention which antagonises the main effect of diuretics that is natriuresis.
Once therapy with particular antihypertensive drugs is Antiarrythmics of Class 1A (quinidine or procainamide) or Class III instituted, patients need to be seen at frequent intervals during (sotalol, amiodarone) can prolong QT interval and may precipitate the period of stabilization in order to monitor changes in blood torsade de pointes in presence of diuretic-induced hypokalemia pressure and see whether non-drug measures are being strictly ACEI or ARBs which retain potassium can counteract the potassium loss of diuretics. This is a favourable drug interaction followed. At least once in a fortnight, blood pressure should be Combined use of ACE inhibitors or ARBs and potassium sparing measured at the clinic or at home. Other CHD risk factors as diuretics may result in hyperkalemia well as co-existing diseases/conditions should be monitored. The β blockers
overall risk category of a patient and the level of blood pressure Metoprolol and carvidelol metabolism is inhibited by paroxetine decide the frequency of follow up visits to a large extent. The (Selective serotonin receptor blocker – antidepressant) and frequency can be reduced once blood pressure is stabilized and propoxyphene (opoid analgesic) resulting in increased other risk factors are controlled. Tobacco avoidance and alcohol antihypertensive effect moderations must be promoted vigorously.
β blockers and non-dihydropyridine CCBs
Concomitant use of tricyclic antidepressants with methyldopa is to be
In order to reduce the overall risk, patients with hypertension need therapies for control of other risk factors for secondary prevention and now with recent available data even for primary or cerebrovascular disease with LDL levels >100 mg/dL should prevention. Low dose aspirin should be prescribed to all receive statins as secondary prevention strategies. Hypertensive hypertensives with cardiovascular disease and stroke (secondary patients without CV diseases but those in high-risk group should prevention). All hypertensive patients with coronary, peripheral, also receive statins for primary prevention.79,80
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